JP2008001689A - Pharmaceutical composition comprising nitrogen-containing fused cyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition which is effective for the treatment or prevention of a disease associated with uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary calculus, renal dysfunction, coronary artery disorder and ischemic heart disease, and which has excellent long-term stability and elution properties (disintegration properties). <P>SOLUTION: The pharmaceutical composition comprises a nitrogen-containing fused cyclic compound represented by general formula [1] or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable additive, wherein the nitrogen-containing fused cyclic compound or the pharmaceutically acceptable salt thereof is not coming into contact with a basic additive. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing a nitrogen-containing fused ring compound having a URAT1 activity inhibitory action or a pharmaceutically acceptable salt thereof.

  Uric acid (uric acid) is a substance having a molecular weight of 168 and a dissociation constant (pKa value) of 5.75, and exists in body fluid as uric acid (urate) which is uric acid or its conjugate base depending on pH. In humans, the function of urate oxidase (uricase) in the liver is lost due to mutation, so uric acid is the final metabolite of purines. That is, the dietary and endogenously produced purines are converted from adenosine to inosine, hypoxanthine to xanthine, or from guanosine to guanine to xanthine. Become. Uric acid is excreted mainly from the kidneys.

  When hyperuricemia develops and the blood level of uric acid exceeds the upper limit of solubility, sodium urate crystals form in cartilage tissue and joints, creating a precipitate called gouty nodules (tophi). This gout nodule causes acute gouty arthritis that, when it progresses, becomes chronic gouty arthritis. In addition, it is clear that renal dysfunction (gout kidney) and urinary calculi are associated as complications due to crystal deposition of sodium urate due to hyperuricemia, and hyperuricemia itself causes renal dysfunction. Is also known.

  Hyperuricemia patients have many complications such as hyperlipidemia, diabetes, hypertension and obesity. Each of these complications alone is a risk factor for coronary artery disease and mortality, but hyperuricemia patients have a significantly higher complication rate for coronary artery disease than patients with normal blood uric acid levels And it has been known for some time that survival is short. Fang et al. Conducted a large-scale study of mortality from coronary artery disease in 5926 patients aged 25 to 74 years who were able to measure blood uric acid levels during 22 years from 1971 to 1992, and blood uric acid levels It was clarified that an increase in the risk of ischemic heart disease alone. In addition to the treatment of complications, treatment that lowers blood uric acid level itself is useful for preventing the onset of coronary artery disease and reducing mortality, and treatment for lowering blood uric acid level in asymptomatic hyperuricemia is also possible. It has also been reported that this should be done actively. Recently, hyperuricemia associated with hypertension has become a definitive risk factor for cardiovascular disease. In addition, 1) gout and hyperuricemia are complicated by renal disorder (also called gout kidney) and urinary calculus, which are complications due to sodium urate crystal deposition, 2) recurrence of cerebrovascular and cardiovascular accidents It is important to control blood uric acid levels from the viewpoint of prevention. 3) Hyperlipidemia and gout patients often have hyperlipidemia. 4) Obesity as a cause or exacerbation factor of hyperuricemia. 5) Use uric acid excretion promoters in principle for hyperuricemia with decreased uric acid excretion, 6) Hyperuricemia associated with hypertension is an independent risk factor for cardiovascular accidents Drugs that lower blood uric acid levels are not only effective in the treatment or prevention of the diseases listed above, but also lower blood uric acid levels because it is known that the possibility is high In combination with a therapeutic or prophylactic agent for these diseases Also said to be effective in the treatment or prevention of these above-mentioned diseases.

  Uric acid is mainly excreted from the kidney, but blood uric acid is almost completely filtered from the kidney glomerulus and then reabsorbed most of the uric acid in the proximal tubules, so there is little in the urine. Only uric acid is excreted. The resorption of uric acid in this proximal tubule is transported via a transporter, and it was revealed by experiments using membrane vesicles prepared from the renal cortex, its substrate selectivity, its inhibitor Etc. have also been clarified.

  Recently, a gene (SLC22A12) encoding a human kidney urate transporter has been identified. The transporter (urate transporter 1, URAT1) encoded by this gene is a 12-transmembrane molecule belonging to the organic anion transporter (OAT) family. In Northern blotting using the full length cDNA as a probe, And it was revealed that it was specifically expressed in fetal kidney. In addition, immunostaining in a human kidney tissue section performed using a specific polyclonal antibody against the C-terminal peptide confirmed that the localization was on the proximal tubular lumen side of the cortex. Experiments using the Xenopus laevis oocyte expression system showed that uric acid uptake via URAT1 increased in a time-dependent manner, and that uric acid uptake was characterized by carrier transport saturating at high uric acid concentrations. Furthermore, the uptake is performed by exchange with organic anions such as lactic acid, pyrazinecarboxylic acid, and nicotinic acid, and the uptake is inhibited by uric acid excretion promoting agents such as probenecid and benzbromarone. This also revealed that URAT1 is a transporter that has been clarified by experiments using the membrane vesicles. That is, it was revealed that URAT1 is a central transporter responsible for uric acid reabsorption in the kidney.

  Furthermore, genetic analysis of patients with idiopathic renal hypouricemia identified URAT1 gene mutations, and it was found that uric acid transport activity was lost when these mutants URAT1 were expressed in Xenopus laevis oocytes did. This fact also reveals that URAT1 is involved in the regulation of blood uric acid levels.

In addition, regarding the relationship between URAT1 and diseases, probenecid or benzbromarone, which inhibits the uric acid transport activity of URAT1, is a therapeutic agent for hyperuricemia, and high blood uric acid levels are involved. It has already been reported to be useful as a therapeutic or prophylactic agent for pathological conditions such as hyperuricemia, gout nodules, gout arthritis, gout kidney, urolithiasis, and renal dysfunction.
In addition, for example, drugs such as nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, immunosuppressive drugs, and the like, there are drugs that increase blood uric acid levels, The progression or worsening of the disease state due to the increase in blood uric acid level is a problem.

  Accordingly, a pharmaceutical composition containing a substance having an inhibitory action on URAT1 is a pathological condition involving uric acid, for example, a pathological condition involving a high blood uric acid level, specifically, hyperuricemia, gout nodules. , Gout arthritis, gout kidney, urinary calculus, renal dysfunction and other therapeutic or prophylactic agents, and also by reducing blood uric acid levels, hyperlipidemia, diabetes, obesity or cardiovascular diseases such as hypertension It can also be said that it is useful as a therapeutic or prophylactic agent for coronary artery disease, vascular endothelial disorder or ischemic heart disease. Furthermore, it can be said that the combined use of these other therapeutic or preventive drugs and a pharmaceutical composition containing a substance having a URAT1 activity inhibitory action is more effective for the treatment or prevention of these diseases.

  In addition, pharmaceutical compositions containing a substance having an inhibitory action on URAT1 include, for example, nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, immunosuppressants, etc. It can be said that it is useful in that an increase in blood uric acid level can be prevented by using in combination with a drug that increases blood uric acid level.

Currently, benzbromarone, which is a uric acid excretion promoter having URAT1 activity inhibitory activity, is used as a therapeutic or preventive agent for hyperuricemia. However, the inhibitory action of benzbromarone on URAT1 activity is not sufficient. In addition, it has a CYP inhibitory action, suggesting the possibility of causing pharmacokinetic drug interactions. Accordingly, there has been a strong demand for the development of a therapeutic or preventive agent for hyperuricemia that has a stronger URAT1 activity inhibitory action and no or very weak CYP inhibitory action.
The present inventors have already described the compound represented by the following general formula [1], which is an active ingredient of the pharmaceutical composition of the present invention, which inhibits URAT1 activity and lowers blood uric acid level, thus involving uric acid Effective for the treatment or prevention of pathological conditions (hyperuricemia, gouty nodules, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease, ischemic heart disease, etc.) And it discovered that there was no CYP inhibitory effect or it was very weak.
However, the compound represented by the general formula [1] has good stability by itself, but depending on the combination with conventionally used additives, the stability is poor and the dissolution property (disintegration property) is poor. It became clear that it might not be enough. Therefore, a pharmaceutical composition having improved stability over time of the compound in the production process or storage thereof, a pharmaceutical composition having rapid dissolution (disintegration), or a combination of these characteristics. The development of the existing pharmaceutical composition seems to be important.
The present invention relates to a new pharmaceutical composition that is more active than conventional URAT1 activity inhibitors and has no or very little CYP inhibitory action. It is an object of the present invention to provide a pharmaceutical composition with improved stability, a pharmaceutical composition having rapid dissolution (disintegration), or a pharmaceutical composition having these characteristics.

  As a result of intensive studies to develop a new therapeutic or preventive agent for hyperuricemia in place of the conventional therapeutic or preventive agent for hyperuricemia, the present inventors have represented by the general formula [1]. The present inventors have found that a pharmaceutical composition excellent in stability over time and dissolution (disintegration) can be obtained by blending a specific component with the compound to be obtained.

  That is, the present invention is as follows.

<1>
A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof (hereinafter also referred to as compound [1]), and one or more pharmaceutically acceptable additives. A pharmaceutical composition wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not in contact with a basic additive.

[Where:
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group A, or 3) saturated or unsaturated having 3 to 14 carbon atoms together with the carbon atom to which R ¹ and R ² are bonded Or the carbocycle may be substituted with one or more substituents selected from group A below, or 4) R ² and R ³ are bonded to each other A saturated or unsaturated carbocycle having 3 to 14 carbon atoms together with the carbon atom to be substituted (the carbocycle may be substituted with one or more substituents selected from the following group A). May form;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is,
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom, or (b) a group selected from group A below, or (c) R ³ and R ⁴ are saturated with 3 to 14 carbon atoms together with the carbon atom to which they are bonded. Alternatively, an unsaturated carbocycle (the carbocycle may be substituted with one or more substituents selected from the same or different groups selected from group A below) may be formed. )
Is;
X ² is,
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CR ⁹ R ¹⁰ — (wherein R ⁹ and R ¹⁰ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁹ and R ¹⁰ Together may form an oxo group. )
Is;
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the following group B, or (c) the same carbon atom R ¹¹ and R ^{12 to} be bonded together form an oxo group, or (d) two of n R ¹¹ and R ¹² bonded to the same or adjacent two carbon atoms are the carbon atoms And a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle may be substituted with one or more substituents selected from the following group A). May be. )
And ring A is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following group A), or 2) A saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group A; May be.)
It is.
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ is as defined above, and R ²² is a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² is as defined above),
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) are
1 ') a halogen atom,
2 ′) a hydroxyl group,
3 ′) a C _1-6 alkoxy group,
4 ′) — NR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′ and R ¹⁹ ′ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen containing R ¹⁸ ′ and R ¹⁹ ′ together with a nitrogen atom to which they are bonded to form a single ring A saturated heterocyclic ring may be formed. ),
^{5 ') - CONR 18' R} 19 '( ^{wherein, R 18'} and ^{R 19} 'has the same meaning as defined above),.
6 ′)-COR ²⁰ ′ (wherein R ²⁰ ′ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7 ′) — NR ²¹ ′ COR ²⁰ ′ (wherein R ²⁰ ′ has the same meaning as described above, and R ²¹ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8 ′) — NR ²¹ ′ CONR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′, R ¹⁹ ′ and R ²¹ ′ are as defined above),
9 ′) — NR ²¹ ′ S (═O) ₂ R ²² ′ (wherein R ²¹ ′ has the same meaning as described above, and R ²² ′ is a C _1-6 alkyl group), and 10 ′. ^{_{) -S (= O) 2 R}} 22 '( ^{wherein, R 22'} has the same meaning as defined above.)
May be substituted with one or more substituents selected from the same or different,
In addition, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) is further one or more substitutions selected from the C _1-6 alkyl group and the above 1 ′) to 10 ′). It may be substituted with a group. ]

<2>
A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives, the basic additive comprising: A pharmaceutical composition containing not more than 1 part by weight of a basic additive with respect to 1 part by weight of a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.

[Each symbol in the formula has the same meaning as the above <1>. ]

<3>
The pharmaceutical composition according to <1>, wherein all of the additives are not basic additives.

<4>
Basic additives include alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal silicic acid The pharmaceutical composition according to any one of <1> to <3>, which is selected from a salt and an alkaline earth metal silicate.
<5>
The pharmaceutical composition according to any one of <1> to <3>, wherein the basic additive is selected from alkali metal silicates and alkaline earth metal silicates.
<6>
The pharmaceutical composition according to any one of <1> to <3> above, wherein the basic additive is calcium silicate.

<7>
One or more pharmaceutically acceptable additives selected from the group consisting of the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and an acidic additive and a neutral additive. A pharmaceutical composition containing no basic additive or basic with respect to 1 part by weight of a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof: A pharmaceutical composition containing less than 1 part by weight of an additive.

[Each symbol in the formula has the same meaning as the above <1>. ]

<8>
A nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising one or more pharmaceutically acceptable additives, all of the additives Is a pharmaceutical composition selected from the group consisting of acidic additives and neutral additives.

[Each symbol in the formula has the same meaning as the above <1>. ]

<9>
Additives included are D-mannitol, crystalline cellulose, low substituted hydroxypropyl cellulose, light anhydrous silicic acid, crospovidone, magnesium stearate, lactose, corn starch, croscarmellose sodium, carmellose, carmellose sodium, carmellose The above <1> to <8>, which is one or more selected from the group consisting of calcium, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, titanium oxide, and macrogol. Pharmaceutical composition.

<10>
The pharmaceutical composition according to any one of the above <1> to <9>, comprising low-substituted hydroxypropylcellulose.
<11>
The pharmaceutical composition according to any one of <1> to <9> above, which contains crospovidone.
<12>
The pharmaceutical composition according to any one of the above <1> to <9>, comprising low-substituted hydroxypropylcellulose and crospovidone.
<13>
The pharmaceutical composition according to any one of the above <1> to <9>, comprising D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone, and magnesium stearate. object.

<14>
A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and a low-substituted hydroxypropylcellulose.

[Each symbol in the formula has the same meaning as the above <1>. ]

<15>
A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and crospovidone.

[Each symbol in the formula has the same meaning as the above <1>. ]

<16>
A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, a low-substituted hydroxypropylcellulose and crospovidone.

[Each symbol in the formula has the same meaning as the above <1>. ]

<17>
The pharmaceutical composition according to any one of <1> to <16> above, which is a tablet.
<18>
The pharmaceutical composition according to the above <17>, which is coated with a coating agent.
<19>
The pharmaceutical composition according to <18>, wherein the coating agent comprises hydroxypropylmethylcellulose, titanium oxide, and macrogol.

<20>
The pharmaceutical composition according to any one of <1> to <19>, which is a URAT1 activity inhibitor.
<21>
The pharmaceutical composition according to any one of <1> to <19>, wherein the pharmaceutical composition is a blood uric acid level lowering agent.
<22>
The pharmaceutical composition according to any one of the above <1> to <19>, which is a therapeutic or prophylactic agent for a disease state involving uric acid.
<23>
<22> above, wherein the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease A pharmaceutical composition according to 1.
<24>
The pharmaceutical composition according to any one of <1> to <19> above, which does not substantially inhibit CYP.

<25>
The <1> to <<24> The pharmaceutical composition according to any one of 24.

[Wherein R ¹ , R ² , R ³ , Y, X ¹ , X ³ and X ⁴ have the same meanings as the above <1>,
Ring A ′ is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is substituted with one or more substituents selected from the following group C), or 2) nitrogen A saturated or unsaturated heterocyclic group having at least one heteroatom selected from an atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group C; ing.)
Wherein the ring A ′ is substituted with at least one —OR ¹³ ′ (R ¹³ ′ is defined in group C below);
X ² '
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CH ₂ —.
It is.
(However, when X ² ′ is —CH ₂ —,
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together with the carbon atom are a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring is substituted with one or more substituents selected from the following group A; May be formed). )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms. )
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ is as defined above, and R ²² is a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² is as defined above),
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) are
1 ') a halogen atom,
2 ′) a hydroxyl group,
3 ′) a C _1-6 alkoxy group,
4 ′) — NR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′ and R ¹⁹ ′ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen containing R ¹⁸ ′ and R ¹⁹ ′ together with a nitrogen atom to which they are bonded to form a single ring A saturated heterocyclic ring may be formed. ),
^{5 ') - CONR 18' R} 19 '( ^{wherein, R 18'} and ^{R 19} 'has the same meaning as defined above),.
6 ′)-COR ²⁰ ′ (wherein R ²⁰ ′ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7 ′) — NR ²¹ ′ COR ²⁰ ′ (wherein R ²⁰ ′ has the same meaning as described above, and R ²¹ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8 ′) — NR ²¹ ′ CONR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′, R ¹⁹ ′ and R ²¹ ′ are as defined above),
9 ′) — NR ²¹ ′ S (═O) ₂ R ²² ′ (wherein R ²¹ ′ has the same meaning as described above, and R ²² ′ is a C _1-6 alkyl group), and 10 ′. ^{_{) -S (= O) 2 R}} 22 '( ^{wherein, R 22'} has the same meaning as defined above.)
May be substituted with one or more substituents selected from the same or different,
In addition, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) is further one or more substitutions selected from the C _1-6 alkyl group and the above 1 ′) to 10 ′). It may be substituted with a group.
[Group C]
1) a halogen atom,
2) —OR ¹³ ′ (wherein R ¹³ ′ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ′ (wherein R ¹⁴ ′ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
8) -NR ¹⁵ 'R ¹⁶ ' (wherein R ¹⁵ 'and R ¹⁶ ' are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ′ and R ¹⁶ 'is a nitrogen-containing saturated heterocycle consisting of a single ring together with the nitrogen atom to which they are bonded (wherein the heterocycle is one or more substituents selected from the following (i) and (ii): May be substituted.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) —NR ¹⁷ ′ COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above, and R ¹⁷ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
_{^{10) -NR 17 'S (=}} O) 2 R 14' ( ^{wherein, R 14} 'and ^{R 17'} has the same meaning as defined above.)
11) —NR ¹⁷ ′ CONR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′, R ¹⁶ ′ and R ¹⁷ ′ are as defined above),
12) —SR ¹³ ′ (wherein R ¹³ ′ has the same meaning as described above),
13) —S (═O) R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
14) —S (═O) ₂ R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
15) —S (═O) ₂ NR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′ and R ¹⁶ ′ are as defined above),
16) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
17) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) cyano group, and 20) nitro group]

<26>
The nitrogen-containing condensed ring compound represented by the general formula [1] is (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone, The pharmaceutical composition according to any one of <1> to <25> above.
<27>
The nitrogen-containing fused ring compound represented by the general formula [1] is (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone, The pharmaceutical composition according to any one of <1> to <25> above.
<28>
The nitrogen-containing condensed ring compound represented by the general formula [1] is (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone. The pharmaceutical composition according to any one of <1> to <25> above.

<29>
One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for stabilizing a salt to be obtained, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not contacted with a basic additive.

[Each symbol in the formula has the same meaning as the above <1>. ]
<30>
One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof In which the basic additive is not blended, or 1 part by weight of the basic additive is added to 1 part by weight of the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof. Stabilization method blended in less than part.

[Each symbol in the formula has the same meaning as the above <1>. ]
<31>
One or more pharmaceutically acceptable additives selected from the group consisting of acidic additives and neutral additives are added to the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof. The basic additive is not added, or the basic additive is added in an amount of less than 1 part by weight to 1 part by weight of the nitrogen-containing condensed ring compound or pharmaceutically acceptable salt thereof. A method for stabilizing a ring compound or a pharmaceutically acceptable salt thereof.

[Each symbol in the formula has the same meaning as the above <1>. ]
<32>
One or more pharmaceutically acceptable additives are blended in the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for stabilizing a salt, wherein all of the additives are selected from the group consisting of acidic additives and neutral additives.

[Each symbol in the formula has the same meaning as the above <1>. ]

<33>
One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for preserving the salt, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not contacted with a basic additive.

[Each symbol in the formula has the same meaning as the above <1>. ]
<34>
One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof In which the basic additive is not added, or the basic additive is less than 1 part by weight with respect to 1 part by weight of the nitrogen-containing fused ring compound or pharmaceutically acceptable salt thereof. Storage method to be blended in.

[Each symbol in the formula has the same meaning as the above <1>. ]
<35>
One or more pharmaceutically acceptable additives selected from the group consisting of acidic additives and neutral additives are added to the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof. The basic additive is not added, or the basic additive is added in an amount of less than 1 part by weight to 1 part by weight of the nitrogen-containing condensed ring compound or pharmaceutically acceptable salt thereof. A method for preserving a ring compound or a pharmaceutically acceptable salt thereof.

[Each symbol in the formula has the same meaning as the above <1>. ]
<36>
One or more pharmaceutically acceptable additives are blended in the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for preserving a salt, wherein all of the additives are selected from the group consisting of an acidic additive and a neutral additive.

[Each symbol in the formula has the same meaning as the above <1>. ]

Compound [1], which is an active ingredient of the pharmaceutical composition of the present invention, effectively inhibits the activity of URAT1 and lowers the blood uric acid level. Therefore, hyperuricemia, gout nodules, acute gouty arthritis, chronic It is effective as a therapeutic or prophylactic agent for pathological conditions involving uric acid such as gouty arthritis, gouty kidney, urinary calculus, renal dysfunction, coronary artery disease, ischemic heart disease and the like. In addition, unlike conventional therapeutic or preventive drugs for hyperuricemia, since CYP is not substantially inhibited, the possibility of causing pharmacokinetic drug interaction is extremely low. Is also expected.
Furthermore, the pharmaceutical composition of the present invention is excellent in stability over time of the compound [1] during the production process or storage, and has the effect of enabling storage over a long period of time. In addition, the pharmaceutical composition of the present invention has the effect of realizing rapid dissolution (disintegration) of compound [1] and promptly improving drug blood concentration.

  The definition of each substituent used in the present specification is as follows.

The “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. Group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group and the like. Preferably, it is a C _1-4 alkyl group. Particularly preferred are a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group.

The “C _1-4 alkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. Group, sec-butyl group, tert-butyl group and the like. Preferably, they are a methyl group, an ethyl group, an isopropyl group, and a tert-butyl group.

The “C _2-6 alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, an n-propenyl group, an isopropenyl group, and an n-butenyl group. , Isobutenyl group, sec-butenyl group, n-pentenyl group, isopentenyl group, 1-methylpropenyl group, n-hexenyl group, isohexenyl group, 1,1-dimethylbutenyl group, 2,2-dimethylbutenyl group 3,3-dimethylbutenyl group, 3,3-dimethylpropenyl group, 2-ethylbutenyl group and the like can be mentioned. Preferably, it is a linear or branched alkenyl group having 2 to 4 carbon atoms. Particularly preferred are vinyl group, n-propenyl group and isopropenyl group.

  The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “C _1-6 alkoxy group” is an alkoxy group whose alkyl moiety is the “C _1-6 alkyl group” defined above, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group. , Isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like. Preferably, it is an alkoxy group whose alkyl group moiety is the “C _1-4 alkyl group” defined above. Particularly preferred are a methoxy group and an ethoxy group.

The “C _1-4 alkoxy group” is an alkoxy group whose alkyl moiety is the “C _1-4 alkyl group” defined above, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group. , Isobutoxy group, sec-butoxy group, tert-butoxy group and the like. Particularly preferred are a methoxy group and an ethoxy group.

  The “saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 14 carbon atoms, and specifically includes an aryl group, a cycloalkyl group, a cycloalkyl group. It means an alkenyl group or a group derived from a condensed carbocyclic ring in which two or more of the rings constituting the alkenyl group are condensed.

  The “aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, an azulenyl group, a phenanthryl group, and a pentarenyl group. Preferably, it is a phenyl group.

  The “cycloalkyl group” is a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Preferred is a cycloalkyl group having 3 to 6 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Particularly preferred are a cyclopropyl group and a cyclohexyl group.

  The “cycloalkenyl group” is a cycloalkenyl group having 3 to 8 carbon atoms and includes at least one, preferably 1 or 2, double bonds. For example, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-yl Group), cycloheptenyl group, cyclooctenyl group and the like. A cycloalkenyl group having 3 to 6 carbon atoms is preferable, and a cyclohexenyl group is particularly preferable.

  Examples of the group derived from a condensed carbocyclic ring in which two or more of the rings constituting these “aryl group”, “cycloalkyl group”, and “cycloalkenyl group” are condensed include, for example, indenyl group, indanyl group, fluorenyl group, 1, 4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthyl group (1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group, etc.), A perhydronaphthyl group is exemplified.

  The “saturated or unsaturated carbocycle having 3 to 14 carbon atoms” is a ring constituting the “saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms” defined above.

An “aralkyl group” is an arylalkyl group in which the aryl moiety is the “aryl group” defined above and the alkyl moiety is the “C _1-6 alkyl group” defined above. For example, a benzyl group, phenethyl Group, 3-phenylpropyl group, 4-phenylbutyl group, 6-phenylhexyl group and the like. Preferably, it is an aralkyl group having 7 to 14 carbon atoms. Particularly preferred is a benzyl group.

The “aralkoxy group” is an arylalkoxy group whose aryl moiety is the “aryl group” as defined above and whose alkoxy moiety is the “C _1-6 alkoxy group” as defined above. For example, a benzyloxy group, A 3-phenylpropyloxy group, 4-phenylbutyloxy group, 6-phenylhexyloxy group, and the like can be given. Preferred is an aralkoxy group having 7 to 14 carbon atoms. Particularly preferred is a benzyloxy group.

The term "cycloalkyl alkoxy group", the "cycloalkyl group" of the cycloalkyl portion is as defined above, and a cycloalkyl alkoxy radical is a "C _1-6 alkoxy group" of the alkoxy portion is defined above, e.g. , Cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, cyclohexylmethoxy group and the like. Preferred is a cycloalkylalkoxy group having 4 to 8 carbon atoms. Particularly preferred are a cyclopropylmethoxy group and a cyclohexylmethoxy group.

  The “aryloxy group” is an aryloxy group whose aryl moiety is the “aryl group” defined above, and examples thereof include a phenoxy group, a naphthyloxy group, and a biphenyloxy group. Preferably, it is a phenoxy group.

  “Saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom” means at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. And preferably a saturated or unsaturated (including partially unsaturated and fully unsaturated) monocyclic 5-membered or 6-membered heterocyclic group having 1 to 4 heteroatoms, or the heterocycles thereof A condensed ring group in which two or more of these are condensed or a condensed ring group in which a heterocyclic ring thereof and a carbocyclic ring selected from benzene, cyclopentane and cyclohexane are condensed.

  Examples of the “saturated monocyclic 5-membered or 6-membered heterocyclic group” include, for example, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group, 1,3- Oxathiolanyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group , 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group and the like.

  Examples of the “unsaturated monocyclic 5- or 6-membered heterocyclic group” include, for example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, 1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, Oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group (eg, 1,2,4-triazolyl group, 1,2,3-triazolyl group, etc.), tetrazolyl group, 1,3,4-oxadiazolyl group, 1 , 2,4-oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group, pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, Pyrazinyl group, 1,3,5-triazinyl group, imidazolinyl group, pyrazolinyl group, oxazolinyl group (eg , 2-oxazolinyl group, 3-oxazolinyl group, 4-oxazolinyl group, etc.), isoxazolinyl group, thiazolinyl group, isothiazolinyl group, pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl group 1,1-dioxo-1H-isothiazolyl group and the like.

  Examples of the “heterocyclic group which is a condensed ring” include, for example, an indolyl group (for example, 4-indolyl group, 7-indolyl group, etc.), isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group. Benzofuranyl group (for example, 4-benzofuranyl group, 7-benzofuranyl group, etc.), indazolyl group, isobenzofuranyl group, benzothiophenyl group (for example, 4-benzothiophenyl group, 7-benzothiophenyl group, etc.), Benzoxazolyl group (for example, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzimidazolyl group (for example, 4-benzimidazolyl group, 7-benzimidazolyl group, etc.), benzothiazolyl group (for example, 4-benzothiazolyl group, 7-benzothiazolyl group, etc.), indolizinyl group, quinolyl group, isoquinolyl 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolidinyl group, purinyl group, pteridinyl group, indolinyl group, isoindolinyl group, 5,6,7,8-tetrahydroquinolyl Group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo [1,3] dioxolyl group, 3,4-methylenedioxypyridyl group 4,5-ethylenedioxypyrimidinyl group, chromenyl group, chromanyl group, isochromanyl group and the like.

  The “nitrogen-containing saturated heterocycle consisting of a single ring” formed together with the adjacent nitrogen atom is, for example, a saturated 5-membered or saturated member having at least one nitrogen atom such as piperidine, morpholine, piperazine, pyrrolidine, etc. A heterocycle consisting of 6-membered monocycles.

  “It may be substituted with one or more substituents which are the same or different” means unsubstituted or substituted with at least one and up to the maximum number of substituents allowed. For example, a methyl group means that it may be substituted with 1 to 3 substituents, and an ethyl group means that it may be substituted with 1 to 5 substituents. The substituents when substituted with two or more substituents may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Preferred is “may be substituted with 1 to 3 substituents which are the same or different”.

  Next, suitable groups for each group are as follows.

R ¹ , R ² and R ³ are preferably the same or different,
1) hydrogen atom,
2) a halogen atom,
³⁾ -OR ^{13 (R} 13 has the same meaning as defined above.)
4) a C _1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group B;
5) -COR ¹⁴ (R ¹⁴ is as defined above),
^{6) -NR 15 R 16 (R} 15 and ^{R 16} have the same meanings as defined above.)
7) —NR ¹⁷ S (═O) ₂ R ¹⁴ (R ¹⁴ and R ¹⁷ are as defined above),
8) —S (═O) ₂ R ¹⁴ (R ¹⁴ has the same meaning as described above),
^{_{9) -S (= O) 2}} NR 15 R 16 (R 15 and ^{R 16} have the same meanings as defined above.)
10) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; Or 11) a nitro group, or
12) R ¹ and R ² or R ² and R ³ together with the carbon atom to which they are bonded together are an unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle is the same selected from the group A) Or may be substituted with one or more different substituents, preferably 2 or 3 substituents).

R ¹ , R ² and R ³ are more preferably the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group is there.),
10) —S (═O) ₂ —C _1-6 alkyl group (preferably —S (═O) ₂ —C _1-4 alkyl group, more preferably —S (═O) ₂ -ethyl group; is there.),
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an ethyl group), or (c) R ¹⁵ And R ¹⁶ together with the nitrogen atom to which they are bonded form a monocyclic nitrogen-containing saturated heterocyclic ring (for example, pyrrolidine, piperidine, imidazolidine, piperazine, etc., preferably pyrrolidine). May be. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (preferably an aryl group, more preferably a phenyl group), or 13) a nitro group.

The following are more preferable for each of R ¹ , R ² , and R ³ .
R ¹ is more preferably
1) hydrogen atom,
2) a hydroxyl group,
3) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an isopropyl group),
4) —COOH, or 5) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group).
It is.

R ² is more preferably
1) hydrogen atom,
2) a halogen atom (preferably a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group),
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group Or 10) a nitro group.

R ³ is more preferably
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group and a tert-butyl group.), A trifluoromethyl group and a hydroxymethyl group.
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —S (═O) ₂ —C _1-6 alkyl group (preferably —S (═O) ₂ —C _1-4 alkyl group, more preferably —S (═O) ₂ -ethyl group; is there.),
10) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same as or different from each other;
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an ethyl group), or (c) R ¹⁵ And R ¹⁶ together with the nitrogen atom to which they are bonded form a monocyclic nitrogen-containing saturated heterocyclic ring (for example, pyrrolidine, piperidine, imidazolidine, piperazine, etc., preferably pyrrolidine). May be. ),
11) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (preferably an aryl group, more preferably a phenyl group), or 12) a nitro group.

R ¹ , R ² and R ³ are particularly preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably an ethyl group), or (b) nitrogen to which R ¹⁵ and R ¹⁶ are bonded. A nitrogen-containing saturated heterocyclic ring consisting of a single ring (preferably pyrrolidine) may be formed together with the atom. Or 8) a nitro group.

The following are particularly preferable for each of R ¹ , R ² , and R ³ .
R ¹ is particularly preferably
1) hydrogen atom,
2) a hydroxyl group,
3) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or isopropyl group), or 4) —CO—C _1-6 alkoxy group (preferably —CO -C _1-4 alkoxy group, more preferably -CO-methoxy group.)
It is.

R ² is particularly preferably
1) hydrogen atom,
2) a halogen atom (preferably a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group),
6) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 7) nitro group.

R ³ is particularly preferably
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group and a tert-butyl group.), A trifluoromethyl group and a hydroxymethyl group.
6) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably an ethyl group), or (b) nitrogen to which R ¹⁵ and R ¹⁶ are bonded. A nitrogen-containing saturated heterocyclic ring consisting of a single ring (preferably pyrrolidine) may be formed together with the atom. Or 8) a nitro group.

  Y is preferably —CO— or —CS—.

X ¹ is preferably
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
It is.

X ¹ is more preferably CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
It is.

X ² is preferably
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group)),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms ( Preferably, it is an aryl group, more preferably a phenyl group, and the carbocyclic group is substituted with one or more substituents selected from a halogen atom (preferably a chlorine atom) and a hydroxyl group. May be good),
_{4) -N (S (= O} ) 2 -C 1-6 alkyl) - (preferably _{-N (-S (= O) 2} -C 1-4 alkyl group) -, and more preferably -N (—S (═O) ₂ -methyl group) —).
5) sulfur atom,
6) -S (= O)-,
7) —S (═O) ₂ — or 8) —CH ₂ —
It is.

X ² 'is preferably
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms ( Preferably, it is an aryl group, more preferably a phenyl group, and the carbocyclic group is substituted with one or more substituents selected from a halogen atom (preferably a chlorine atom) and a hydroxyl group. May be good),
_{4) -N (S (= O} ) 2 -C 1-6 alkyl) - (preferably _{-N (-S (= O) 2} -C 1-4 alkyl group) -, and more preferably -N (—S (═O) ₂ -methyl group) —).
5) sulfur atom,
6) -S (= O)-,
7) —S (═O) ₂ — or 8) —CH ₂ —
It is.

X ² ′ is more preferably an oxygen atom.

-X ³ -X ⁴ - is preferably,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together may form a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) together with the carbon atom. Good. )
It is.
N in — (CR ¹¹ R ¹² ) n— represented by —X ³ —X ⁴ — is preferably 2 or 3, more preferably 2.

As-(CR ¹¹ R ¹² ) n-, specifically,
1) —CH ₂ —,
_{2) -CH (CH 3) -} ,
_{3) -CH (CH 2 CH 3} ) -,
_{4) -CH (CH (CH 3} ) 2) -,
_{5) -CH} 2 -CH 2 -,
_{6) -CH (CH 3) -CH} 2 -,
_{7) -CH (CH 2 CH 3} ) -CH 2 -,
8) —CH (CH (CH ₃ ) ₂ ) —CH ₂ —,
_{9) -CH 2 -CH (CH 3} ) -,
_{10) -CH 2 -CH (CH 2} CH 3) -,
_{11) -CH 2 -CH (CH (} CH 3) 2) -,
_{12) -CH 2 -CH 2 -CH 2} -,
_{13) -CH 2 -CH (CH 3} ) -CH 2 -,
_{14) -CH 2 -CH 2 -CH (} CH 3) -,
15) -CO-,
16) _-CO-CH 2 -,
₁₇₎ -CH 2 -CO-,
18) _-CO-CH 2 -,
_{19) -CO-CH 2 -CH 2} -,
_{20) -CH 2 -CO-CH 2} -,
₂₁₎ -CH ₂ -CH ₂ -CO-,
22)

Etc.

-X ³ -X ⁴ - is more preferably _-CH 2 -CH ₂ -.

Ring A is preferably an unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is one or more substituents selected from Group A, preferably 2 or 3 Substituted with a substituent group), or an unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or selected from the group A) One or more different substituents, preferably substituted with 2 or 3 substituents).
Ring A is more preferably

(Wherein R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group A. ).

R ^{23 to} R ²⁷ on ring A are preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
³⁾ -OR ^{13 (R} 13 has the same meaning as defined above.)
4) a C _1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group B;
5) -COR ¹⁴ (R ¹⁴ is as defined above),
^{6) -NR 15 R 16 (R} 15 and ^{R 16} have the same meanings as defined above.)
7) —NR ¹⁷ S (═O) ₂ R ¹⁴ (R ¹⁴ and R ¹⁷ are as defined above), or 8) a nitro group.

R ^{23 to} R ²⁷ on ring A are more preferably the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) One or more same or different selected from —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) which may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
7) -COOH,
8) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group; Or 11) a nitro group.

For each of R ^{23 to} R ²⁷ on ring A, the following are more preferable.
R ²³ on ring A is more preferably
1) hydrogen atom,
2) Hydroxyl group, or 3) -COOH
It is.

R ²⁴ on ring A is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁵ on ring A is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) One or more same or different selected from —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group Or 10) a nitro group.

R ²⁶ on ring A is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁷ on ring A is more preferably
1) hydrogen atom,
2) Hydroxyl group, or 3) -COOH
It is.

  As such a ring A,

Etc.

R ^{23 to} R ²⁷ on ring A are particularly preferably the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

For each of R ^{23 to} R ²⁷ on ring A, the following are particularly preferable.
R ²³ on ring A is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

R ²⁴ on ring A is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁵ on ring A is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) a hydroxyl group, or 4) a nitro group.

R ²⁶ on ring A is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁷ on ring A is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

Ring A ′ is preferably an unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is one or more substituents selected from Group C, and preferably 2 or 3 Or an unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same selected from the group C) Or substituted with one or more different substituents, preferably substituted with 2 or 3 substituents.), Wherein the ring A ′ is at least one —OR ¹³ ′ (wherein R ¹³ ′ is as defined above). Is synonymous.)
Ring A ′ is preferably

(Wherein R ^{23 to} R ²⁷ are the same or different,
1) a hydrogen atom, or 2) a group selected from the group C, and at least one of R ^{23 to} R ²⁷ is —OR ¹³ ′ (R ¹³ ′ is as defined above). ).

R ^{23 to} R ²⁷ on ring A ′ are preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
3) —OR ¹³ ′ (R ¹³ ′ is as defined above),
4) a C _1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group B;
5) -COR ¹⁴ '(R ¹⁴ ' is as defined above),
^{6) -NR 15 'R 16'} (R 15 ' and ^{R 16'} has the same meaning as defined above.)
7) —NR ¹⁷ ′ S (═O) ₂ R ¹⁴ ′ (R ¹⁴ ′ and R ¹⁷ ′ are as defined above), or 8) a nitro group and at least one of R ^{23 to} R ²⁷ One of them is —OR ¹³ ′ (R ¹³ ′ is as defined above).

R ^{23 to} R ²⁷ on ring A ′ are more preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) One or more same or different selected from —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
7) -COOH,
8) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group; Or 11) a nitro group and at least one of R ^{23 to} R ²⁷ is a hydroxyl group or a C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group). And the C _1-6 alkoxy group is —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). And may be substituted with one or more of the same or different substituents selected from:) and —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, More preferably -O CO- is a methyl group.) Is a group selected from.

For each of R ^{23 to} R ²⁷ on ring A ′, the following are more preferable.
R ²³ on ring A ′ is more preferably
1) hydrogen atom,
2) Hydroxyl group, or 3) -COOH
It is.

R ²⁴ on ring A ′ is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁵ on ring A ′ is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) One or more same or different selected from —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group Or 10) a nitro group.

R ²⁶ on ring A ′ is more preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-6 alkoxy group, more preferably a methoxy group),
5) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group).
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group), or 8) nitro group.

R ²⁷ on ring A ′ is more preferably
1) hydrogen atom,
2) a hydroxyl group, or 3) -COOH.

  As such a ring A ′,

Etc.

R ^{23 to} R ²⁷ on ring A ′ are particularly preferably the same or different from each other,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. ), Or 5) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group.

For each of R ^{23 to} R ²⁷ on ring A ′, the following are particularly preferable.
R ²³ on ring A ′ is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

R ²⁴ on ring A ′ is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁵ on ring A ′ is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) a hydroxyl group, or 4) a nitro group.

R ²⁶ on ring A ′ is particularly preferably
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. , A trifluoromethyl group), or 5) a nitro group.

R ²⁷ on ring A ′ is particularly preferably
1) a hydrogen atom, or 2) a hydroxyl group.

Of the compounds [1], the compound [2] is preferable. Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -COOH,
7) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
8) an amino group,
9) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group is there.),
10) —S (═O) ₂ —C _1-6 alkyl group (preferably —S (═O) ₂ —C _1-4 alkyl group, more preferably —S (═O) ₂ -ethyl group; is there.),
11) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group or an ethyl group), or (c) R ¹⁵ And R ¹⁶ together with the nitrogen atom to which they are bonded form a monocyclic nitrogen-containing saturated heterocyclic ring (for example, pyrrolidine, piperidine, imidazolidine, piperazine, etc., preferably pyrrolidine). May be. ),
12) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (preferably an aryl group, more preferably a phenyl group), or 13) a nitro group;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
Is;
X ² '
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group)),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (b) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms ( Preferably, it is an aryl group, more preferably a phenyl group, and the carbocyclic group is substituted with one or more substituents selected from a halogen atom (preferably a chlorine atom) and a hydroxyl group. May be good),
_{4) -N (S (= O} ) 2 -C 1-6 alkyl) - (preferably _{-N (-S (= O) 2} -C 1-4 alkyl group) -, and more preferably -N (—S (═O) ₂ -methyl group) —).
5) sulfur atom,
6) -S (= O)-,
7) —S (═O) ₂ — or 8) —CH ₂ —
Is;
-X ³ -X ⁴ - is,
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different, respectively, (a) are hydrogen atoms, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together may form a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) together with the carbon atom. Good. )
And ring A ′ is

(Wherein R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) One or more same or different selected from —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). A C _1-6 alkoxy group (preferably a C _1-4 alkoxy group (preferably a methoxy group), a carboxymethoxy group, or an (ethoxycarbonyl) methoxy group) that may be substituted with a substituent of
5) —O—CO—C _1-6 alkyl group (preferably —O—CO—C _1-4 alkyl group, more preferably —O—CO-methyl group);
6) A C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. A trifluoromethyl group. ),
7) -COOH,
8) —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-methoxy group),
9) an amino group,
10) —NHS (═O) ₂ —C _1-6 alkyl group (preferably —NHS (═O) ₂ —C _1-4 alkyl group, more preferably —NHS (═O) ₂ -methyl group; Or 11) a nitro group and at least one of R ^{23 to} R ²⁷ is a hydroxyl group or a C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group). The C _1-6 alkoxy group is —COOH and —CO—C _1-6 alkoxy group (preferably —CO—C _1-4 alkoxy group, more preferably —CO-ethoxy group). ) than may be substituted by the same or different one or more substituents selected) and _{-O-CO-C 1-6} alkyl group (preferably a _{-O-CO-C 1-4} alkyl group, more Preferably -O- An O- methyl group.) Is a group selected from. );
(However, when X ² ′ is —CH ₂ —,
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n R ¹¹ and R ¹² Two of them bonded to the same or adjacent two carbon atoms together with the carbon atom are saturated or unsaturated carbocycles having 3 to 14 carbon atoms (preferably aromatic hydrocarbons, more preferably benzene A ring). )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms. )
Compounds are preferred.

Above all,
R ¹ , R ² and R ³ are the same or different,
1) hydrogen atom,
2) a halogen atom (preferably a fluorine atom or a chlorine atom),
3) hydroxyl group,
4) C _1-6 alkoxy group (preferably a C _1-4 alkoxy group, more preferably a methoxy group),
5) C _1-6 alkyl group (preferably C _1-4 alkyl group (preferably C _1-6 alkyl group) which may be substituted with one or more substituents selected from halogen atom (preferably fluorine atom) and hydroxyl group. Are a methyl group, an isopropyl group, and a tert-butyl group.), A trifluoromethyl group, and a hydroxymethyl group.
6) -CO- _C1-6 alkoxy group (preferably -CO- _C1-4 alkoxy group, more preferably -CO-methoxy group),
7) —S (═O) ₂ —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different;
(A) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably an ethyl group), or (b) nitrogen to which R ¹⁵ and R ¹⁶ are bonded. A nitrogen-containing saturated heterocyclic ring consisting of a single ring (preferably pyrrolidine) may be formed together with the atom. Or 8) a nitro group;
Y is
1) -CO-, or 2) -CS-
Is;
X ¹ is CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a methyl group), or (d) a —CO—C _1-6 alkoxy group (preferably —CO— A C _1-4 alkoxy group, more preferably a —CO-methoxy group), or (e) R ³ and R ⁴ (R ³ is as defined above), A saturated or unsaturated carbocycle having 3 to 14 carbon atoms (preferably an aromatic hydrocarbon, more preferably a benzene ring) may be formed together with the carbon atoms to be bonded. )
Is;
X ² 'is an oxygen atom;
-X ³ -X ⁴ - _is, -CH ₂ -CH 2 - and is; and rings A ',

(Where
R ^{23 to} R ²⁷ are the same or different,
1) hydrogen atom,
2) a halogen atom,
3) hydroxyl group,
4) a C _1-6 alkyl group (preferably a C _1-4 alkyl group (preferably a methyl group)) which may be substituted with one or more halogen atoms (preferably a fluorine atom) which are the same or different. ), Or 5) a nitro group, and at least one of R ^{23 to} R ²⁷ is a hydroxyl group. );
Compounds are more preferred.

In particular, a compound selected from the following group or a pharmaceutically acceptable salt thereof is preferred.
(1) (3-Chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(2) (3-Bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(3) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(4) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(5) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone,
(6) (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(7) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone,
(8) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone,
(9) (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone,
(10) (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone,
(11) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione,
(12) (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(13) (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(14) (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(15) (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(16) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(17) (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(18) (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(19) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(20) (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(21) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide,
(22) 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) phenol,
(23) (6-tert-butyl-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(24) 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one,
(25) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid amide,
(26) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone,
(27) (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone,
(28) (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(29) (5-chloro-6-hydroxypyridin-3-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(30) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone,
(31) (3-Chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(32) (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(33) (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone,
(34) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid ethylamide,
(35) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid dimethylamide;
(36) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone,
(37) 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one,
(38) (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(39) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone,
(40) (3-Chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(41) (4-Chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(42) (2,6-dichloropyridin-4-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(43) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-nitrophenyl) -methanone,
(44) (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(45) 2- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(46) methyl 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(47) 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(48) methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate,
(49) 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid,
(50) (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(51) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(52) (7-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(53) [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(54) (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(55) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester,
(56) (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(57) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid,
(58) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-5-carboxylic acid methyl ester,
(59) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester,
(60) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid,
(61) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester,
(62) 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid,
(63) (3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(64) (3,5-dichloro-4-hydroxyphenyl)-(phenoxazin-10-yl) -methanone,
(65) (3,5-dichloro-4-hydroxyphenyl)-(6-phenyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(66) (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(67) (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(68) (6-Amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(69) (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(70) (3,5-dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(71) (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(72) N- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazin-7-yl] -methanesulfonamide,
(73) 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone,
(74) (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(75) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone,
(76) (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone,
(77) (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone,
(78) (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone,
(79) (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(80) (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone,
(81) (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(82) (6-Chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone,
(83) (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone,
(84) (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(85) (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(86) (3,5-dichloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(87) Acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester,
(88) (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone,
(89) (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(90) (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(91) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester,
(92) [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid,
(93) (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone,
(94) N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide, and (95) (3,5-dichloro-4 -Hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone.

  Of these, (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone is most preferred.

Compound [1] can also be obtained as a crystal. For example,
(1) It has characteristic diffraction peaks at 12.94 °, 17.36 °, 23.50 °, 26.10 ° and 26.94 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 1),
(2) It has characteristic diffraction peaks at 16.96 °, 17.54 °, 21.66 °, 25.68 ° and 26.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 2),
(3) It has characteristic diffraction peaks at 7.40 °, 14.90 °, 22.68 °, 22.92 ° and 26.46 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 3),
(4) It has characteristic diffraction peaks at 7.40 °, 14.92 °, 16.64 °, 22.68 ° and 26.12 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 4),
(5) It has characteristic diffraction peaks at 7.28 °, 15.84 °, 23.10 °, 29.54 ° and 37.16 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone (Reference Example 5),
(6) It has characteristic diffraction peaks at 15.58 °, 17.92 °, 18.48 °, 19.86 ° and 25.90 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 6),
(7) It has characteristic diffraction peaks at 12.46 °, 23.38 °, 23.98 °, 24.32 ° and 25.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (Reference Example 7),
(8) It has characteristic diffraction peaks at 16.62 °, 18.64 °, 19.20 °, 21.60 ° and 23.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (Reference Example 10),
(9) It has characteristic diffraction peaks at 11.58 °, 14.36 °, 22.18 °, 22.48 ° and 23.36 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 12),
(10) It has characteristic diffraction peaks at 11.82 °, 14.88 °, 22.62 °, 25.56 ° and 26.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 14),
(11) It has characteristic diffraction peaks at 7.02 °, 14.14 °, 21.30 °, 21.80 ° and 26.56 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 15),
(12) It has characteristic diffraction peaks at 12.40 °, 18.36 °, 21.34 °, 23.66 ° and 24.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Reference Example 16),
(13) It has characteristic diffraction peaks at 10.54 °, 11.24 °, 21.24 °, 21.60 ° and 24.38 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 17),
(14) It has characteristic diffraction peaks at 12.32 °, 13.52 °, 22.70 °, 24.88 ° and 26.10 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 18),
(15) It has characteristic diffraction peaks at 11.16 °, 14.58 °, 21.38 °, 22.54 °, and 22.76 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 19),
(16) It has characteristic diffraction peaks at 15.46 °, 20.90 °, 22.92 °, 24.68 ° and 25.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 20),
(17) 4 having characteristic diffraction peaks at 13.48 °, 15.52 °, 19.18 °, 20.58 °, and 21.80 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction 4 -(3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (Reference Example 21),
(18) It has characteristic diffraction peaks at 11.66 °, 22.20 °, 22.48 °, 24.68 ° and 25.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (Reference Example 26),
(19) It has characteristic diffraction peaks at 17.60 °, 21.78 °, 22.78 °, 24.96 ° and 32.98 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (Reference Example 27),
(20) It has characteristic diffraction peaks at 12.16 °, 14.90 °, 22.16 °, 23.46 ° and 24.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 31),
(21) It has characteristic diffraction peaks at 11.58 °, 14.78 °, 18.80 °, 23.66 ° and 25.52 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (Reference Example 36),
(22) It has characteristic diffraction peaks at 19.94 °, 21.86 °, 22.52 °, 23.84 ° and 26.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 38),
(23) It has characteristic diffraction peaks at 7.58 °, 12.10 °, 15.24 °, 22.30 ° and 24.40 ° at diffraction angles (2θ) measured by powder X-ray crystal diffraction ( 2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone (Reference Example 39),
(24) It has characteristic diffraction peaks at 10.06 °, 17.10 °, 17.48 °, 21.78 °, and 22.26 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 40),
(25) It has characteristic diffraction peaks at 19.06 °, 20.76 °, 22.30 °, 26.58 ° and 27.60 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 41),
(26) It has characteristic diffraction peaks at 11.70 °, 22.44 °, 22.74 °, 23.58 ° and 23.90 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 44),
(27) It has characteristic diffraction peaks at 7.26 °, 22.62 °, 25.12 °, 25.70 ° and 27.92 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 50),
(28) It has characteristic diffraction peaks at 11.72 °, 21.78 °, 22.54 °, 22.82 ° and 23.68 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (Reference Example 51),
(29) It has characteristic diffraction peaks at 21.04 °, 22.22 °, 23.74 °, 24.72 ° and 27.38 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 56),
(30) It has characteristic diffraction peaks at 14.80 °, 16.44 °, 22.28 °, 22.76 ° and 24.14 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 66),
(31) It has characteristic diffraction peaks at 14.52 °, 21.52 °, 21.88 °, 27.84 ° and 30.92 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 67),
(32) It has characteristic diffraction peaks at 7.16 °, 14.40 °, 20.96 °, 27.58 ° and 34.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 69),
(33) 1 having characteristic diffraction peaks at 15.48 °, 19.24 °, 22.48 °, 25.54 ° and 30.30 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction -[4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (Reference Example 73),
(34) It has characteristic diffraction peaks at 10.48 °, 11.32 °, 20.18 °, 22.84 ° and 25.76 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (Reference Example 76),
(35) It has characteristic diffraction peaks at 12.10 °, 22.48 °, 23.40 °, 24.42 ° and 25.98 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone (Reference Example 77),
(36) It has characteristic diffraction peaks at 9.30 °, 14.52 °, 18.64 °, 23.96 ° and 27.12 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 79),
(37) It has characteristic diffraction peaks at 8.92 °, 17.98 °, 18.26 °, 21.10 ° and 23.40 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Reference Example 80),
(38) It has characteristic diffraction peaks at 7.12 °, 14.32 °, 21.62 °, 21.92 ° and 22.80 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 81),
(39) It has characteristic diffraction peaks at 7.22 °, 14.54 °, 22.34 °, 29.08 ° and 33.22 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone (Reference Example 82),
(40) It has characteristic diffraction peaks at 17.58 °, 19.00 °, 21.04 °, 21.52 ° and 23.24 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction ( 3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 85),
(41) Acetic acid having characteristic diffraction peaks at 15.76 °, 16.38 °, 24.12 °, 25.88 ° and 27.62 ° at a diffraction angle (2θ) measured by powder X-ray crystal diffraction 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (Reference Example 87)
Etc.

  The “pharmaceutically acceptable salt” may be any salt that forms a non-toxic salt with compound [1] (hereinafter also including compound [2]), for example, hydrochloric acid, sulfuric acid, phosphoric acid Salts with inorganic acids such as hydrobromic acid; oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid , Salts with organic acids such as benzenesulfonic acid; salts with inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; methylamine, diethylamine, triethylamine, triethanolamine, Salts with organic bases such as ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cinchonine; lysine, arginine Salts with amino acids alanine and the like.

In compound [1], those hydrates, hydrates and solvates are also included.
In compound [1], various isomers exist. For example, E isomers and Z isomers exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist, and tautomerism There can also be a body. Thus, compound [1] includes all these isomers and mixtures thereof. In addition, prodrug compounds of these compounds as equivalent compounds of compound [1] can also be useful drugs.

Here, the “prodrug” has a group that can be chemically or metabolically decomposed, and is a derivative that exhibits pharmacological activity by hydrolysis, solvolysis, or decomposition under physiological conditions. It is. Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site. It is well established in the pharmaceutical field what kind of group that can be chemically or metabolically decomposed and how to introduce such a group into a compound. Various known techniques may be employed. Examples of the modification site for prodrug formation include highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, and a thiol group in the compound of the present invention. For example, the case where —OR ¹³ of compound [1], or —OR ¹³ or —OR ¹³ ′ of compound [2] is a hydroxyl group, and the like can be mentioned.

For example, for the hydroxyl group, -CO-C _1-6 alkyl group, -CO ₂ -C _1-6 alkyl group, -CONH-C _1-6 alkyl group, -CO-C _2-6 alkenyl group,- CO ₂ -C _2-6 alkenyl group, _{-CONH-C 2-6} alkenyl group, -CO- aryl, -CO ₂ - aryl, -CONH- aryl group, -CO- heterocyclic group, -CO ₂ - heterocyclic group, -CONH- Hajime Tamaki (said _{C 1-6} alkyl _{groups, C 2-6} alkenyl group, an aryl group, a heterocyclic group, each a halogen _{atom, C 1-6} alkyl groups, hydroxyl _{group, C 1- 6} alkoxy group, a carboxy group, an amino group, an amino acid _{residue, -PO 3 H 2, -SO 3} H, -CO- polyethylene glycol residue, -CO ₂ - polyethylene glycol residue, -CO- polyethylene glycol mono Ruki ether residue, -CO 2 _- include derivatives of polyethylene glycol monoalkyl ether residue and the like may be substituted) substituents such as have been introduced..

For amino groups, _{-CO-C 1-6} alkyl _group, -CO _{2 -C 1-6} alkyl group, _{-CO-C 2-6} alkenyl _group, -CO _{2 -C 2-6} alkenyl group, - CO- aryl group, -CO ₂ - aryl group, -CO- heterocyclic group, -CO ₂ - Hajime Tamaki (said _{C 1-6} alkyl _{groups, C 2-6} alkenyl group, an aryl group, a heterocyclic group, Halogen atom, C _1-6 alkyl group, hydroxyl group, C _1-6 alkoxy group, carboxy group, amino group, amino acid residue, —PO ₃ H ₂ , —SO ₃ H, —CO-polyethylene glycol residue, — CO 2 _- polyethylene glycol residue, -CO- polyethylene glycol monoalkyl ether residue, -CO 2 _-. may be substituted with polyethylene glycol monoalkyl ether residue, etc.) substituted such There include derivatives that have been introduced.

For a carboxyl group, a C _1-6 alkoxy group and an aryloxy group (the C _1-6 alkoxy group and aryloxy group are a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and a C _1-6 alkoxy group, respectively. , A carboxy group, an amino group, an amino acid residue, —PO ₃ H ₂ , —SO ₃ H, a polyethylene glycol residue, a polyethylene glycol monoalkyl ether residue, etc.) may be substituted. And derivatives thereof.

The pharmaceutical composition of the present invention comprises:
(1) does not substantially inhibit CYP,
(2) By inhibiting URAT1 activity and lowering blood uric acid level, it is useful for the treatment or prevention of pathological conditions involving uric acid.

  Here, “substantially does not inhibit CYP” means that the function as a drug metabolizing enzyme cytochrome P450 (CYP), preferably CYP2D6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4, more preferably CYP2C9 is substantially used. For example, based on the conditions of Reference Test Example 2 described later, preferably, under the conditions of Reference Test Example 2, the 50% inhibitory concentration against CYP is 1 μM or more, preferably 3 μM or more. Preferably it means 10 μM or more, still more preferably 25 μM or more, particularly preferably 50 μM or more.

  “Inhibiting URAT1 activity” means to specifically inhibit the function of URAT1 as a uric acid transporter to eliminate or attenuate its activity. For example, based on the conditions of Reference Test Example 1 described later , Which specifically inhibits the function of URAT1, and preferably, under the conditions of Reference Test Example 1 described later, the 50% inhibitory concentration against URAT1 is less than 3 μM, more preferably less than 1 μM, still more preferably 0. Means less than 3 μM, even more preferably less than 0.1 μM, even more preferably less than 0.03 μM. As a URAT1 activity inhibitor, URAT1 in vivo substrates such as uric acid are not included.

  “Reducing blood uric acid level” means reducing uric acid (including urate) in blood (including serum or plasma), preferably lowering high blood uric acid level More preferably, it means that the serum uric acid level is lowered to less than 8 mg / dL (preferably less than 7 mg / dl, more preferably less than 6 mg / dL as the serum uric acid level).

  “Pathology involving uric acid” means a pathological condition involving uric acid (including urate) in the body such as blood (including serum or plasma) or urine, specifically high blood Pathologies caused by uric acid levels (including serum or plasma) or high urinary uric acid levels, such as hyperuricemia, gouty nodules, acute gouty arthritis, chronic gouty arthritis, gouty kidneys, urolithiasis, kidneys Examples include dysfunction, coronary artery disease, ischemic heart disease and the like.

  For example, “high blood uric acid level” means that the serum uric acid level is 6 mg / dL or more, preferably 7 mg / dL or more, more preferably 8 mg / dL or more. In addition, “a pathological condition caused by a high blood uric acid level” is a pathological condition caused by or contributed by a high blood uric acid level. For example, according to “Guideline for Treatment of Hyperuricemia / Gout (1st Edition)” (Gout and Nucleic Acid Metabolism, Vol. 26, Appendix 1, 2002. Japanese Society of Gout and Nucleic Acid Metabolism) Regardless of the upper limit of normal, which is 7 mg / dL, which is the uric acid dissolution concentration in plasma, a value exceeding this is defined as hyperuricemia, and treatment of hyperuricemia / gout, onset of gout arthritis For prevention, it is mentioned that it is desirable to control the serum uric acid level to 6 mg / dL or less.

  The “pharmaceutical composition” includes a combination with other drugs in addition to a so-called “composition” composed of a pharmaceutical active ingredient and a pharmaceutically acceptable additive. It goes without saying that the pharmaceutical composition of the present invention may be used in combination with any other drug within a range acceptable in the medical field. Therefore, it can also be said that this pharmaceutical composition is a pharmaceutical composition for combined use with other drugs.

  Compound [1] is an active ingredient of a pharmaceutical composition, a URAT1 activity inhibitor, a blood uric acid level reducing agent, or a therapeutic or prophylactic agent for a pathological condition involving uric acid, together with one or more pharmaceutically acceptable additives. May be contained.

  As shown in Test Examples described later, the present inventors have obtained the knowledge that Compound [1] is decomposed by contacting Compound [1] with a basic additive. Therefore, in order to improve the temporal stability of the compound [1] during the production process or storage of the pharmaceutical composition, the pharmaceutical composition of the present invention comprises (substantially) the compound [1] and a basic additive. It is characterized by not touching.

“Compound [1] does not (substantially contact) the basic additive” means, for example, the following embodiment.
(1) Embodiment in which the layer containing the compound [1] and the layer containing the basic additive are not in contact As the embodiment, specifically,
(A) The compound [1] and the basic additive are separately contained in layers (for example, the first layer and the third layer) of the multilayer tablet that do not contact each other,
(B) A compound [1] and a basic additive are separately contained in a non-contact layer of the dry-coated tablet (for example, a coated inner core tablet and an outer layer).

(2) The content of the basic additive is more than the amount usually used in a pharmaceutical preparation, for example, the amount used as an excipient (for example, about 10 to 30 parts by weight with respect to 1 part by weight of the active compound). A mode in which the probability that the compound [1] and the basic additive are brought into contact with each other is reduced by far less. As this mode, specifically,
(A) Do not contain basic additives (all of the additives are not basic additives, that is, all of the additives are selected from the group consisting of acidic additives and neutral additives),
(B) When a basic additive is contained, the allowable content is less than 1 part by weight (preferably less than 0.5 part by weight, more preferably 0 with respect to 1 part by weight of compound [1]). Less than 1 part by weight, even more preferably less than 0.025 part by weight),
Etc.

  The amount of the basic additive contained in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0 to 15 w / w%, more preferably 0 to 5 w / w, based on the total amount of the pharmaceutical composition. %.

  In the pharmaceutical composition of the present invention, there is a mode in which the probability that the compound [1] and the basic additive are brought into contact with each other is reduced by making the content of the basic additive much smaller than the amount usually used in the pharmaceutical preparation. Among them, it is more preferable that no basic additive is contained in the pharmaceutical composition of the present invention. This makes it possible to improve the temporal stability of compound [1] during the manufacturing process or storage of the pharmaceutical composition.

The “basic additive” means an additive having an aqueous solution or suspension obtained by adding 100 mL of water to 5.0 g of the additive and having a pH exceeding 8 at room temperature (15 to 25 ° C.). The measured value of pH may vary depending on the measuring device, measurement conditions, and the like, but if within the normal error range, it is assumed to be within the above pH range.
Moreover, the additive whose pH standard value described in the 14th revision pharmacopoeia or pharmaceutical additive standard 2003 exceeds 8 is also meant.

  Specific examples of basic additives include alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (eg, magnesium hydroxide, barium hydroxide, etc.), alkali metals Carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (eg, magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (eg, sodium bicarbonate, etc.), alkaline earth metal bicarbonates Salts (eg, magnesium hydrogen carbonate, barium hydrogen carbonate, etc.), alkali metal silicates (eg, sodium silicate, etc.), alkaline earth metal silicates (eg, magnesium silicate, calcium silicate, etc.), etc. It is done.

  Examples of basic additives include alkali metal silicates, alkaline earth metal silicates and the like, and specific examples include calcium silicate.

“Acid additive” and “neutral additive” mean additives other than the “basic additive” defined above.
Specific examples of “acid additives” and “neutral additives” include D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, light anhydrous silicic acid, crospovidone, magnesium stearate, lactose, corn starch, cloth Carmellose sodium, carmellose, carmellose sodium, carmellose calcium, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, titanium oxide, macrogol and the like.
As the pH of these acidic additives and neutral additives, for example, the following values are described in the 14th revised pharmacopoeia or pharmaceutical additive standard 2003.
D-mannitol (D-mannitol injection solution): pH 4.5 to 7.0
Crystalline cellulose (supernatant after adding 40 mL of boiling cooling water to 5.0 g and shaking): pH 5.0 to 7.0
・ Low-substituted hydroxypropylcellulose (liquid obtained by adding 100 mL of boiling cooling water to 1.0 g and shaking): pH 5.0 to 7.5
Crospovidone (liquid in which 1 g is suspended in 100 mL of water): pH 5.0 to 8.0
Corn starch (Suspension obtained by adding 50 mL of water to 1 g and boiling and cooling): Neutral Carmellose (Suspension obtained by adding 100 mL of water to 1.0 g and shaking): pH 3.5 to 5.0
Carmellose sodium (1.0 g is gradually dissolved in 100 mL of hot water and then cooled): pH 6.0 to 8.0
Carmellose calcium (suspension obtained by adding 100 mL of water to 1.0 g and shaking): pH 4.5 to 6.0
・ Carboxymethyl starch sodium (liquid obtained by adding 100 mL of water to 1.0 g and stirring while heating): pH 5.5 to 8.0
Hydroxypropyl cellulose (1.0 g dissolved in boiling water 50 mL): pH 5.0-7.5
Hydroxypropyl methylcellulose (100 g of hot water added to 1.0 g, shaken and suspended, cooled liquid): pH 5.0 to 8.0
Povidone (liquid obtained by dissolving 1.0 g in 20 mL of water): pH 3.0 to 7.0
Titanium oxide (liquid obtained by adding 10 mL of water to 1 g and shaking): Neutral Macrogol (liquid obtained by dissolving 1.0 g in 20 mL of water): pH 4.0 to 7.5
These acidic additives and neutral additives are, for example, an aqueous solution or suspension obtained by adding 100 mL of water to 1.0 to 5.0 g of the additive according to the 14th revised pharmacopoeia or pharmaceutical additive standard 2003. The pH of the suspension is 8 or less.

  In the pharmaceutical composition of the present invention, as shown in Test Examples, compound [1] can be rapidly eluted by containing one (preferably both) of low-substituted hydroxypropylcellulose and crospovidone. Can do.

  In particular, a pharmaceutical composition containing compound [1], D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone and magnesium stearate is preferable.

  The amount of compound [1] (including solvates such as hydrates) contained in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 10 to 60 w / w with respect to the total amount of the pharmaceutical composition. %, And more preferably 20 to 50 w / w%. When the pharmaceutical composition is a tablet, it is preferably 10 to 200 mg / tablet, more preferably 10, 25, 50, 100, or 200 mg / tablet.

  The amount of D-mannitol contained in the pharmaceutical composition of the present invention as an additive is not particularly limited, but is preferably 1 part by weight of Compound [1] (including solvates such as hydrates). The amount is 0.05 to 100 parts by weight, and more preferably 0.5 to 50 parts by weight. The total amount of the pharmaceutical composition is preferably 5 to 60 w / w%, more preferably 10 to 40 w / w%. When the pharmaceutical composition is a tablet, it is preferably 10 to 90 mg / tablet, more preferably about 10 to 50 mg / tablet. When using crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, etc. as additives such as excipients, binders, and disintegrants, these additives are listed above. It can mix | blend suitably according to the compounding quantity of D-mannitol.

  The amount of crystalline cellulose contained in the granulation step, which is contained in the pharmaceutical composition of the present invention as an additive, is not particularly limited, but is compound [1] (including solvates such as hydrates) 1 Preferably it is 0-100 weight part with respect to a weight part, More preferably, it is 0-50 weight part. The total amount of the pharmaceutical composition is preferably 0 to 60 w / w%, more preferably 0 to 40 w / w%. When the dosage form of the pharmaceutical composition is a tablet, the dosage is preferably 0 to 90 mg / tablet, more preferably 0 to 50 mg / tablet. D-mannitol, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, etc. as additives such as excipients, lubricants, fluidizing agents, binders, and disintegrants When used, these additives can be appropriately blended depending on the blending amount of the crystalline cellulose.

  The amount of crystalline cellulose to be blended in the mixing step for obtaining a tableting powder contained in the pharmaceutical composition of the present invention as an additive is not particularly limited, but is not limited to compound [1] (solvents such as hydrates thereof) The amount is preferably 0.01 to 20 parts by weight, more preferably 0.1 to 10 parts by weight with respect to 1 part by weight (including Japanese products). The total amount of the pharmaceutical composition is preferably 1 to 20 w / w%, more preferably 2.5 to 10 w / w%. Further, when the dosage form of the pharmaceutical composition is a tablet, it is preferably 1 to 15 mg / tablet, more preferably 6.5 mg / tablet. Additives such as excipients, lubricants, fluidizers, binders, disintegrants, etc., D-mannitol, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, etc. When these are used, these additives can be appropriately blended according to the blending amount of the crystalline cellulose.

  The amount of low-substituted hydroxypropylcellulose contained in the pharmaceutical composition of the present invention as an additive is not particularly limited, but is preferably relative to compound [1] (including solvates such as hydrates). The amount is 0.05 to 100 parts by weight, more preferably 0.1 to 50 parts by weight. The total amount of the pharmaceutical composition is preferably 1 to 50 w / w%, more preferably 10 to 32 w / w%, still more preferably 20 to 32 w / w%, and particularly preferably 27 to 32 w%. / W%, most preferably 28.6 w / w%. In addition, when the dosage form of the pharmaceutical composition is a tablet, it is preferably 10 to 100 mg / tablet, more preferably 40 mg / tablet. When the dosage form of the pharmaceutical composition is a coated tablet, it is preferably 20 to 32 w / w%, more preferably 27 to 32 w / w%, particularly with respect to the total amount of uncoated tablets. Preferably it is 29.6 w / w%. When D-mannitol, crystalline cellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, etc. are used as additives such as excipients, binders, and disintegrants, these additives have the above low substitution degree. It can mix | blend suitably according to the compounding quantity of a hydroxypropyl cellulose.

  The amount of light anhydrous silicic acid contained in the pharmaceutical composition of the present invention as an additive is not particularly limited but is preferably 1 part by weight of Compound [1] (including solvates such as hydrates). Is preferably 0.01 to 10 parts by weight, more preferably about 0.01 to 5 parts by weight. The total amount of the pharmaceutical composition is preferably about 1 to 10 w / w%, more preferably 1 to 5 w / w%. When the dosage form of the pharmaceutical composition is a tablet, the dosage is preferably 1 to 10 mg / tablet, more preferably 2.5 mg / tablet. When using D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, etc. as additives such as excipients, lubricants, fluidizing agents, binders, and disintegrants These additives can be appropriately blended according to the blending amount of the light silicic anhydride.

  The amount of hydroxypropylmethylcellulose contained in the pharmaceutical composition of the present invention as an additive is not particularly limited, but is preferably 1 part by weight of Compound [1] (including solvates such as hydrates). 0.01 to 10 parts by weight, more preferably 0.05 to 5 parts by weight. The total amount of the pharmaceutical composition is preferably 1 to 10 w / w%, more preferably 1.5 to 6 w / w%. When the dosage form of the pharmaceutical composition is a tablet, it is preferably 2 to 10 mg / tablet, more preferably 4 mg / tablet. In the case of using D-mannitol, crystalline cellulose, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, etc. as additives such as excipients, binders, and disintegrants, these additives are It can mix | blend suitably according to the compounding quantity of the said hydroxypropyl methylcellulose.

  The amount of crospovidone contained as an additive in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.1 with respect to compound [1] (including solvates such as hydrates thereof). To 50 parts by weight, more preferably 0.1 to 30 parts by weight. The total amount of the pharmaceutical composition is preferably 1 to 30 w / w%, more preferably 1 to 20 w / w%, still more preferably 5 to 20 w / w%, still more preferably 5 to 17 w / w%, particularly preferably 10 to 17 w / w%, and most preferably 10 w / w%. Further, when the dosage form of the pharmaceutical composition is a tablet, it is preferably 1 to 30 mg / tablet, more preferably 14 mg / tablet. When the dosage form of the pharmaceutical composition is a coated tablet, it is preferably 5 to 20 w / w%, more preferably 5 to 17 w / w%, based on the total amount of uncoated tablets before coating, More preferably, it is 10 to 17 w / w%, and particularly preferably 10.4 w / w%. When D-mannitol, crystalline cellulose, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium stearate, etc. are used as additives such as excipients and disintegrants, these additives are It can mix | blend suitably according to the compounding quantity of povidone.

  The amount of magnesium stearate contained in the pharmaceutical composition of the present invention as an additive is not particularly limited, but is preferably based on 1 part by weight of compound [1] (including solvates such as hydrates thereof). Is 0.005 to 5 parts by weight, more preferably 0.01 to 3 parts by weight. The total amount of the pharmaceutical composition is preferably 0.2 to 2 w / w%, more preferably 0.5 to 1.5 w / w%. Further, when the dosage form of the pharmaceutical composition is a tablet, it is preferably 0.5 to 3 mg / tablet, more preferably 1.5 mg / tablet. When D-mannitol, crystalline cellulose, light silicic acid anhydride, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crospovidone, or the like is used as an additive such as an excipient and a fluidizing agent, these additives are the above stearic acids. It can mix | blend suitably according to the compounding quantity of magnesium.

  As additives, in addition to the above-mentioned components, various organic or inorganic carrier substances commonly used as formulation materials are used unless otherwise affected, and excipients, lubricants, fluidizing agents, binders, disintegrants, solvents And as a coating agent. If necessary, other additives such as stabilizers, preservatives, antioxidants, sweeteners, colorants, light-shielding agents, corrigents, adsorbents, wetting agents, and antistatic agents can be used. .

  Examples of the excipient include lactose, sucrose, starch and the like in addition to D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone and magnesium stearate.

  Examples of the lubricant include crystalline cellulose, light anhydrous silicic acid, magnesium stearate, hydroxypropyl cellulose, calcium stearate, talc and the like.

  Examples of the fluidizing agent include crystalline cellulose, light anhydrous silicic acid, magnesium stearate, and talc.

  Examples of the binder include D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, sucrose, dextrin, hydroxypropylcellulose, polyvinylpyrrolidone and the like.

  Disintegrants include D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch Sodium etc. are mentioned.

  Examples of the solvent include water, alcohol, propylene glycol, macrogol, sesame oil, corn oil, propylene glycol fatty acid ester, and the like.

  Examples of the coating agent include Opadry (R) OY-7300 (a mixture of hydroxypropylmethylcellulose 2910, titanium oxide and Macrogol 400).

  Examples of the pharmaceutical composition of the present invention include pharmaceutical preparations such as tablets, pills, powders, fine granules, granules, suppositories, capsules, and troches.

  The pharmaceutical composition of the present invention can be obtained by mixing compound [1] and one or more pharmaceutically acceptable additives. When the dosage form of the pharmaceutical composition of the present invention is a tablet, the following method can be mentioned as a preferred specific example. First, compound [1] is pulverized by a jet mill. The pulverized compound [1], D-mannitol, low-substituted hydroxypropylcellulose and light anhydrous silicic acid, and if necessary, further mixed with crystalline cellulose to obtain a mixed powder. A binder solution is added to the obtained mixed powder and then granulated to obtain a granulated powder. The obtained granulated powder is sized and then dried to obtain a sized powder. Crospovidone and crystalline cellulose are added to the obtained sized powder and mixed. Add magnesium stearate and mix further. This is tableted to obtain an uncoated tablet. The uncoated tablet is coated by spraying a coating solution to obtain a film-coated tablet containing compound [1].

  The pharmaceutical composition of the present invention can be administered systemically or locally, orally or parenterally. The dose varies depending on the age, body weight, symptoms, therapeutic effects, etc. For example, it can be administered once or several times a day, usually in the range of 0.1 mg to 1 g per adult. The pharmaceutical composition of the present invention can be used not only for humans but also for therapeutic and prophylactic agents for the above-mentioned diseases of animals other than humans, particularly mammals. The same applies when the pharmaceutical composition of the present invention is used as a therapeutic or prophylactic agent for hyperlipidemia, diabetes, obesity or cardiovascular disease such as hypertension, coronary artery disease, vascular endothelial disorder or ischemic heart disease.

  The pharmaceutical composition of the present invention can be administered not only to humans but also to other mammals (mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.). Therefore, the pharmaceutical composition of the present invention is useful not only for humans but also for veterinary drugs.

  The pharmaceutical composition, URAT1 activity inhibitor, blood uric acid level-lowering agent, or therapeutic or prophylactic agent for a pathological condition involving uric acid is used in combination with another pharmaceutical composition or drug (hereinafter also referred to as a concomitant drug). can do.

  “Combination” means that a plurality of pharmaceutical agents are used in combination as an active ingredient, and specifically, used as a combination agent, as a kit, and separately administered by the same or different administration routes. The combination use etc. which are characterized by this are mentioned.

  The timing of administration of the pharmaceutical composition of the present invention, URAT1 activity inhibitor, blood uric acid level-lowering agent, or therapeutic or prophylactic agent for pathological conditions involving uric acid, and concomitant drugs is not limited. They may be administered at the same time or may be administered with a time difference. The dose of the concomitant drug may be in accordance with the clinically used dose, and may be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form, administration method, combination, etc. it can. The administration form of the concomitant drug is not particularly limited, and the pharmaceutical composition of the present invention, the URAT1 activity inhibitor, the blood uric acid level-lowering agent, or the therapeutic or preventive drug for the pathological condition involving uric acid and the concomitant drug at the time of administration may be It only has to be combined.

As a concomitant drug,
(1) Therapeutic and / or prophylactic agent for hyperuricemia (2) Therapeutic and / or prophylactic agent for gout arthritis (3) Therapeutic and / or prophylactic agent for gout kidney (4) Therapeutic agent for urolithiasis And / or prophylactic agent (5) therapeutic agent and / or prophylactic agent for hypertension or hypertensive complications (6) therapeutic agent and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications (7) diabetes or diabetic complications Therapeutic agent and / or preventive agent for infectious disease (8) therapeutic agent and / or preventive agent for obesity or obesity complications (9) therapeutic agent for primary disease causing secondary uric acid excretion type secondary hyperuricemia and / or Or prophylactic agent (10) treatment and / or prophylactic agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia (11) nucleic acid antimetabolite, and these 1 to 3 drugs and the compound of the present invention Can be used in combination.

  Examples of the “treatment and / or prevention agent for hyperuricemia” include uric acid production inhibitors such as xanthine oxidase inhibitors, uric acid excretion promoters, and the like. Specifically, allopurinol, probenecid, bucolome, febu Xostat, benzbromarone, oxypurinol and the like.

  Examples of the “treatment and / or prevention agent for gout arthritis” include NSAIDs such as indomethacin, naproxen, fenbufen, pranoprofen, and oxaprozin, colchicine, and corticosteroids.

  Examples of “therapeutic and / or prophylactic agent for gout kidney” include uric acid production inhibitors such as xanthine oxidase inhibitor, uric acid excretion promoters, citric acid preparations, urine alkalizing agents such as sodium bicarbonate, etc. Specific examples include allopurinol, probenecid, bucolome, febuxostat, benzbromarone, and oxypurinol.

  Examples of “therapeutic agent and / or preventive agent for urinary calculus” include urine alkalizing agents such as citric acid preparations and sodium bicarbonate.

  Examples of the “therapeutic and / or preventive agent for hypertension or hypertensive complications” include, for example, loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β blockers, α, β blockers More specifically, for example, furosemide sustained release agent, captopril, captopril sustained release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride , Quinapril hydrochloride, trandolapril, perindopril erbumine, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride Drugs, nisoldipine, nitrendipine, manidipine hydrochloride, varnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, propranolol hydrochloride sustained release, pindolol, pindolol sustained release, indenolol hydrochloride, carteolol hydrochloride, medical chart Orol sustained release agent, bunitrolol hydrochloride, bunitrolol hydrochloride sustained release agent, atenolol, acebutol hydrochloride hydrochloride, metoprolol tartrate, metoprolol tartrate, nipradilol, penbutolol sulfate, tirisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, Bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, Examples thereof include prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent, urapidil, phentolamine mesylate and the like.

  Examples of “therapeutic and / or prophylactic agent for hyperlipidemia or hyperlipidemic complication” include, for example, statin drugs, anion exchange resins, probucol, nicotinic acid preparations, fibrate drugs, eicocypentaene More specifically, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, colestimide, cholestyramine, niceritrol, nicomol, fenofibrate, bezafibrate, clinofibrate, clofibrate, icosapent Examples include ethyl acid.

  Examples of “therapeutic and / or preventive agent for diabetes or diabetic complications” include, for example, insulin preparations, sulfonylurea drugs, insulin secretagogues, sulfonamide drugs, biguanide drugs, α-glucosidase inhibitors, insulin resistance improving drugs, Angiotensin converting enzyme inhibitor, aldose reductase inhibitor, antiarrhythmic agent and the like, and more specifically, for example, insulin, chlorpropamide, glibenclamide, glipizide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, Examples include tolazamide, gliclazide, nateglinide, glybazole, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, pioglitazone hydrochloride, mexiletine.

  Examples of “therapeutic and / or prophylactic agent for obesity or obesity complications” include mazindol, acarbose, voglibose, orlistat and the like.

  Examples of the “therapeutic and / or preventive agent for the primary disease causing hypouria excretion type secondary hyperuricemia” include, for example, chronic kidney disease, polycystic kidney disease, pregnancy toxemia, lead nephropathy, hyperlactic acid blood Treatment, prevention agents such as dehydration, Down syndrome, sarcoidosis, glycogenosis type I (via hyperlactic acidemia), dehydration, and the like.

  Examples of “therapeutic and / or preventive agent for renal failure, cardiovascular disorder, and cerebrovascular disorder caused by hyperuricemia” include, for example, loop diuretic (eg, furosemide), citric acid preparation, sodium bicarbonate, cation Exchange resins, aluminum hydroxide, alphacalcidol, β-blockers (eg propranolol hydrochloride), ACE inhibitors (eg captopril), cardiotonic agents (eg digoxin), angina treatments (eg isosorbide nitrate), Ca antagonist (for example, diltiazem hydrochloride), uric acid production inhibitor (for example, allopurinol), amino acid preparation, hyperammonemia ameliorating agent, antiarrhythmic agent (for example, mexiletine), anemia agent (for example, mepithiostan, erythropoietin) Others, “Therapeutic and / or preventive agents for hypertension or hypertensive complications” Is a therapeutic and / or prophylactic agent for hyperlipidemic complications, "" a therapeutic and / or prophylactic agent for diabetes or diabetic complications "," a therapeutic and / or prophylactic agent for obesity or obesity complications " Etc.

  Examples of the “nucleic acid metabolism antagonist” include azathioprine, mizoribine, mycophenolic acid and the like.

  The pharmaceutical composition of the present invention, URAT1 activity inhibitor, blood uric acid level lowering agent, or therapeutic or prophylactic agent for a pathological condition involving uric acid is used in combination with a drug that increases blood uric acid level. An increase in the value can also be suppressed.

  Examples of drugs that increase blood uric acid levels include nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, immunosuppressants, salicylic acid, pyrazinamide, ethambutol, Examples include nicotinic acid, ethanol, and cyclosporine.

Compound [1] is preferably in the form of crystals. The crystal | crystallization of compound [1] should just be contained in the pharmaceutical composition, Preferably, the pharmaceutical composition contains the said crystal | crystallization substantially substantially.
“Substantially containing most of the crystal of compound [1]” means that the crystal in compound [1] is 80 w / w% or more, preferably 90 w / w% or more, more preferably 95 w / w% or more. Means that.

  Next, the production method of compound [1] will be specifically described. However, it goes without saying that the present invention is not limited to these production methods. In producing the compound [1], the order of the reaction can be appropriately changed. The reaction may be performed from a process or a site that seems reasonable.

  In addition, a substituent conversion (substituent conversion or further modification) step may be appropriately inserted between the steps. When there is a reactive functional group, protection and deprotection may be appropriately performed. Moreover, in order to accelerate | stimulate progress of reaction, reagents other than the illustrated reagent can be used suitably. In addition, raw material compounds whose production methods are not described are commercially available or can be easily prepared by combining known synthetic reactions.

The compound obtained in each step can be isolated and purified by a conventional method such as crystallization, recrystallization, column chromatography, preparative HPLC, etc. The process can be proceeded to.
In the following production method, “room temperature” means 1 to 40 ° C.

Manufacturing method 1
In compound [1], a compound in which X ² is an oxygen atom and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

First Step Compound 2 can be obtained by subjecting Compound 1 to an amidation reaction with acid halide B in a solvent in the presence of a base.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide, dimethyl sulfoxide and water These may be used alone or in combination of two or more. A preferable solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate, water or tetrahydrofuran.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, Alkali metal hydrides such as potassium hydride; Alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and the like, preferably triethylamine, pyridine, sodium hydroxide or carbonic acid Sodium hydride.

The reaction temperature is about 0 ° C. to 80 ° C., preferably about 0 ° C. to room temperature.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Compound 2 can be obtained by subjecting the second step compound 2 to a cyclization reaction in a solvent in the presence of a base and, if necessary, in the presence of a catalytic amount of sodium iodide, potassium iodide or the like.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is acetone or N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as potassium; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide Alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkyllithiums such as n-butyllithium and s-butyllithium; lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide and the like Alkali metal amides and the like, preferably potassium carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 1 hour to 24 hours.

Third Step Compound 4 can be obtained by reducing the compound 3 in a solvent using a reducing agent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol, ethanol and isopropyl alcohol. And alcohol solvents such as tert-butanol, etc., preferably toluene, diethyl ether or tetrahydrofuran.

  Examples of the reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diborane, diisobutylaluminum hydride, borane-tetrahydrofuran complex, sodium bis (2-methoxyethoxy) aluminum hydride, and preferably Bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride or borane-tetrahydrofuran complex.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 130 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 4 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to give an acid chloride, and then amidated with compound 4 in the presence of a base in a solvent as necessary. Thus, compound 5 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, the compound 4 and the carboxylic acid compound C are converted into, for example, water-soluble carbodiimide (WSC · HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 5 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP) or the like. Alternatively, carboxylic acid compound C is reacted with chloroformate such as ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, etc. in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 4 in the presence of a base. To obtain compound 5.

For compounds in which X ⁴ is other than —CH ₂ —, the corresponding compounds can be obtained by the same method as in the fourth step using known compounds.

  Moreover, a 1st process and a 2nd process can obtain the compound 3 by 1 process according to Synthesis, 10,851-852 (1984).

Manufacturing method 2
In compound [1], a compound in which X ² is an oxygen atom and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Fifth Step Compound 6 can be obtained by subjecting Compound 1 to a silylation reaction using tert-butylchlorodimethylsilane in a solvent in the presence of a base.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, imidazole, 4-dimethylaminopyridine and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; hydrogenation Examples thereof include alkali metal hydrides such as sodium and potassium hydride; alkali metals such as sodium carbonate and potassium carbonate; alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate. A preferred base in this reaction is imidazole.

The reaction temperature is about 0 ° C. to 150 ° C., preferably about 0 ° C. to room temperature.
The reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 12 hours.

Step 6 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to form an acid chloride, and then amidated with compound 6 in the presence of a base in a solvent as necessary. Thus, compound 7 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. A preferred solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, compound 6 and carboxylic acid compound C can be converted into, for example, water-soluble carbodiimide (WSC · HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 7 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP) or the like. Alternatively, the carboxylic acid compound C is reacted with a chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 6 in the presence of a base. To give compound 7.

Step 7 Compound 8 can be obtained by desilylating compound 7 in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, polar solvents such as dimethyl sulfoxide and the like, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is N, N-dimethylformamide.

  Examples of the reagent used for the reaction include potassium carbonate, tetrabutylammonium fluoride and the like, and potassium carbonate is preferable.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 8 Compound 9 can be obtained by cyclizing compound 8 with halide D in the presence of a base in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. A preferred base in this reaction is potassium carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 3 hours to 24 hours.

Manufacturing method 3
In compound [1], the compound in which X ² is a carbon atom or a sulfur atom and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 9 Compound 11 can be obtained by subjecting known compound 10 to a reduction reaction in a solvent using a reducing agent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol, ethanol and isopropyl alcohol. And alcohol solvents such as tert-butanol, etc., preferably toluene, diethyl ether or tetrahydrofuran.

  Examples of the reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diborane, diisobutylaluminum hydride, borane-tetrahydrofuran complex, sodium bis (2-methoxyethoxy) aluminum hydride, and preferably Bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride or borane-tetrahydrofuran complex.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 130 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 10 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to form an acid chloride, and then amidated with compound 11 in the solvent, if necessary, in the presence of a base. Thus, compound 12 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride and hydrogen Examples thereof include alkali metal hydrides such as potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, the compound 11 and the carboxylic acid compound C are converted into, for example, water-soluble carbodiimide (WSC · HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 12 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP), or the like. Alternatively, the carboxylic acid compound C is reacted with a chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 11 in the presence of a base. To give compound 12.

For compounds in which X ⁴ is other than —CH ₂ —, the corresponding compounds can be obtained by the same method as in Step 10 using known compounds.

Manufacturing method 4
In compound [1], a compound in which X ² is S═O or S (═O) ₂ and Y is C═O can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 14 Compound 14 can be obtained by subjecting compound 13 to an oxidation reaction in a solvent using an oxidizing agent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, dimethyl sulfoxide, water, acetic acid and other polar solvents, and the like can be used alone or in admixture of two or more. A preferred solvent in this reaction is methylene chloride or chloroform.

  Examples of the oxidizing agent used in the reaction include 3-chloroperbenzoic acid, hydrogen peroxide, sodium periodate, tert-butyl hydroperoxide, and the like, preferably 3-chloroperbenzoic acid.

The reaction temperature is about 0 ° C. to 80 ° C., preferably about 0 ° C. to room temperature.
The reaction time is about 10 minutes to 48 hours, preferably about 2 hours to 24 hours.

Manufacturing method 5
In the compound [1], a compound in which X ² is NR ⁵ , N (COR ⁶ ), N (S (═O) ₂ R ⁶ ) or N (CONR ⁷ R ⁸ ) and Y is C═O It can be manufactured by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 12 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to give an acid chloride, and then amidated with known compound 15 in a solvent, if necessary, in the presence of a base. Thus, compound 16 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, the known compound 15 and the carboxylic acid compound C can be converted into, for example, water-soluble carbodiimide (WSC / HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide. Compound 16 can also be obtained by a condensation reaction using (DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP) or the like. Alternatively, after reacting carboxylic acid compound C with chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, in the presence of known compound 15 and the base Compound 16 can also be obtained by reacting.

R ⁵ , COR ⁶ , S (═O) ₂ R ⁶ or CONR ⁷ R ⁸ can be introduced into the nitrogen atom of X ² either before or after the twelfth step, and react in an order that seems reasonable. Just do it.

Manufacturing method 6
In compound [1], the compound in which Y is C═S can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 13 Compound 18 can be obtained by reacting Compound 17 with Lawesson's reagent, diphosphorus pentasulfide and the like in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, polar solvents such as dimethyl sulfoxide and the like, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is tetrahydrofuran or toluene.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
The reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 12 hours.

Manufacturing method 7
In compound [1], a compound in which Y is S (═O) ₂ can be produced by the following steps.

(In the formula, each symbol has the same meaning as described above.)

Step 14 Compound 20 can be obtained by subjecting compound 19 to an amidation reaction with known acid chloride E in a solvent in the presence of a base as necessary.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. Preferred solvents for this reaction are methylene chloride, chloroform, toluene, ethyl acetate, N, N-dimethylformamide or tetrahydrofuran.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Preferably this reaction is carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium bicarbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Manufacturing method 8
In compound [1], a compound in which X ² is an oxygen atom and Y is C═O can be produced by the following steps.

(Wherein, TBDMS is tert- butyldimethylsilyl group.-OMs is _{-OS (= O) 2 -CH 3} . Other symbols are as defined above.)

Fifteenth step Compound 22 can be obtained by reacting compound 21 with halide F in a solvent in the presence of a base and, if necessary, in the presence of sodium iodide, potassium iodide or the like.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is acetone or N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as potassium; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide Alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkyllithiums such as n-butyllithium and s-butyllithium; lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide and the like It includes alkali metal amides such as, preferably sodium hydride or potassium carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 130 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 1 hour to 24 hours.

Step 16 Compound 23 can be obtained by subjecting compound 22 to a reduction reaction in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol, ethanol and isopropyl alcohol. Alcohol solvents such as tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide, and the like. The above can be mixed and used. A preferred solvent in this reaction is tetrahydrofuran, ethyl acetate or ethanol.

  Examples of the reduction reaction include a hydrogenation reaction with a noble metal catalyst (eg, palladium carbon, palladium barium sulfate, palladium black, platinum carbon, platinum oxide, rhodium carbon, Raney nickel, etc.), tin dichloride, iron, sodium hydrosulfite. A hydrogenation reaction with a noble metal catalyst (palladium carbon) is preferable.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 17 Carboxylic acid compound C is reacted with oxalyl chloride, thionyl chloride, etc. in a solvent to give an acid chloride, and then amidated with compound 23 in the solvent, if necessary, in the presence of a base. Thus, compound 24 can be obtained.

  Examples of the solvent used in the reaction for obtaining the acid chloride include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogenated hydrocarbon solvents such as methylene, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and the like. These may be used alone or in combination of two or more. Can be used. Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate containing a catalytic amount of N, N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Examples of the solvent used in the amidation reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform Halogenated hydrocarbon solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These may be used alone or in combination of two or more. A preferred solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate or tetrahydrofuran.

  Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. This reaction is preferably carried out in the absence of a base or in the presence of triethylamine, pyridine, sodium hydroxide or sodium hydrogen carbonate.

The reaction temperature is about 0 ° C. to 120 ° C., preferably about 0 ° C. to 95 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

  Further, compound 23 and carboxylic acid compound C can be converted into, for example, water-soluble carbodiimide (WSC / HCl: 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide ( Compound 24 can also be obtained by a condensation reaction using DPPA), carbonyldiimidazole (CDI), 1-hydroxy-1H-benzotriazole (HOBT), 4-dimethylaminopyridine (DMAP), or the like. Alternatively, the carboxylic acid compound C is reacted with a chloroformate such as ethyl chloroformate, isopropyl chloroformate, and isobutyl chloroformate in the presence of a base such as triethylamine to form a mixed acid anhydride, and then reacted with compound 23 in the presence of a base. To obtain the compound 24.

Step 18 Compound 25 can be obtained by desilylating compound 24 in a solvent.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, N , N-dimethylformamide, polar solvents such as dimethyl sulfoxide and the like, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is tetrahydrofuran or N, N-dimethylformamide.

  Examples of the reagent used for the reaction include potassium carbonate and tetrabutylammonium fluoride, and tetrabutylammonium fluoride is preferred.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 80 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 19 Compound 25 can be converted to Compound 26.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. This reaction is preferably carried out without solvent or in methylene chloride or chloroform.

  Examples of the reagent used for the reaction include carbon tetrachloride in the presence of triphenylphosphine; N-chlorosuccinimide (NCS) in the presence of triphenylphosphine; thionyl chloride; carbon tetrabromide in the presence of triphenylphosphine; N-bromosuccinimide (NBS) in the presence of phosphine; phosphorus tribromide; phosphorus bromide; iodine in the presence of triphenylphosphine and imidazole; methanesulfonyl chloride in the presence of a base (pyridine, triethylamine, etc.), etc. Preferred is methanesulfonyl chloride in the presence of a base (pyridine, triethylamine, etc.).

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

Step 20 Compound 27 can be obtained by subjecting compound 26 to a cyclization reaction in a solvent in the presence of a base, and optionally in the presence of sodium iodide, potassium iodide or the like.

  Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; methylene chloride, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide and dimethyl sulfoxide These can be used alone or in admixture of two or more. A preferred solvent in this reaction is tetrahydrofuran or N, N-dimethylformamide.

  Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as potassium; alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carboxylates such as sodium acetate and potassium acetate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide Alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkyllithiums such as n-butyllithium and s-butyllithium; lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide and the like It includes alkali metal amides like, preferably potassium or sodium hydride carbonate.

The reaction temperature is about 0 ° C. to 150 ° C., preferably room temperature to 100 ° C.
The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.

The compound [1] obtained by the production method of the present invention may be obtained in an amorphous state or as a crystal by a crystallization method known per se, but is preferably obtained as a crystal.
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.

The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolytic method), a hydrothermal growth method, a flux method, and the like. Examples of the solvent used include aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, etc.), saturated hydrocarbon solvents (eg, hexane, Heptane, cyclohexane, etc.), ether solvents (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole, etc.), nitrile solvents (eg, acetonitrile, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.) ), Sulfoxide solvents (eg, dimethyl sulfoxide, etc.), acid amide solvents (eg, N, N-dimethylformamide, etc.), ester solvents (eg, methyl acetate, ethyl acetate, n-butyl acetate, etc.), alcohols Solvent (eg, methanol, ethanol, 1-propyl Panol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-methyl-1-propanol), organic acid solvents (eg, acetic acid, formic acid, etc.), organic base solvents (eg, pyridine, etc.) ), Water, etc. are used. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
Examples of the “crystallization from the melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). And liquid phase epitaxy method).

Further, the amorphous or crystalline compound [1] can be further purified by the above crystallization method, and for this purpose, the “crystallization method from solution” is preferred.
As the solvent used, the solubility of compound [1] (particularly (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone) From the viewpoint of aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, ether solvent, nitrile solvent, ketone solvent, sulfoxide solvent, acid amide solvent, ester solvent, alcohol solvent, organic acid solvent Solvents and the like are preferable, and ester solvents, ether solvents, alcohol solvents, and ketone solvents are more preferable. Among these, alcohol solvents and ketone solvents are particularly preferable. As the alcohol solvent, 1-propanol and 1-butanol are preferable, and as the ketone solvent, methyl ethyl ketone and methyl isobutyl ketone are preferable.
These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). These solvents and water or saturated hydrocarbon solvents may be used. A mixed solvent may be used.
In addition, the usage-amount of a solvent is 1-100 mL with respect to 1 g of compound [1] from a viewpoint of industrial implementation, Preferably it is 1-50 mL, More preferably, it is 1-30 mL, Most preferably 20-30 mL.

  If the difference between the melting temperature of the compound [1] and the boiling point of the solvent is small, it is difficult to stably dissolve the compound, and there is a possibility that crystals will precipitate during dust removal filtration performed before crystallization. As a result, there is a risk that the workability of the production will deteriorate. Therefore, considering this point, the boiling point of the solvent used and the compound [1] (especially (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) ) -Methanone) is preferably 5 ° C. or higher, more preferably 10 ° C. or higher, and particularly preferably 20 ° C. or higher. Furthermore, since the solvent may remain in the obtained crystal and lead to deterioration in quality, the boiling point of the solvent used is preferably 150 ° C. or lower.

Specific examples of the purification method of the compound [1] by crystallization include the compound [1] (for example, (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazine- 4-yl) -methanone) at a temperature of 90 to 100 ° C. at an appropriate solvent (for example, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, ether solvent, nitrile solvent, ketone solvent, sulfoxide solvent) Solvent, acid amide solvent, ester solvent, alcohol solvent, organic acid solvent, etc., preferably ester solvent, ether solvent, ketone solvent, alcohol solvent, etc., more preferably ketone solvent An alcohol solvent, more preferably methyl isobutyl ketone and 1-butanol, and particularly preferably 1-butanol. A method of cooling the resulting solution to a temperature equal to or lower than the melting temperature (for example, 0 to 90 ° C., preferably 20 to 30 ° C.), a method of using a poor solvent (for example, a saturated hydrocarbon solvent, water, etc.), or the like These combinations are mentioned.
The thus purified crystal of compound [1] can be isolated, for example, by filtration.

In compound [1] obtained by the above production method, coloring due to impurities may be observed. Even when crystals are obtained by the above purification, impurities that cause coloring may not be removed, and coloring may still remain. However, in such a case, by treating the compound [1] with an adsorbent (eg, activated carbon, alumina, activated clay, silica gel, celite, etc., preferably activated carbon), impurities that cause coloring can be removed. . The treatment with the adsorbent may be performed together with the purification step, or may be performed separately before or after the purification step.
As a treatment method using an adsorbent, compound [1] (for example, (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone) is used. Suitable solvent (for example, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, ether solvent, nitrile solvent, ketone solvent, sulfoxide solvent, acid amide solvent, ester solvent, alcohol solvent, organic An acid solvent, preferably an ester solvent, an ether solvent, a ketone solvent, an alcohol solvent, etc., more preferably a ketone solvent, an alcohol solvent, and more preferably methyl isobutyl ketone, 1-butanol, particularly preferably 1-butanol), adsorbent added, room temperature to heated (preferably, 0.5 to 24 hours at 0 to 100 ° C.), preferably for 1 to 10 hours.
Although the usage-amount of an adsorbent is not specifically limited, From a viewpoint which removes an impurity and isolate | separates an adsorbent efficiently, it is 1 to 20 weight% with respect to compound [1], Preferably it is 5 to 15 weight%.

  Next, the compounds used in the present invention will be specifically described with reference examples and reference test examples. However, the compound is not limited by these reference examples and reference test examples. In addition, the room temperature in a reference example means 1-40 degreeC.

Reference example 1
Preparation of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3-chloro-4-methoxybenzoyl chloride Chloroform (20 mL) was added to 3-chloro-4-methoxybenzoic acid (2.0 g), and oxalyl chloride (1.84 mL) and N, N-dimethyl were added under ice cooling. Formamide (1 drop) was added. After stirring at room temperature for 3 hours, the mixture was concentrated and azeotroped with toluene to give the title compound (2.063 g).

Process 2
Preparation of 3,4-dihydro-2H-benzo [1,4] oxazine Synthesis was performed with reference to Australian journal of chemistry, 9, 397-405 (1956). Specifically, lithium aluminum hydride (3 g) was suspended in tetrahydrofuran (120 mL), and 2H-1,4-benzoxazin-3 (4H) -one (6 g) was added little by little under ice cooling. After heating to reflux for 10 hours, water (3 mL), 15% aqueous sodium hydroxide (3 mL), and water (9 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (4.9239 g) as an orange oil.

Process 3
Preparation of (3-Chloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-Dihydro-2H-benzo [1,4] oxazine (525 mg ) Was dissolved in chloroform (10 mL), and triethylamine (0.65 mL) and 3-chloro-4-methoxybenzoyl chloride (836 mg) were added under ice cooling. After stirring at room temperature for 12 hours, the reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (1.180 g) as a white solid.

Process 4
Preparation of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (3-chloro-4-methoxyphenyl)-(2,3-dihydro Benzo [1,4] oxazin-4-yl) -methanone (1.175 g) was dissolved in chloroform (10 mL). Boron tribromide (1.0 M methylene chloride solution, 7.74 mL) was added dropwise at −45 ° C., and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with chloroform. The obtained chloroform layer was washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 65: 35) to give the title compound (124 mg) as white crystals.

Reference example 2
Preparation of (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3-bromo-4-hydroxybenzoyl chloride 1,3-Dimethoxyethane (30 mL) was added to 3-bromo-4-hydroxybenzoic acid (3.25 g), and the mixture was heated to 80 ° C. to dissolve. Thionyl chloride (1.6 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (3.6181 g) as a white solid.

Process 2
Production of (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H obtained in Step 2 of Reference Example 1 -Benzo [1,4] oxazine (203 mg) and 3-bromo-4-hydroxybenzoyl chloride (353 mg) were dissolved in ethyl acetate (4 mL) and stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (236.7 mg) as beige crystals.

Reference example 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-dichloro-4-hydroxybenzoyl chloride 1,5-Dimethoxyethane (30 mL) was added to 3,5-dichloro-4-hydroxybenzoic acid (1.242 g) and heated to 80 ° C. to dissolve. . Thionyl chloride (0.57 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (1.358 g) as a white solid.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (135 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (225 mg) were dissolved in ethyl acetate (3.2 mL), and the mixture was stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (282 mg) as white crystals.

Reference example 4
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-dibromo-4-hydroxybenzoyl chloride 1,3-Dimethoxyethane (20 mL) was added to 3,5-dibromo-4-hydroxybenzoic acid (2.96 g), and the mixture was heated to 80 ° C. to dissolve. . Thionyl chloride (1.1 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (3.1562 g) as a white solid.

Process 2
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (270 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (629 mg) were dissolved in ethyl acetate (10 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (700.9 mg) as pale orange crystals.

Reference Example 5
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone

Process 1
Preparation of 4-hydroxy-3,5-diiodobenzoyl chloride Add 1,2-dimethoxyethane (12 mL) to 4-hydroxy-3,5-diiodobenzoic acid (2.34 g), warm to 80 ° C. and dissolve did. Thionyl chloride (0.66 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (2.4922 g) as a cream solid.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone 3,4-obtained in Step 2 of Reference Example 1 Dihydro-2H-benzo [1,4] oxazine (406 mg) and 4-hydroxy-3,5-diiodobenzoyl chloride (1.26 g) were dissolved in ethyl acetate (15 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (1.2887 g) as pale orange crystals.

Reference Example 6
Preparation of (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3,5-difluoro-4-methoxybenzoyl chloride Chloroform (20 mL) was added to 3,5-difluoro-4-methoxybenzoic acid (2 g), and oxalyl chloride (1.87 mL) and N, N were added under ice cooling. -Dimethylformamide (1 drop) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound as an oil.

Process 2
Preparation of (3,5-difluoro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (300 mg) was dissolved in chloroform (6 mL), and triethylamine (0.371 mL) and 3,5-difluoro-4-methoxybenzoyl chloride (459 mg) were added under ice cooling. . After stirring at room temperature for 12 hours, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (709 mg) as an oil.

Process 3
Preparation of (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (3,5-difluoro-4-methoxyphenyl)-(2 , 3-Dihydrobenzo [1,4] oxazin-4-yl) -methanone (672 mg) was dissolved in methylene chloride (7 mL). After cooling to −78 ° C. and boron tribromide (1.0 M methylene chloride solution, 3.3 mL) was added dropwise, the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into water and extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 3) to give the title compound (258 mg) as white crystals.

Reference Example 7
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone

Process 1
Preparation of 4-benzyloxy-3,5-dimethylbenzoyl chloride To 4-benzyloxy-3,5-dimethylbenzoic acid (256 mg), methylene chloride (8 mL) was added, and oxalyl chloride (0.1 mL) was added under ice cooling. N, N-dimethylformamide (1 drop) was added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (276.7 mg) as a pale yellow solid.

Process 2
Production of (4-benzyloxy-3,5-dimethylphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-obtained in Step 2 of Reference Example 1 Dihydro-2H-benzo [1,4] oxazine (135 mg) was dissolved in methylene chloride (7 mL), and triethylamine (0.17 mL) and 4-benzyloxy-3,5-dimethylbenzoyl chloride (275 mg) were cooled with ice. Was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to give the title compound (378.3 mg) as an oil.

Process 3
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (4-benzyloxy-3,5-dimethylphenyl)-( 2,3-Dihydrobenzo [1,4] oxazin-4-yl) -methanone (370.1 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (37 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (220.1 mg) as white crystals.

Reference Example 8
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone

Process 1
Preparation of ethyl 4-benzyloxy-3,5-dichlorobenzoate Ethyl 3,5-dichloro-4-hydroxybenzoate (55.64 g) was dissolved in N, N-dimethylformamide (280 mL) and potassium carbonate (42 .56 g) was added. Under ice-cooling, benzyl bromide (36 mL) was added dropwise, and the mixture was stirred at 70 ° C. overnight. After the solvent was distilled off, the reaction solution was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was recrystallized from n-hexane to obtain the title compound (32.45 g). The filtrate was concentrated to obtain the title compound (42.19 g).

Process 2
Production of 4-benzyloxy-3,5-dichlorobenzoic acid Ethyl 4-benzyloxy-3,5-dichlorobenzoate (42.19 g) was dissolved in methanol (70 mL) and tetrahydrofuran (140 mL). Under ice cooling, 2N lithium hydroxide water (130 mL) was added dropwise, and the mixture was stirred overnight at room temperature. A small amount of insoluble matter was removed by filtration, the filtrate was concentrated, water was added, and the mixture was acidified with 1N hydrochloric acid dropwise under ice cooling. The precipitated solid was collected by filtration to give the title compound (34.83 g).

Process 3
Preparation of 4-benzyloxy-3,5-dichlorobenzoyl chloride Chloroform (175 mL) was added to 4-benzyloxy-3,5-dichlorobenzoic acid (34.83 g), and oxalyl chloride (15.3 mL) was cooled with ice. And N, N-dimethylformamide (2 drops) were added. After stirring at room temperature for 4 hours, the insoluble material was removed by filtration, and the filtrate was concentrated and azeotroped with toluene to give the title compound (37.371 g) as a pale yellow solid.

Process 4
Production of 3,4-dihydro-2H-benzo [1,4] thiazine Lithium aluminum hydride (1 g) was suspended in tetrahydrofuran (40 mL), and 4H-benzo [1,4] thiazine-3- under ice cooling. On (2 g) was added in small portions. After heating to reflux for 8 hours, water (1 mL), 15% aqueous sodium hydroxide (1 mL), and water (3 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added, dried and concentrated to give the title compound (1.9181 g) as a yellow oil.

Process 5
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone 3,4-Dihydro-2H-benzo [1,4] thiazine (1 g) was dissolved in chloroform (19 mL), and triethylamine (1.1 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (2.08 g) were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (2.3350 g) as an oil.

Step 6
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone (4-Benzyloxy-3,5-dichlorophenyl)-(2 , 3-Dihydrobenzo [1,4] thiazin-4-yl) -methanone (223.7 mg) was dissolved in toluene (2 mL), and trifluoroacetic acid (2 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 1.5 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (101.6 mg) as white crystals.

Reference Example 9
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone

Process 1
Production of (4-Benzyloxy-3,5-dichlorophenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone Process of Reference Example 8 (4-benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone (426 mg) obtained in 5 was dissolved in chloroform (10 mL), Under ice-cooling, 3-chloroperbenzoic acid (171 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 3) to obtain the title compound (398.4 mg) as a white amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1-oxo-2,3-dihydro-1H-1λ ⁴ -benzo [1,4] thiazin-4-yl) -methanone (4-benzyloxy 3,5-dichlorophenyl) - (1-oxo-2,3-dihydro-1H-1 [lambda ⁴ - benzo [1,4] thiazin-4-yl) - dissolved methanone (210.9Mg) in toluene (2 mL) And trifluoroacetic acid (2 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 1.5 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (157.5 mg) as pale-water crystals.

Reference Example 10
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone

Process 1
Production of (4-benzyloxy-3,5-dichlorophenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone Reference Example 8 (4-Benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] thiazin-4-yl) -methanone (496.6 mg) obtained in Step 5 of the above was dissolved in chloroform (15 mL). 3-Chloroperbenzoic acid (597 mg) was added under ice cooling, and the mixture was stirred at room temperature overnight. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to give the title compound (363.9 mg) as a white solid.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (4- Benzyloxy-3,5-dichlorophenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (245 mg) in toluene (2. 5 mL) and trifluoroacetic acid (2.5 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 2 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (112 mg) as white crystals.

Reference Example 11
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione

Process 1
Production of (4-benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Reference Example 1 -H-benzo [1,4] oxazine (0.4 g) was dissolved in chloroform (20 mL), and tribenzylamine (0.5 mL) and 4-benzyloxy- obtained in Step 3 of Reference Example 8 under ice-cooling. 3,5-Dichlorobenzoyl chloride (0.947 g) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to give the title compound (1.0635 g) as a white solid.

Process 2
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione (4-benzyloxy-3,5-dichlorophenyl)-(2 , 3-Dihydrobenzo [1,4] oxazin-4-yl) -methanone (400 mg) and Lawesson's reagent (235 mg) were suspended in tetrahydrofuran (3 mL), and the mixture was heated and stirred at 95 ° C. for 2 hours. The reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (372.4 mg) as an orange amorphous.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanethione (4-benzyloxy-3,5-dichlorophenyl)-(2 , 3-Dihydrobenzo [1,4] oxazin-4-yl) -methanethione (366.8 mg) was dissolved in toluene (4 mL) and trifluoroacetic acid (4 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 2 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (84.6 mg) as orange crystals.

Reference Example 12
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (0.8 g) was suspended in tetrahydrofuran (50 mL), and 6-methyl-4H- was added under ice cooling. Benzo [1,4] oxazin-3-one (1.76 g) was added in small portions. After heating to reflux for 6 hours, water (0.8 mL), 15% aqueous sodium hydroxide (0.8 mL), and water (2.4 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (1.5719 g) as an orange oil.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (298 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (451 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (7 mL) at 95 ° C. Stir overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (606.4 mg) as pale orange crystals.

Reference Example 13
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 7-methyl-4H-benzo [1,4] oxazin-3-one 2-Amino-5-methylphenol (2.463 g) and benzyltriethylammonium chloride (4.56 g) were suspended in chloroform (50 mL). Then, sodium hydrogen carbonate (13.44 g) and chloroacetyl chloride (1.9 mL) were added under ice cooling, and stirring was continued for 1 hour under ice cooling. Thereafter, the mixture was heated and stirred at 55 ° C. overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (1.7636 g) as an ocher solid.

Process 2
Preparation of 7-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (0.8 g) was suspended in tetrahydrofuran (50 mL), and 7-methyl-4H— was cooled with ice. Benzo [1,4] oxazin-3-one (1.76 g) was added in small portions. After heating to reflux for 6 hours, water (0.8 mL), 15% aqueous sodium hydroxide (0.8 mL), and water (2.4 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (1.5038 g) as a red-brown oil.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 7-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (298 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (451 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (7 mL) at 95 ° C. Stir overnight. The reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (609.3 mg) as an amorphous white solid.

Reference Example 14
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-chloro-N- (2-hydroxy-6-methylphenyl) -acetamide 2-Amino-3-methylphenol (737 mg) was dissolved in tetrahydrofuran (20 mL), and triethylamine (1 mL) and chloromethane were cooled with ice. Acetyl chloride (0.5 mL) was added and stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.2217 g) as an ocher solid.

Process 2
Preparation of 5-methyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-6-methylphenyl) -acetamide (1.2217 g) was converted to N, N-dimethylformamide ( 7 mL), and potassium carbonate (0.99 g) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (813.5 mg) as a pale yellow solid.

Process 3
Preparation of 5-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (0.4 g) was suspended in tetrahydrofuran (40 mL), and 5-methyl-4H- was added under ice cooling. Benzo [1,4] oxazin-3-one (810 mg) was added in small portions. After heating to reflux for 7 hours, water (0.4 mL), 15% aqueous sodium hydroxide (0.4 mL), and water (1.2 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (471.7 mg) as a red-brown oil.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 5-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (224 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (338 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (3.5 mL), and 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (331.9 mg) as gray crystals.

Reference Example 15
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 4-bromo-2-methylphenol o-Cresol (5 g) was dissolved in acetic acid (50 mL) and 48% aqueous hydrogen bromide (25 mL), and dimethyl sulfoxide (25 mL) was added dropwise at room temperature. After stirring at room temperature for 1 hour, the reaction solution was neutralized with sodium carbonate. Water was added and extracted with ethyl ether. The obtained ethyl ether layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, it was used in the next step without purification.

Process 2
Preparation of 4-bromo-2-methyl-6-nitrophenol To a mixture of 4-bromo-2-methylphenol and sodium nitrite (10.4 g) prepared in Step 1, n-hexane (75 mL) and isopropyl ether ( 35 mL) and water (50 mL) were added, and 4.5 N sulfuric acid (110 mL) was added dropwise at room temperature. After stirring at room temperature for 15 hours, the reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to obtain the title compound (7.14 g) as a yellow solid.

Process 3
Preparation of 2-amino-6-methylphenol hydrobromide 4-Bromo-2-methyl-6-nitrophenol (7.1 g) was dissolved in methanol (50 mL). 7.5% Palladium-carbon (1.5 g) was added to this solution to form a hydrogen atmosphere (2 kgf / cm ² ), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through celite and then concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (5.40 g) as a brown solid.

Process 4
Preparation of 2-chloro-N- (2-hydroxy-3-methylphenyl) -acetamide 2-Amino-6-methylphenol hydrobromide (408 mg) was suspended in tetrahydrofuran (10 mL) and triethylamine was cooled with ice. (0.7 mL) and chloroacetyl chloride (0.17 mL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (384.6 mg) as a dark brown solid.

Process 5
Preparation of 8-methyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-3-methylphenyl) -acetamide (380 mg) N, N-dimethylformamide (4 mL) And potassium carbonate (315 mg) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (284.3 mg) as a red brown solid.

Step 6
Preparation of 8-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (150 mg) was suspended in tetrahydrofuran (25 mL), and 8-methyl-4H-benzo [ 1,4] Oxazin-3-one (280 mg) was added in small portions. After heating to reflux for 7 hours, water (0.15 mL), 15% aqueous sodium hydroxide (0.15 mL), and water (0.45 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (145.2 mg) as a red-brown oil.

Step 7
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 8-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (116.3 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (176 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (2 mL), At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (121.3 mg) as pale brown crystals.

Reference Example 16
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone

Process 1
Preparation of 2-chloro-N- (2-hydroxynaphthalen-1-yl) -acetamide 1-aminonaphthalen-2-ol hydrochloride (1.1739 g) was suspended in tetrahydrofuran (20 mL) and triethylamine was cooled with ice. (2 mL) and chloroacetyl chloride (0.5 mL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate, and the resulting ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.227 g) as a dark brown solid.

Process 2
Preparation of 1H-naphtho [2,1-b] [1,4] oxazin-2-one 2-Chloro-N- (2-hydroxynaphthalen-1-yl) -acetamide (1.22 g) was converted to N, N- Dissolved in dimethylformamide (10 mL), potassium carbonate (860 mg) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.0553 g) as a dark brown solid.

Process 3
Preparation of 2,3-dihydro-1H-naphtho [2,1-b] [1,4] oxazine Lithium aluminum hydride (400 mg) was suspended in tetrahydrofuran (40 mL), and 1H-naphtho [2] under ice cooling. , 1-b] [1,4] oxazin-2-one (1.055 g) was added in small portions. After heating to reflux for 7 hours, water (0.4 mL), 15% aqueous sodium hydroxide (0.4 mL), and water (1.2 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (361.4 mg) as a dark brown oil.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone 2,3-dihydro-1H- Naphtho [2,1-b] [1,4] oxazine (185 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (225 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (3 mL). And stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (334.5 mg) as gray crystals.

Reference Example 17
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-amino-4-methoxyphenol 4-Methoxy-2-nitrophenol (3.38 g) was dissolved in tetrahydrofuran (100 mL). 7.5% Palladium-carbon (0.34 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (2.8528 g) as a beige solid.

Process 2
Preparation of 6-methoxy-4H-benzo [1,4] oxazin-3-one 2-Amino-4-methoxyphenol (2.85 g) and benzyltriethylammonium chloride (4.56 g) were suspended in chloroform (50 mL). Then, sodium hydrogen carbonate (6.72 g) and chloroacetyl chloride (1.9 mL) were added under ice cooling, and stirring was continued for 1 hour under ice cooling. Thereafter, the mixture was heated and stirred at 55 ° C. overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (1.3884 g) as a pale orange solid. The mother liquor was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (151 mg) as a white solid.

Process 3
Preparation of 6-methoxy-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (700 mg) was suspended in tetrahydrofuran (50 mL), and 6-methoxy-4H-benzo [ 1,4] Oxazin-3-one (1.53 g) was added in small portions. After heating under reflux for 6 hours, water (0.7 mL), 15% aqueous sodium hydroxide (0.7 mL), and water (2.1 mL) were successively added under ice cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (1.3294 g) as a pale yellow solid.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-methoxy-3,4-dihydro-2H -Benzo [1,4] oxazine (600 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (818 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (14 mL) at 95 ° C. Stir overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (1.059 g) as white crystals.

Reference Example 18
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-amino-5-methoxyphenol 5-Methoxy-2-nitrophenol (1.059 g) was dissolved in tetrahydrofuran (30 mL). 7.5% Palladium-carbon (0.1 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (0.9615 g) as a pale orange solid.

Process 2
Preparation of 2-chloro-N- (2-hydroxy-4-methoxyphenyl) -acetamide 2-Amino-5-methoxyphenol (0.96 g) was dissolved in tetrahydrofuran (35 mL), and triethylamine (1. 15 mL) and chloroacetyl chloride (0.58 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound. (1.5106 g) was obtained as a bright yellow solid.

Process 3
Preparation of 7-methoxy-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-4-methoxyphenyl) -acetamide (1.51 g) was converted to N, N-dimethylformamide ( 7 mL), and potassium carbonate (1.04 g) and sodium iodide (catalytic amount) were added at room temperature. After stirring at 80 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with 1N hydrochloric acid and water, subsequently washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (682.6 mg) as a bright yellow solid.

Process 4
Preparation of 7-methoxy-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (300 mg) was suspended in tetrahydrofuran (20 mL), and 7-methoxy-4H-benzo [ 1,4] Oxazin-3-one (680 mg) was added in small portions. After heating to reflux for 6 hours, water (0.3 mL), 15% aqueous sodium hydroxide (0.3 mL), and water (0.9 mL) were sequentially added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to give the title compound (588.1 mg) as a red-brown oil.

Process 5
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 7-methoxy-3,4-dihydro-2H -Benzo [1,4] oxazine (367.6 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (496 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (4 mL), and 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (518.2 mg) as mauve crystals.

Reference Example 19
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Obtained in Step 4 of Reference Example 17 ( 3,5-Dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (500 mg) was dissolved in methylene chloride (10 mL). After cooling to −78 ° C., boron tribromide (1.0 M methylene chloride solution, 2.1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 10: 1) to obtain the title compound (157.6 mg) as a pale water crystal.

Reference Example 20
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone obtained in Step 5 of Reference Example 18 ( 3,5-Dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (504 mg) was dissolved in methylene chloride (10 mL). After cooling to −78 ° C., boron tribromide (1.0 M methylene chloride solution, 4.2 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, and the precipitated solid was collected by filtration. The solid collected by filtration was purified by silica gel chromatography (chloroform-methanol = 30: 1) to obtain the title compound (355.7 mg) as white crystals.

Reference Example 21
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide

Process 1
Preparation of 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide 3-Amino-N, N-diethyl-4-methoxybenzenesulfonamide (5 g) was dissolved in methylene chloride (150 mL). Under ice-cooling, boron tribromide (1.0 M methylene chloride solution, 38.7 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Water (150 mL) was added dropwise to the reaction solution under ice cooling, and the aqueous layer was washed with chloroform. To the obtained aqueous layer, 4N aqueous sodium hydroxide was added under ice cooling to make it weakly acidic. The precipitated solid was collected by filtration to give the title compound (4.0344 g) as a light beige solid.

Process 2
Preparation of 3-amino-4- (tert-butyldimethylsilyloxy) -N, N-diethylbenzenesulfonamide 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide (1.5 g) was converted to N, N- Dissolved in dimethylformamide (8 mL), imidazole (0.61 g) and tert-butylchlorodimethylsilane (1.18 g) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours, poured into water and extracted with ethyl ether. The obtained ethyl ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 1) to give the title compound (2.0654 g) as a white solid.

Process 3
Preparation of 4-benzyloxy-3,5-dichloro-N- (5-diethylsulfamoyl-2-hydroxyphenyl) -benzamide 3-amino-4- (tert-butyldimethylsilyloxy) -N, N-diethylbenzene Sulfonamide (1.5 g) was dissolved in methylene chloride (40 mL), and 4-benzyloxy-3,5-dichlorobenzoyl chloride obtained in Step 3 of Reference Example 8 with pyridine (0.41 mL) under ice-cooling. (1.32 g) was added and stirred at room temperature overnight. After the solvent was distilled off, the residue was dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (2.89 g) was added at room temperature. After stirring with heating at 60 ° C. for 1.5 hours, the mixture was acidified by adding water and a 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration to give the title compound (2.1455 g) as a cream solid.

Process 4
Preparation of 4- (4-benzyloxy-3,5-dichlorobenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide 4-Benzyloxy-3,5-dichloro- N- (5-diethylsulfamoyl-2-hydroxyphenyl) -benzamide (2.136 g) is dissolved in N, N-dimethylformamide (40 mL) and potassium carbonate (1.41 g) and 1,2- Dibromoethane (0.42 mL) was added. After stirring at 70 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 2) to obtain the title compound (1.6181 g) as a white amorphous.

Process 5
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide 4- (4-benzyloxy-3,5- Dichlorobenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (1.6151 g) was dissolved in tetrahydrofuran (70 mL). 7.5% Palladium-carbon (0.16 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl ether to give the title compound (1.2863 g) as white crystals.

Reference Example 22
Production of 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) phenol 3,4-dihydro-2H-benzo [1 obtained in Step 2 of Reference Example 1 , 4] oxazine (246 mg) and 3,5-dichloro-4-hydroxybenzenesulfonyl chloride (475 mg) were dissolved in chloroform (8 mL) and stirred at room temperature overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to give the title compound (146.8 mg) as beige crystals.

Reference Example 23
Preparation of (6-tert-butyl-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone In the same manner as in Reference Example 14, The title compound (539.6 mg) was obtained as white crystals by using 2-amino-4-tert-butylphenol instead of 2-amino-3-methylphenol.

Reference Example 24
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one

Process 1
Preparation of 4- (4-benzyloxy-3,5-dichlorobenzoyl) -4H-benzo [1,4] oxazin-3-one 4H-benzo [1,4] oxazin-3-one (224 mg) was added to tetrahydrofuran (224 mg). 10 mL), and 60% sodium hydride (78 mg) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (473 mg) obtained in Step 3 of Reference Example 8 were sequentially added under ice-cooling and stirring at room temperature. Stir overnight. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (294.3 mg) as a yellow solid.

Process 2
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -4H-benzo [1,4] oxazin-3-one 4- (4-Benzyloxy-3,5-dichlorobenzoyl) -4H-benzo [ 1,4] oxazin-3-one (290 mg) was dissolved in tetrahydrofuran (12 mL). 7.5% Palladium-carbon (29 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (176.8 mg) as yellow crystals.

Reference Example 25
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid amide The same method as in steps 2 to 5 of Reference Example 21 Used 3-amino-4-hydroxybenzenesulfonamide instead of 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide to give the title compound (160.6 mg) as white crystals.

Reference Example 26
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone 1,2,3,4-tetrahydroquinoline (147 mg) in chloroform (6 mL) And triethylamine (0.18 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (347 mg) obtained in Step 3 of Reference Example 8 were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (407.9 mg) as a white amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(3,4 Dihydro-2H-quinolin-1-yl) -methanone (398.7 mg) was dissolved in tetrahydrofuran (12 mL). 7.5% Palladium-carbon (40 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (267.4 mg) as white crystals.

Reference Example 27
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone

Process 1
Preparation of 2,3,4,5-tetrahydro-1H-benzo [b] azepine Lithium aluminum hydride (100 mg) was suspended in tetrahydrofuran (10 mL), and 1,3,4,5-tetrahydrobenzoic acid was cooled with ice. [B] Azepin-2-one (245 mg) was added in small portions. After heating under reflux for 5.5 hours, water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.3 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added, dried and concentrated to give the title compound (301.6 mg) as a yellow oil.

Process 2
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone 2,3,4,5-tetrahydro-1H-benzo [B] Azepine (301 mg) was dissolved in methylene chloride (10 mL), and tribenzylamine (0.25 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride obtained in Step 3 of Reference Example 8 under ice-cooling. (480 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to give the title compound (531.9 mg) as a yellow-green oil.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)- (2,3,4,5-Tetrahydrobenzo [b] azepin-1-yl) -methanone (530 mg) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (53 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound (259.6 mg) as white crystals.

Reference Example 28
Production of (4-amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro- obtained in Step 2 of Reference Example 1 2H-benzo [1,4] oxazine (270 mg), 4-amino-3,5-dichlorobenzoic acid (412 mg) and N, N-dimethylaminopyridine (269 mg) were dissolved in chloroform (8 mL), and ice-cooled. WSC · HCl (422 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to obtain the title compound (412.5 mg) as bright yellow crystals.

Reference Example 29
Preparation of (5-chloro-6-hydroxypyridin-3-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in Step 2 of Reference Example 1 -Dihydro-2H-benzo [1,4] oxazine (270 mg), 5-chloro-6-hydroxynicotinic acid (347 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (12 mL), and the mixture was ice-cooled. WSC · HCl (422 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (chloroform-methanol = 20: 1) to obtain the title compound (295.7 mg) as cream crystals.

Reference Example 30
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone

Process 1
Production of 4-hydroxy-3,5-dinitrobenzoyl chloride 1,4-Dimethoxyethane (5 mL) was added to 4-hydroxy-3,5-dinitrobenzoic acid (1 g), and the mixture was heated to 70 ° C. and dissolved. Thionyl chloride (0.415 mL) was added, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound as a yellow solid.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dinitrophenyl) -methanone 3,4-dihydro compound obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (135 mg) and 4-hydroxy-3,5-dinitrobenzoyl chloride (271 mg) were dissolved in ethyl acetate (4 mL) and heated to reflux for 3 hours. The solvent was distilled off, and the obtained solid was crystallized from methanol to give the title compound (211 mg) as pale yellow crystals.

Reference Example 31
Preparation of (3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of methyl 3-chloro-4-methoxy-5-nitrobenzoate Concentrated sulfuric acid (200 mL) was added to methyl 3-chloro-4-methoxybenzoate (24.6 g) under ice-cooling, followed by fuming. A mixture of nitric acid (10.3 mL) and concentrated sulfuric acid (20 mL) was added dropwise under ice cooling. After stirring under ice cooling, the reaction solution was poured into ice water (1 L). The precipitated solid was collected by filtration to give the title compound (28.8 g) as a cream solid.

Process 2
Preparation of 3-chloro-4-hydroxy-5-nitrobenzoic acid Methyl 3-chloro-4-methoxy-5-nitrobenzoate (28.8 g) was suspended in dimethyl sulfoxide (130 mL) and under ice cooling, 50% aqueous potassium hydroxide (130 mL) was added. After stirring with heating at 80 ° C. for 1.5 hours, the mixture was ice-cooled, and 6N hydrochloric acid (200 mL) and water were added. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from n-hexane to obtain the title compound (21.3 g) as a lemon-colored solid.

Process 3
Preparation of 3-chloro-4-hydroxy-5-nitrobenzoyl chloride 1,2-Dimethoxyethane (5 mL) was added to 3-chloro-4-hydroxy-5-nitrobenzoic acid (1 g) and heated to 70 ° C. Dissolved. Thionyl chloride (0.436 mL) was added, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried to give the title compound (1.10 g) as a yellow solid.

Process 4
Preparation of (3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in step 2 of Reference Example 1 -Dihydro-2H-benzo [1,4] oxazine (270 mg) and 3-chloro-4-hydroxy-5-nitrobenzoyl chloride (519 mg) were dissolved in ethyl acetate (6 mL) and stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (537 mg) as yellow crystals.

Reference Example 32
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 4-bromo-2-isopropylphenol 2-Isopropylphenol (25 g) was dissolved in acetic acid (250 mL) and 48% aqueous hydrogen bromide (125 mL), and dimethyl sulfoxide (125 mL) was added dropwise at room temperature. After stirring at room temperature for 2 hours, sodium carbonate (257 g) was added to the reaction solution to neutralize it. Water was added and extracted with ethyl ether. The obtained ethyl ether layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (40.2 g) as a pale yellow solid.

Process 2
Preparation of 4-bromo-2-isopropyl-6-nitrophenol To a mixture of 4-bromo-2-isopropylphenol (40.2 g) and sodium nitrite (41.5 g) prepared in Step 1, n-hexane (300 mL) ), Isopropyl ether (130 mL) and water (200 mL) were added, and 4.5N sulfuric acid (430 mL) was added dropwise at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 20: 1) to obtain the title compound (41.1 g) as a yellow oil.

Process 3
Preparation of 2-amino-6-isopropylphenol hydrobromide 4-Bromo-2-isopropyl-6-nitrophenol (41.1 g) was dissolved in methanol (300 mL). 7.5% Palladium-carbon (8 g) was added to this solution to form a hydrogen atmosphere (2 kgf / cm ² ), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting solid was crystallized from ethyl acetate to give the title compound (27.4 g) as a beige solid.

Process 4
Preparation of 2-bromo-3-methylbutyryl chloride Chloroform (200 mL) was added to 2-bromo-3-methylbutyric acid (25 g), and oxalyl chloride (14.5 mL) and N, N-dimethylformamide ( 3 drops) was added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound as a yellow oil.

Process 5
Preparation of 2-bromo-N- (2-hydroxy-3-isopropylphenyl) -3-methylbutyramide 2-amino-6-isopropylphenol hydrobromide obtained in Step 3 (6.14 g) was mixed with acetic acid. Ethyl (70 mL) and water (80 mL) were added and dissolved, and then sodium bicarbonate (6.68 g) and 2-bromo-3-methylbutyryl chloride (5.80 g) obtained in Step 4 were added at room temperature. Stir at room temperature for 2 hours. The reaction mixture was separated, and the obtained ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (9.0 g ) Was obtained as a pale pink solid.

Step 6
Preparation of 2,8-diisopropyl-4H-benzo [1,4] oxazin-3-one 2-Bromo-N- (2-hydroxy-3-isopropylphenyl) -3-methylbutyramide (9.0 g) , N-dimethylformamide (45 mL), potassium carbonate (4.94 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid, water was added, and the precipitated solid was collected by filtration. The obtained solid was crystallized from n-hexane-isopropyl ether to give the title compound (4.5 g) as a white solid.

Step 7
Preparation of 2,8-diisopropyl-3,4-dihydro-2H-benzo [1,4] oxazine 2,8-diisopropyl-4H-benzo [1,4] oxazin-3-one (1.0 g) was added to tetrahydrofuran (1.0 g). 10 mL), added borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 5.14 mL), and heated to reflux for 14.5 hours. 6N hydrochloric acid (5 mL) was added, and the mixture was heated and stirred again. The mixture was allowed to cool to room temperature, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (768 mg) as a colorless oil.

Process 8
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 2,8-diisopropyl-3,4 -Dihydro-2H-benzo [1,4] oxazine (150 mg) was dissolved in chloroform (5 mL), and 4-benzyloxy- obtained in Step 3 of Reference Example 8 with pyridine (0.066 mL) under ice-cooling. 3,5-Dichlorobenzoyl chloride (227 mg) was added. After stirring overnight at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to obtain the title compound (375 mg) as an oil.

Step 9
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (4-benzyloxy-3,5 -Dichlorophenyl)-(2,8-diisopropyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (370 mg) was dissolved in tetrahydrofuran (5 mL). 7.5% Palladium-carbon (70 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from n-hexane to give the title compound (212 mg) as white crystals.

Reference Example 33
Preparation of (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone

Process 1
Production of 4-methoxy-3-nitrobenzenesulfonyl chloride 1-Methoxy-2-nitrobenzene (11 mL) was added dropwise to chlorosulfonic acid (25 mL) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water and extracted with ethyl ether. The resulting ethyl ether layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (15.527 g) as a reddish brown oil. Obtained as a thing.

Process 2
Preparation of 1- (4-methoxy-3-nitrobenzenesulfonyl) pyrrolidine 4-Methoxy-3-nitrobenzenesulfonyl chloride (5.1353 g) was dissolved in pyridine (17 mL), and pyrrolidine (2.05 g) was added under ice cooling. And stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was poured into water, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1) to obtain the title compound (4.158 g) as a yellow solid.

Process 3
Preparation of 2-nitro-4- (pyrrolidine-1-sulfonyl) phenol 1- (4-Methoxy-3-nitrobenzenesulfonyl) pyrrolidine (2.054 g) was dissolved in dimethyl sulfoxide (40 mL), and the mixture was ice-cooled. 50% aqueous potassium hydroxide (40 mL) was added. After stirring with heating at 80 ° C. for 6 hours, the mixture was cooled with ice and 6N hydrochloric acid (80 mL) was added. The mixture was extracted with chloroform, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (2.198 g) as a yellow solid.

Process 4
Preparation of 2-amino-4- (pyrrolidine-1-sulfonyl) phenol 2-Nitro-4- (pyrrolidine-1-sulfonyl) phenol (2.19 g) was dissolved in tetrahydrofuran (50 mL). 7.5% Palladium-carbon (0.2 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1) to obtain the title compound (1.5494 g) as a cream solid.

Process 5
Preparation of 2- (tert-butyldimethylsilyloxy) -5- (pyrrolidine-1-sulfonyl) phenylamine 2-amino-4- (pyrrolidine-1-sulfonyl) phenol (1.54 g) was converted to N, N-dimethylformamide. (9 mL) was dissolved, and imidazole (0.649 g) and tert-butylchlorodimethylsilane (1.254 g) were added under ice cooling. The mixture was stirred at room temperature for 1.5 hours, poured into water and extracted with ethyl ether. The obtained ethyl ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 1) to give the title compound (2.1549 g) as a white solid.

Step 6
Preparation of 4-benzyloxy-3,5-dichloro-N- [2-hydroxy-5- (pyrrolidine-1-sulfonyl) phenyl] benzamide 2- (tert-butyldimethylsilyloxy) -5- (pyrrolidine-1- (Sulfonyl) phenylamine (727.8 mg) was dissolved in methylene chloride (17 mL), and 4-benzyloxy-3,5-dichloro obtained in Step 3 of Reference Example 8 with pyridine (0.2 mL) under ice-cooling. Benzoyl chloride (644 mg) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N, N-dimethylformamide (4 mL), and potassium carbonate (1.41 g) was added at room temperature. After stirring with heating at 60 ° C. for 1.5 hours, the mixture was acidified by adding water and a 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration to give the title compound (1.0619 g) as a cream solid.

Step 7
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone 4-Benzyloxy- 3,5-Dichloro-N- [2-hydroxy-5- (pyrrolidine-1-sulfonyl) phenyl] benzamide (500 mg) was dissolved in N, N-dimethylformamide (5 mL) and potassium carbonate (332 mg) was dissolved at room temperature. 1,2-Dibromoethane (0.099 mL) was added. After stirring at 70 ° C. overnight, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to obtain the title compound (459.5 mg) as a white amorphous.

Process 8
Preparation of (3,5-dichloro-4-hydroxyphenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone (4-benzyloxy -3,5-dichlorophenyl)-[6- (pyrrolidin-1-sulfonyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone (442.5 mg) dissolved in tetrahydrofuran (20 mL) did. 7.5% Palladium-carbon (45 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1) to obtain the title compound (384.5 mg) as an amorphous white solid.

Reference Example 34
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid ethylamide Method similar to steps 2 to 8 of Reference Example 33 Gave the title compound (341.8 mg) as an amorphous white solid using ethylamine instead of pyrrolidine.

Reference Example 35
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid dimethylamide Similar to steps 2 to 8 of Reference Example 33 The method gave the title compound (379.2 mg) as an amorphous white solid using dimethylamine instead of pyrrolidine.

Reference Example 36
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine Lithium aluminum hydride (2 g) was suspended in tetrahydrofuran (80 mL), and 4H-pyrido [3 , 2-b] [1,4] oxazin-3-one (3.956 g) was added in small portions. After heating under reflux for 2 hours, water (2 mL), 15% aqueous sodium hydroxide (2 mL) and water (6 mL) were successively added under ice-cooling, and the mixture was stirred at room temperature. Anhydrous sodium sulfate was added and dried. The solvent was distilled off, and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 9) to obtain the title compound (3.407 g) as a white solid.

Process 2
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone 3,4-Dihydro-2H-pyrido [3,2-b] [1,4] oxazine (272 mg) was dissolved in chloroform (15 mL), and tribenzylamine (0.335 mL) and 4-benzyloxy obtained in Step 3 of Reference Example 8 under ice-cooling. −3,5-Dichlorobenzoyl chloride (662 mg) was added. After stirring at room temperature for 12 hours, the reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (646 mg) as a white solid.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (4-Benzyloxy-3,5 -Dichlorophenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (415 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (40 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate-tetrahydrofuran to give the title compound (266 mg) as white crystals.

Reference Example 37
Preparation of 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one

Process 1
Preparation of 1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one Polyphosphoric acid (1.5 g) with acrylic acid (8.6 g) and benzene-1,2-diamine (5 .4g) was added and heated to reflux for 3 hours. Water (100 mL), chloroform (200 mL) and N, N-dimethylformamide (50 mL) were added to the reaction solution, and the mixture was extracted with chloroform. The obtained chloroform layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 4) to obtain the title compound (490 mg).

Process 2
Preparation of 5- (3,5-dichloro-4-hydroxybenzoyl) -1,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-2-one 1,3,4,5-tetrahydrobenzo [B] [1,4] diazepin-2-one (194.4 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (177.99 mg) obtained in Step 1 of Reference Example 3 were mixed with ethyl acetate (3 mL). And heated and stirred at 95 ° C. for 12 hours. The reaction mixture was purified by silica gel chromatography to give the title compound (118 mg) as white crystals.

Reference Example 38
Preparation of (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3,5-dichloro-2-hydroxybenzoyl chloride 3,5-Dichloro-2-hydroxybenzoic acid (600 mg) was suspended in toluene (6 mL), thionyl chloride (0.275 mL) and N, N-dimethyl. Formamide (1 drop) was added. After stirring with heating at 70 ° C. for 2 hr, the mixture was concentrated and azeotroped with toluene to give the title compound as a pale yellow solid.

Process 2
Preparation of (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (391.7 mg) and 3,5-dichloro-2-hydroxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL) and heated at 90 ° C. for 1 hour. Stir. Ethyl acetate (6 mL) was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 85: 15) to obtain the title compound (457 mg) as pale yellow crystals.

Reference Example 39
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone

Process 1
Preparation of 4-hydroxy-3-trifluoromethylbenzoyl chloride 4-hydroxy-3-trifluoromethylbenzoic acid (610 mg) was suspended in toluene (6 mL), thionyl chloride (0.28 mL) and N, N-dimethyl. Formamide (1 drop) was added. After stirring with heating at 70 ° C. for 2 hours, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone 3,4-dihydro compound obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (400 mg) and 4-hydroxy-3-trifluoromethylbenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL), and the mixture was heated and stirred at 90 ° C for 1 hour. . Ethyl acetate was added to the reaction mixture, which was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (359 mg) as crystals.

Reference Example 40
Preparation of (3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 3-chloro-4-hydroxy-5-methoxybenzoyl chloride 3-Chloro-4-hydroxy-5-methoxybenzoic acid (598 mg) was suspended in toluene (6 mL), thionyl chloride (0.28 mL) and N , N-dimethylformamide (1 drop) was added. After stirring with heating at 70 ° C. for 2 hours, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 2
Preparation of (3-Chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in Step 2 of Reference Example 1 -Dihydro-2H-benzo [1,4] oxazine (400 mg) and 3-chloro-4-hydroxy-5-methoxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL), and 1 at 90 ° C. Stir for hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (428 mg) as crystals.

Reference Example 41
Preparation of (4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 4-chloro-3-hydroxybenzoyl chloride 4-Chloro-3-hydroxybenzoic acid (510 mg) was suspended in toluene (6 mL), thionyl chloride (0.28 mL) and N, N-dimethylformamide (1 drop). ) Was added. After stirring with heating at 70 ° C. for 2 hours, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 2
Production of (4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H obtained in Step 2 of Reference Example 1 -Benzo [1,4] oxazine (400 mg) and 4-chloro-3-hydroxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL), and the mixture was heated and stirred at 90 ° C for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained solid was crystallized from ethyl acetate to give the title compound (583 mg) as crystals.

Reference Example 42
Preparation of (2,6-dichloropyridin-4-yl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro obtained in Step 2 of Reference Example 1 -2H-benzo [1,4] oxazine (270 mg), 2,6-dichloroisonicotinic acid (384 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (12 mL), and WSC · HCl was cooled under ice cooling. (422 mg) was added. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (419.8 mg) as pale yellow crystals.

Reference Example 43
Production of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-nitrophenyl) -methanone 3,4-dihydro-2H-benzo [1 obtained in Step 2 of Reference Example 1 , 4] oxazine (135 mg) and 4-nitrobenzoyl chloride (185 mg) were dissolved in ethyl acetate (3 mL), and the mixture was heated and stirred at 95 ° C. overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (288.1 mg) as a yellow solid.

Reference Example 44
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6-fluoro-3,4-dihydro-2H-benzo [1,4] oxazine 6-fluoro-4H-benzo [1,4] oxazin-3-one (1.5 g) was dissolved in tetrahydrofuran (20 mL). Borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 11 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. 6N hydrochloric acid (5 mL) was added, and the mixture was heated with stirring at 70 ° C. The mixture was allowed to cool to room temperature, made weak alkaline by adding 4N aqueous sodium hydroxide and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (954 mg) as an oil.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-fluoro-3,4-dihydro-2H -Benzo [1,4] oxazine (230 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (338 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (3.5 mL), and 95 ° C. At rt overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (374.9 mg) as pale beige crystals.

Reference Example 45
Production of 2- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid 3,4-dihydro-2H-benzo [1,4] oxazine obtained in Step 2 of Reference Example 1 ( 300 mg) and phthalic anhydride (329 mg) were dissolved in toluene (3 mL) and heated to reflux for 4 hours. The reaction mixture was allowed to cool, and the precipitated solid was collected by filtration to give the title compound (519 mg) as crystals.

Reference Example 46
Production of methyl 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate 3,4-dihydro-2H-benzo [1,4] oxazine obtained in Step 2 of Reference Example 1 (154 mg) was dissolved in chloroform (6 mL), and triethylamine (0.18 mL) and methyl 4-chlorocarbonylbenzoate (226 mg) were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 2) to give the title compound (287.4 mg) as a pale orange solid.

Reference Example 47
Preparation of 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl obtained in Reference Example 46 ) Methyl benzoate (283 mg) was dissolved in methanol (10 mL) and tetrahydrofuran (5 mL), and 4N aqueous lithium hydroxide (1.5 mL) was added. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid under ice cooling. The precipitated solid was collected by filtration to give the title compound (207.6 mg) as a white solid.

Reference Example 48
Preparation of methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate

Process 1
Production of methyl 3-chlorocarbonylbenzoate Chloroform (5 mL) was added to isophthalic acid monomethyl ester (198 mg), and oxalyl chloride (0.12 mL) and N, N-dimethylformamide (1 drop) were added under ice cooling. After stirring at room temperature for 7 hours, it was concentrated and azeotroped with toluene to give the title compound.

Process 2
Production of methyl 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoate 3,4-dihydro-2H-benzo [1,4] oxazine obtained in Step 2 of Reference Example 1 (154 mg) was dissolved in chloroform (6 mL), and triethylamine (0.18 mL) and methyl 3-chlorocarbonylbenzoate obtained in the previous step were added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (323.7 mg) as a white solid.

Reference Example 49
Production of 3- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) benzoic acid 3- (2,3-dihydrobenzo [1,4] oxazine-obtained in Step 2 of Reference Example 48 Methyl 4-carbonyl) benzoate (293 mg) was dissolved in methanol (10 mL) and tetrahydrofuran (5 mL), and 4N aqueous lithium hydroxide (1.5 mL) was added. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was purified by silica gel chromatography (chloroform-methanol = 10: 1) to obtain the title compound (71.8 mg) as an amorphous white solid.

Reference Example 50
Preparation of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Production of 3,5-dichloro-2,4-dihydroxybenzoic acid 2,4-Dihydroxybenzoic acid (25.0 g) was dissolved in ethyl acetate (400 mL), and hypochlorous acid tert-butyl ester ( 61.9 g) was added dropwise and stirred for 2 hours. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl ether-n-hexane to give the title compound (11.88 g) as a solid.

Process 2
Preparation of 3,5-dichloro-2,4-dihydroxybenzoyl chloride 3,5-Dichloro-2,4-dihydroxybenzoic acid (605 mg) was suspended in toluene (6 mL), thionyl chloride (0.25 mL) and N , N-dimethylformamide (1 drop) was added. After heating at reflux for 1 hour, the mixture was concentrated and azeotroped with toluene to give the title compound.

Process 3
Preparation of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4 obtained in Step 2 of Reference Example 1 -Dihydro-2H-benzo [1,4] oxazine (366 mg) and 3,5-dichloro-2,4-dihydroxybenzoyl chloride obtained in the previous step were dissolved in ethyl acetate (6 mL) and heated to reflux for 1 hour. . The reaction solution was washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was crystallized from ethyl acetate to give the title compound (171 mg) as crystals.

Reference Example 51
Preparation of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone

Process 1
Preparation of 2-chloro-N- (5-chloro-2-hydroxyphenyl) -acetamide 2-Amino-4-chlorophenol (1.0061 g) was dissolved in ethyl acetate (10 mL) and water (10 mL) was cooled with ice. ) And sodium hydrogen carbonate (1.185 g) were added, followed by dropwise addition of chloroacetyl chloride (0.67 mL). After stirring at room temperature for 2.5 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (1.5455 g) as a yellow solid.

Process 2
Preparation of 6-chloro-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (5-chloro-2-hydroxyphenyl) -acetamide (1.54 g) was converted to N, N-dimethylformamide ( 15 mL) and potassium carbonate (1.26 g) was added at room temperature. After stirring at room temperature overnight, 1N hydrochloric acid (12 mL) was added under ice cooling, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (1.281 g) as a pale yellow solid.

Process 3
Preparation of 6-chloro-3,4-dihydro-2H-benzo [1,4] oxazine 6-Chloro-4H-benzo [1,4] oxazin-3-one (764 mg) was dissolved in tetrahydrofuran (8 mL), Borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 6.2 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. After stirring with heating at 70 ° C. for 1 hour, methanol (3 mL) was added dropwise at the same temperature, and the mixture was further stirred with heating for 1 hour. Next, 1N hydrochloric acid (6.2 mL) was added dropwise with heating to 70 ° C., and the mixture was further stirred with heating for 0.5 hours, and then allowed to cool to room temperature. The mixture was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to obtain the title compound (640.1 mg) as a solid.

Process 4
Preparation of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone 6-chloro-3,4-dihydro-2H -Dissolve benzo [1,4] oxazine (168.4 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (242.7 mg) obtained in Step 1 of Reference Example 3 in ethyl acetate (3 mL); Heated to reflux overnight. The solvent was distilled off, and the obtained solid was crystallized from methanol to give the title compound (318.4 mg) as white crystals.

Reference Example 52
Production of (7-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone Similar to steps 1 to 4 in Reference Example 51 By the method, 2-amino-5-chlorophenol was used instead of 2-amino-4-chlorophenol to obtain the title compound (749.3 mg) as white crystals.

Reference Example 53
Preparation of [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone , 3,4-Tetrahydroquinoxaline (68.1 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (250.5 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (5 mL) overnight. Heated to reflux. The solvent was distilled off, and the resulting solid was crystallized from methanol to give the title compound (122.0 mg) as light gray crystals.

Reference Example 54
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone 1,2,3,4-Tetrahydroquinoxaline (805.3 mg) was dissolved in ethyl acetate (30 mL), and triethylamine (1.0 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (1.88988 g) obtained in Step 3 of Reference Example 8 were added under ice-cooling. And stirred overnight. Methanol was added to the reaction solution and then concentrated. The obtained solid was crystallized from ethyl acetate-water to give the title compound (2.042 g) as a pale-yellow solid.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(3,4 Dihydro-2H-quinoxalin-1-yl) -methanone (287.7 mg) was dissolved in tetrahydrofuran (6 mL). 7.5% Palladium-carbon (26 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained solid was crystallized from methanol to give the title compound (194.1 mg) as pale-yellow crystals.

Reference Example 55
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester

Process 1
Preparation of methyl 4-hydroxy-3-nitrobenzoate Methanol (50 mL) and concentrated sulfuric acid (0.5 mL) were added to 4-hydroxy-3-nitrobenzoic acid (5.20022 g), and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off, and the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. 1N Hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (5.3436 g) as a yellow solid.

Process 2
Preparation of methyl 3-amino-4-hydroxybenzoate Methyl 4-hydroxy-3-nitrobenzoate (5.3436 g) was dissolved in tetrahydrofuran (27 mL) and methanol (27 mL). 7.5% Palladium-carbon (276.6 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (4.6803 g) as a solid.

Process 3
Preparation of 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester Methyl 3-amino-4-hydroxybenzoate (4.6803 g) and benzyltriethylammonium chloride (6 1787 g) was suspended in chloroform (50 mL), sodium bicarbonate (9.10 g) and chloroacetyl chloride (2.6 mL) were added under ice cooling, and stirring was continued for 1 hour under ice cooling. Then, it heated and stirred at 70 degreeC. The reaction mixture was concentrated, water and ethyl acetate were added, and the precipitated solid was collected by filtration. The mother liquor was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue and the previously collected solid were combined and crystallized from methanol to give the title compound (4.80805 g) as a solid.

Process 4
Preparation of 3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester 3-Oxo-3,4-dihydro in borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 11 mL) under ice-cooling -2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (1.009 g) was added, and the mixture was heated and stirred at 70 ° C for 3.5 hours. Methanol (3 mL) was added dropwise, and the mixture was further stirred with heating for 3 hours. The reaction solution was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 98: 2) to give the title compound (281.3 mg) as a pink solid and (3,4-dihydro- 2H-benzo [1,4] oxazin-6-yl) methanol (413.8 mg) was obtained.

Process 5
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester 3,4-Dihydro-2H-benzo [1 , 4] Oxazine-6-carboxylic acid methyl ester (81.2 mg) was dissolved in ethyl acetate (3 mL), and 3,5-dichloro-4-hydroxy obtained in Step 1 of Reference Example 3 under ice-cooling. Benzoyl chloride (108.3 mg) was added, and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (167.8 mg) as an amorphous white solid.

Reference Example 56
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6- (tert-butyldimethylsilyloxymethyl) -3,4-dihydro-2H-benzo [1,4] oxazine (3,4-dihydro-2H-benzo [3] obtained in Step 4 of Reference Example 55 1,4] oxazin-6-yl) methanol (406.1 mg) was dissolved in N, N-dimethylformamide (4 mL), and under ice cooling, imidazole (203.8 mg) and tert-butylchlorodimethylsilane (443. 4 mg) was added. After stirring at room temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to give the title compound (659.0 mg) as a pale yellow oil.

Process 2
Preparation of [6- (tert-butyldimethylsilyloxymethyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone 6- ( tert-Butyldimethylsilyloxymethyl) -3,4-dihydro-2H-benzo [1,4] oxazine (279.1 mg) was dissolved in ethyl acetate (3 mL), and triethylamine (0.167 mL) was cooled with ice. And 3,5-dichloro-4-hydroxybenzoyl chloride (249.4 mg) obtained in Step 1 of Reference Example 3 was added, and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (131.7 mg) as a pale yellow solid.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone [6- (tert-butyldimethylsilyloxy Methyl) -2,3-dihydrobenzo [1,4] oxazin-4-yl]-(3,5-dichloro-4-hydroxyphenyl) -methanone (131.7 mg) was dissolved in tetrahydrofuran (1.5 mL). Under ice-cooling, 1M tetrabutylammonium fluoride / tetrahydrofuran solution (0.34 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 97: 3) to obtain the title compound (50.0 mg) as crystals.

Reference Example 57
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid 4- (obtained in Step 5 of Reference Example 55 3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid methyl ester (140.8 mg), methanol (1.5 mL) and tetrahydrofuran ( 1.5N) and 2N aqueous sodium hydroxide (0.55 mL) was added. After stirring overnight at room temperature, the solvent was distilled off, and the mixture was acidified with 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was crystallized from methanol to give the title compound (81.3 mg) as crystals.

Reference Example 58
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-5-carboxylic acid methyl ester Similar to steps 1 to 5 of Reference Example 55 The method used 3-hydroxy-2-nitrobenzoic acid in place of 4-hydroxy-3-nitrobenzoic acid to give the title compound (246.0 mg) as an amorphous white solid.

Reference Example 59
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester Similar to steps 1 to 5 of Reference Example 55 By the method, 3-hydroxy-4-nitrobenzoic acid was used instead of 4-hydroxy-3-nitrobenzoic acid to obtain the title compound (317.9 mg) as white crystals.

Reference Example 60
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid 4- (3,5 obtained in Reference Example 59 -Dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-7-carboxylic acid methyl ester (257.4 mg), methanol (2.5 mL) and tetrahydrofuran (2.5 mL) 2N aqueous sodium hydroxide (1.0 mL) was added. After stirring with heating at 60 ° C. for 2.5 hours, the solvent was distilled off, and the mixture was acidified with 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was crystallized from methanol to give the title compound (76.6 mg) as crystals.

Reference Example 61
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester Similar to steps 1 to 5 in Reference Example 55 By the method, 2-hydroxy-3-nitrobenzoic acid was used instead of 4-hydroxy-3-nitrobenzoic acid to obtain the title compound (313.8 mg) as white crystals.

Reference Example 62
Preparation of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid 4- (3,5 obtained in Reference Example 61 -Dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid methyl ester (244.2 mg), methanol (2.5 mL) and tetrahydrofuran (2.5 mL) And 2N aqueous sodium hydroxide (0.96 mL) was added. After stirring overnight at room temperature, the solvent was distilled off, and the mixture was acidified with 10% aqueous citric acid solution under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was crystallized from ethyl acetate to give the title compound (186.6 mg) as crystals.

Reference Example 63
Production of (3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H-benzo [obtained in Step 2 of Reference Example 1 1,4] oxazine (250.1 mg) and 3,5-dichlorobenzoyl chloride (426.9 mg) were dissolved in ethyl acetate (5 mL), and the mixture was heated and stirred at 80 ° C. overnight. The solvent was distilled off, and the obtained residue was crystallized from methanol to give the title compound (469.6 mg) as pale beige crystals.

Reference Example 64
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(phenoxazin-10-yl) -methanone 3,5-Dichloro-4 obtained in Step 1 of Reference Example 3 with phenoxazine (276.1 mg) -Hydroxybenzoyl chloride (370.8 mg) was dissolved in ethyl acetate (3 mL), and the mixture was heated and stirred at 80 ° C. overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (397.6 mg) as a yellow green solid.

Reference Example 65
Production of (3,5-dichloro-4-hydroxyphenyl)-(6-phenyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Similar to steps 2 to 5 of Reference Example 21 By the method, 2-amino-4-phenylphenol was used instead of 3-amino-N, N-diethyl-4-hydroxybenzenesulfonamide to obtain the title compound (160.0 mg) as white crystals.

Reference Example 66
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Steps 1 to 4 of Reference Example 51 and By the same method, 2-amino-4,6-dimethylphenol was used instead of 2-amino-4-chlorophenol to give the title compound (152.7 mg) as crystals.

Reference Example 67
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 6-nitro-4H-benzo [1,4] oxazin-3-one 2-Amino-4-nitrophenol (4.6283 g) and benzyltriethylammonium chloride (6.8877 g) were suspended in chloroform (46 mL). Sodium bicarbonate (10.10 g) and chloroacetyl chloride (4.0707 g) were added under ice-cooling, and stirring was continued for 1 hour under ice-cooling. Then, it heated and stirred at 70 degreeC. The reaction mixture was concentrated, water and ethyl acetate were added, and the precipitated solid was collected by filtration. The mother liquor was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue and the previously collected solid were combined and crystallized from ethanol to give the title compound (5.4344 g) as a solid.

Process 2
Preparation of 6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine Boron-tetrahydrofuran complex (1M tetrahydrofuran solution, 33.5 mL) was cooled to 6-nitro-4H-benzo [1, 4] Oxazin-3-one (3.00084 g) was added, and the mixture was heated with stirring at 70 ° C for 5 hours. Methanol (5 mL) was added dropwise, and the mixture was further stirred with heating for 2.5 hours. Concentrated hydrochloric acid (5 mL) was added dropwise, and the mixture was further stirred with heating for 1.5 hr. The reaction solution was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (2.2092 g) as a solid.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-nitro-3,4-dihydro-2H -Benzo [1,4] oxazine (376.1 mg) was dissolved in ethyl acetate (3 mL), and 3,5-dichloro-4-hydroxybenzoyl chloride (Step 1 of Reference Example 3) was obtained under ice cooling ( 270.7 mg) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (538.0 mg) as pale yellow crystals.

Reference Example 68
Preparation of (6-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone Obtained in Step 3 of Reference Example 67 ( 3,5-Dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (200.0 mg) was dissolved in tetrahydrofuran (12 mL). 7.5% Palladium-carbon (19.4 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to give the title compound (6.4 mg) as crystals.

Reference Example 69
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6 obtained in Step 2 of Reference Example 67 -Nitro-3,4-dihydro-2H-benzo [1,4] oxazine (179.8 mg) was dissolved in ethyl acetate (5 mL) and obtained in Step 1 of Reference Example 4 under ice-cooling. 5-Dibromo-4-hydroxybenzoyl chloride (346.6 mg) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (437.0 mg) as yellow crystals.

Reference Example 70
Production of (3,5-dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone Similar to steps 1 to 3 in Reference Example 67 By the method, 2-amino-5-nitrophenol was used instead of 2-amino-4-nitrophenol to give the title compound (485.2 mg) as yellow crystals.

Reference Example 71
Preparation of (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone obtained in Reference Example 70 (3,5 -Dichloro-4-hydroxyphenyl)-(7-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (303.1 mg) dissolved in tetrahydrofuran (6 mL) and methanol (3 mL) did. 7.5% Palladium-carbon (30 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was crystallized from ethanol to give the title compound (257.9 mg) as yellow crystals.

Reference Example 72
Preparation of N- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazin-7-yl] -methanesulfonamide obtained in Reference Example 71 (7-amino-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (251.7 mg) in methylene chloride (5 mL) Suspension was performed, and pyridine (0.0776 mL) and methanesulfonyl chloride (0.0689 mL) were added under ice cooling, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (173.6 mg) as an amorphous light orange solid.

Reference Example 73
Preparation of 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone

Process 1
Preparation of 1- [4- (4-benzyloxy-3,5-dichlorobenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone Obtained in Step 1 of Reference Example 54 (4- Benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (400 mg) was suspended in methylene chloride (8 mL) and triethylamine (0. 162 mL) and acetyl chloride (0.082 mL) were added and stirred at room temperature overnight. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to obtain the title compound (295.9 mg) as a pale yellow amorphous.

Process 2
Preparation of 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone 1- [4- (4-Benzyloxy-3,5 -Dichlorobenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (288.6 mg) was dissolved in tetrahydrofuran (6 mL). 7.5% Palladium-carbon (27.7 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 97: 3) and crystallized from n-hexane-ethyl acetate to give the title compound (108.1 mg) as white crystals.

Reference Example 74
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyl) obtained in Step 1 of Reference Example 54 Oxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (401.6 mg) was dissolved in N, N-dimethylformamide (8 mL) and potassium carbonate (335. 7 mg) and iodomethane (0.076 mL) were added, and the mixture was heated and stirred at 50 ° C. Poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to give the title compound (114.7 mg) as amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-( 4-Methyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (114.7 mg) was dissolved in tetrahydrofuran (5 mL). 7.5% Palladium-carbon (10.0 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (56.3 mg) as pale-yellow crystals.

Reference Example 75
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone

Process 1
Production of 4-hydroxy-3-nitrobenzoyl chloride 1,4-Dimethoxyethane (20 mL) was added to 4-hydroxy-3-nitrobenzoic acid (1.83 g), and the mixture was heated to 80 ° C. to dissolve. Thionyl chloride (1.1 mL) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (2.0551 g) as a yellow oil.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-nitrophenyl) -methanone 3,4-dihydro-2H obtained in Step 2 of Reference Example 1 -Benzo [1,4] oxazine (203 mg) and 4-hydroxy-3-nitrobenzoyl chloride (302 mg) were dissolved in ethyl acetate (2 mL) and heated to reflux overnight. The reaction solution was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (460.7 mg) as an amorphous yellow solid.

Reference Example 76
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone 2-methyl-2,3-dihydro-1H-indole (139.3 mg ) In methylene chloride (2.5 mL), pyridine (0.1 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (396.6 mg) obtained in Step 3 of Reference Example 8 were added, Stir at room temperature overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 6: 1) to obtain the title compound (449.4 mg) as a yellow oil.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(2-methyl -2,3-Dihydroindol-1-yl) -methanone (437.1 mg) was dissolved in toluene (4 mL), and trifluoroacetic acid (2.5 mL) was added at room temperature. The mixture was stirred at 80 ° C. and concentrated. The obtained solid was crystallized from n-hexane-ethyl acetate to give the title compound (300.3 mg) as white crystals.

Reference Example 77
Production of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone According to the same method as in steps 1 and 2 of Reference Example 76, Substituting 2,3-dihydro-1H-indole for dihydro-1H-indole, the title compound (230.6 mg) was obtained as white crystals.

Reference Example 78
Preparation of (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(5-nitro-2,3-dihydroindol-1-yl) -methanone 5-nitro-2,3-dihydro-1H-indole (329.5 mg ) Is dissolved in methylene chloride (5 mL), and pyridine (0.194 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (762.1 mg) obtained in Step 3 of Reference Example 8 are added thereto at room temperature. Stir overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) to obtain the title compound (539.7 mg) as a yellow solid.

Process 2
Preparation of (5-amino-2,3-dihydroindol-1-yl)-(4-benzyloxy-3,5-dichlorophenyl) -methanone (4-benzyloxy-3,5-dichlorophenyl)-(5-nitro -2,3-Dihydroindol-1-yl) -methanone (539.7 mg) was dissolved in tetrahydrofuran (10 mL). Platinum (IV) oxide (14 mg) was added to this solution, and the mixture was placed in a hydrogen atmosphere, and then stirred overnight at room temperature. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. Water was added and the mixture was extracted with chloroform. The resulting chloroform layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the mixture of the title compound and (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (489.5 mg) was yellow. Obtained as amorphous.

Process 3
Preparation of (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (5-amino-2,3-dihydroindol-1-yl)- A mixture of (4-benzyloxy-3,5-dichlorophenyl) -methanone and (5-amino-2,3-dihydroindol-1-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (489) 0.5 mg) was dissolved in toluene (5 mL), and trifluoroacetic acid (2.75 mL) was added at room temperature. The mixture was heated and stirred at 80 ° C. for 2.5 hours and then concentrated. The obtained solid was crystallized from ethyl acetate to give the title compound (282.4 mg) as pale gray crystals.

Reference Example 79
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6 obtained in Step 1 of Reference Example 44 -Fluoro-3,4-dihydro-2H-benzo [1,4] oxazine (230 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (472 mg) obtained in Step 1 of Reference Example 4 were mixed with ethyl acetate ( 3.5 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (533.7 mg) as white crystals.

Reference Example 80
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone Obtained in Step 3 of Reference Example 16. 2,3-dihydro-1H-naphtho [2,1-b] [1,4] oxazine (140.9 mg) obtained and 3,5-dibromo-4-hydroxybenzoyl obtained in Step 1 of Reference Example 4 Chloride (239 mg) was dissolved in ethyl acetate (2.3 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (298.8 mg) as dark blue crystals.

Reference Example 81
Preparation of (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6 obtained in Step 1 of Reference Example 12 -Methyl-3,4-dihydro-2H-benzo [1,4] oxazine (149 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (314 mg) obtained in Step 1 of Reference Example 4 were mixed with ethyl acetate ( 3.5 mL) and stirred at 95 ° C. overnight. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (368.2 mg) as beige crystals.

Reference Example 82
Preparation of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone 6 obtained in Step 3 of Reference Example 51 -Chloro-3,4-dihydro-2H-benzo [1,4] oxazine (170.6 mg) and 3,5-dibromo-4-hydroxybenzoyl chloride (349.3 mg) obtained in Step 1 of Reference Example 4 Was dissolved in ethyl acetate (5 mL) and heated to reflux overnight. The solvent was distilled off, and the obtained solid was crystallized from methanol to give the title compound (441.0 mg) as crystals.

Reference Example 83
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone

Process 1
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone obtained in Step 1 of Reference Example 54 (4- Benzyloxy-3,5-dichlorophenyl)-(3,4-dihydro-2H-quinoxalin-1-yl) -methanone (399.7 mg) was dissolved in methylene chloride (8 mL), and triethylamine (0 .162 mL) and methanesulfonyl chloride (0.094 mL) were added and stirred overnight at room temperature. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 98: 2) to obtain the title compound (451.5 mg) as a pale yellow amorphous.

Process 2
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl)- (4-Methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl) -methanone (451.5 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (43.1 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (335.9 mg) as an amorphous light yellow solid.

Reference Example 84
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-chloro-N- (5-ethanesulfonyl-2-hydroxyphenyl) acetamide 2-Amino-4-ethanesulfonylphenol (1.5063 g) was dissolved in ethyl acetate (15 mL), and water ( 15 mL) and sodium hydrogen carbonate (1.2588 g) were added, and then chloroacetyl chloride (0.715 mL) was added dropwise. After stirring at room temperature for 5 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.9375 g) as a brown solid.

Process 2
Preparation of 6-ethanesulfonyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (5-ethanesulfonyl-2-hydroxyphenyl) acetamide (1.9375 g) was converted to N, N-dimethylformamide. (20 mL) and potassium carbonate (1.2520 g) was added at room temperature. After stirring at room temperature overnight, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting solid was crystallized from methanol to give the title compound (1.3358 g) as a solid.

Process 3
Preparation of 6-ethanesulfonyl-3,4-dihydro-2H-benzo [1,4] oxazine 6-ethanesulfonyl-4H-benzo [1,4] oxazin-3-one (802.3 mg) in tetrahydrofuran (4 mL) Borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 7 mL) was added under ice cooling. After stirring with heating at 70 ° C. for 9 hours, methanol (5 mL) was added dropwise at the same temperature, and the mixture was further stirred with heating for 1 hour. Next, 1N hydrochloric acid (5 mL) was added dropwise with heating to 70 ° C., and the mixture was further stirred with heating for 1 hour, and then allowed to cool to room temperature. The mixture was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (748.7 mg) as an orange oil.

Process 4
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-ethanesulfonyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-ethanesulfonyl-3,4-dihydro -H-benzo [1,4] oxazine (233.5 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (255.4 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (5 mL). And heated to reflux overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (446.9 mg) as an amorphous white solid.

Reference Example 85
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-amino-4-trifluoromethylphenol 2-Nitro-4-trifluoromethylphenol (3.0951 g) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (299.8 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure to give the title compound (2.6346 g) as a gray solid.

Process 2
Preparation of 2-chloro-N- (2-hydroxy-5-trifluoromethylphenyl) acetamide 2-Amino-4-trifluoromethylphenol (1.0075 g) was dissolved in ethyl acetate (10 mL), and the mixture was cooled with ice. Water (10 mL) and sodium bicarbonate (0.9531 g) were added, and chloroacetyl chloride (0.55 mL) was added dropwise. After stirring overnight at room temperature, the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.4341 g) as a light brown solid.

Process 3
Preparation of 6-trifluoromethyl-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-5-trifluoromethylphenyl) acetamide (1.4244 g) was converted to N, N- Dissolved in dimethylformamide (14 mL) and potassium carbonate (1.00072 g) was added at room temperature. After stirring at room temperature for 2 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (1.2084 g) as a light gray solid.

Process 4
Preparation of 6-trifluoromethyl-3,4-dihydro-2H-benzo [1,4] oxazine 6-trifluoromethyl-4H-benzo [1,4] oxazin-3-one (810.8 mg) was added to tetrahydrofuran (810.8 mg). 4 mL), and borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 7.4 mL) was added under ice cooling. After stirring with heating at 70 ° C. for 6 hours, methanol (5 mL) was added dropwise at the same temperature, and the mixture was further stirred with heating for 1 hour. Next, 1N hydrochloric acid (5 mL) was added dropwise while heating to 70 ° C., and the mixture was further stirred with heating for 30 minutes, and then allowed to cool to room temperature. The mixture was extracted with ethyl acetate, and the resulting ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 99: 1) to obtain the title compound (718.3 mg) as a white solid.

Process 5
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 6-trifluoromethyl-3,4 -Dihydro-2H-benzo [1,4] oxazine (205.3 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (252.5 mg) obtained in Step 1 of Reference Example 3 were mixed with ethyl acetate (5 mL). And heated to reflux overnight. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (chloroform-methanol = 95: 5) to obtain the title compound (286.5 mg) as white crystals.

Reference Example 86
Preparation of (3,5-dichloro-4-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone obtained in Step 2 of Reference Example 3 (3,5- Dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (100 mg) was dissolved in acetone (5 mL), and potassium carbonate (47 mg) and iodomethane (0. 096 mL) was added, and the mixture was heated and stirred at 45 ° C. overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (109.2 mg) as a white solid.

Reference Example 87
Preparation of acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (3,5-dichloro-4-l) obtained in Step 2 of Reference Example 3 Hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (100 mg) was dissolved in chloroform (5 mL), and triethylamine (0.064 mL) and acetyl chloride were cooled with ice. (0.026 mL) was added and stirred at room temperature overnight. The reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 5: 1) to give the title compound (123.1 mg) as white crystals.

Reference Example 88
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone

Process 1
Production of (4-benzyloxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3,4-dihydro-2H-benzo [obtained in Step 2 of Reference Example 1 1,4] oxazine (270 mg), 4-benzyloxybenzoic acid (457 mg) and 4-dimethylaminopyridine (269 mg) were dissolved in chloroform (7 mL), and WSC · HCl (422 mg) was added under ice cooling. After stirring at room temperature overnight, the reaction mixture was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (636.2 mg) as an orange oil.

Process 2
Preparation of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxyphenyl) -methanone (4-benzyloxyphenyl)-(2,3-dihydrobenzo [1,4] oxazine -4-yl) -methanone (630 mg) was dissolved in tetrahydrofuran (20 mL). 7.5% Palladium-carbon (70 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was filtered through celite, the residue was washed with tetrahydrofuran, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (149.1 mg) as white crystals.

Reference Example 89
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-chloro-N- (2,6-dihydroxyphenyl) -acetamide 2-Aminobenzene-1,3-diol hydrochloride (2.00 g) was dissolved in ethyl acetate (20 mL) and water (20 mL) was added. After adding sodium hydrogen carbonate (2.50 g), chloroacetyl chloride (1.02 mL) was added dropwise under ice cooling. After stirring at room temperature for 12 hours, the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 65: 35) to obtain the title compound (1.508 g) as a pale orange solid.

Process 2
Preparation of 5-hydroxy-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2,6-dihydroxyphenyl) -acetamide (1.274 g) was converted to N, N-dimethylformamide (10 mL). And potassium carbonate (873 mg) was added at room temperature. After stirring at room temperature for 2.5 hours, water (30 mL) was added. After stirring for 0.5 hour under ice-cooling, the precipitated solid was collected by filtration to give the title compound (915 mg) as a pale orange solid.

Process 3
Preparation of 5-benzyloxy-4H-benzo [1,4] oxazin-3-one 5-hydroxy-4H-benzo [1,4] oxazin-3-one (200 mg) was added to N, N-dimethylformamide (2 mL). And potassium carbonate (167 mg) and benzyl bromide (158 mL) were added at room temperature. The mixture was stirred at room temperature for 3 hours and further heated and stirred at 60 ° C. for 1 hour, and then water was added. The precipitated solid was collected by filtration to give the title compound (283 mg) as a pale yellow solid.

Process 4
Preparation of 5-benzyloxy-3,4-dihydro-2H-benzo [1,4] oxazine Lithium aluminum hydride (50 mg) was suspended in tetrahydrofuran (2 mL), and 5-benzyloxy-4H— was cooled with ice. Benzo [1,4] oxazin-3-one (276 mg) was added in small portions. Stir at room temperature for 1 hour, then heat and stir at 60 ° C. for 1 hour, and then add water (0.05 mL), 15% aqueous sodium hydroxide (0.05 mL), and water (0.15 mL) sequentially under ice cooling. And stirred at room temperature. Anhydrous sodium sulfate was added for drying, followed by concentration. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (54 mg) as an oil.

Process 5
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(5-benzyloxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 5-benzyloxy-3,4-dihydro -H-benzo [1,4] oxazine (47 mg) was dissolved in chloroform (2 mL), and tribenzylamine (0.0716 mL) and 4-benzyloxy-3,5-dichlorobenzoyl obtained in Step 3 of Reference Example 8 were used. Chloride (689.3 mg) was added. After stirring at room temperature for 25 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 85: 15) to give the title compound (54.7 mg) as a white solid.

Step 6
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(5-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl )-(5-Benzyloxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (52 mg) was dissolved in tetrahydrofuran (2 mL). 7.5% Palladium-carbon (10 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the resulting solid was crystallized from ethyl ether to give the title compound (14.8 mg) as a pale yellow solid.

Reference Example 90
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 2-methoxy-6-nitrophenol 1,2-Dimethoxyethane (100 mL) was added to 2-methoxyphenol (6.21 g) and cooled to -50 ° C. Nitronium tetrafluoroborate (6.77 g) was added, and the mixture was stirred at -50 ° C. After completion of the reaction, the reaction solution was poured into ice water, and ethyl acetate and ethyl ether were added. The insoluble material was removed by filtration, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1-3: 1) to give the title compound (2.46 g) as a yellow solid.

Process 2
Preparation of 2-amino-6-methoxyphenol hydrochloride 2-Methoxy-6-nitrophenol (2.46 g) was dissolved in tetrahydrofuran (20 mL). 7.5% Palladium-carbon (400 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. Under ice cooling, 4N hydrogen chloride-ethyl acetate (10 mL) was added dropwise and stirred for 30 minutes. The precipitated solid was collected by filtration to give the title compound (2.41 g) as a white solid.

Process 3
Preparation of 2-chloro-N- (2-hydroxy-3-methoxyphenyl) -acetamide 2-Amino-6-methoxyphenol hydrochloride (2.40 g) was dissolved in ethyl acetate (25 mL) and water was added under ice cooling. (30 mL) and sodium bicarbonate (2.76 g) were added, and chloroacetyl chloride (1.2 mL) was added dropwise. After stirring at room temperature for 0.5 hour, the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (2.95 g) as a pale orange solid.

Process 4
Preparation of 8-methoxy-4H-benzo [1,4] oxazin-3-one 2-Chloro-N- (2-hydroxy-3-methoxyphenyl) -acetamide (2.95 g) was prepared from N, N-dimethylformamide (2.95 g). 20 mL) and potassium carbonate (2.46 g) was added under ice cooling. After stirring at room temperature for 4 hours, water was added. After stirring at room temperature for 0.5 hour, the precipitated solid was collected by filtration to give the title compound (2.06 g) as a pink solid.

Process 5
Preparation of 8-hydroxy-4H-benzo [1,4] oxazin-3-one 8-Methoxy-4H-benzo [1,4] oxazin-3-one (950 mg) was dissolved in methylene chloride (90 mL). After cooling to −78 ° C. and boron tribromide (1.0 M methylene chloride solution, 13.3 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound (864 mg) as an ocher solid.

Step 6
Preparation of 8- (tert-butyldimethylsilyloxy) -4H-benzo [1,4] oxazin-3-one 8-hydroxy-4H-benzo [1,4] oxazin-3-one (900 mg) was converted to N, N -Dissolved in dimethylformamide (10 mL), imidazole (482 mg) and tert-butylchlorodimethylsilane (986 mg) were added. After stirring at room temperature for 1 hour, water and a 10% aqueous citric acid solution were added. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 7: 3) to give the title compound (1.41 g) as a white solid.

Step 7
Preparation of 8- (tert-butyldimethylsilyloxy) -3,4-dihydro-2H-benzo [1,4] oxazine 8- (tert-butyldimethylsilyloxy) -4H-benzo [1,4] oxazine-3 -On (700 mg) was dissolved in tetrahydrofuran (5 mL), borane-tetrahydrofuran complex (1M tetrahydrofuran solution, 3.76 mL) was added, and the mixture was heated to reflux for 2.5 hours. The mixture was allowed to cool to room temperature, made weak alkaline by adding water and saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (675 mg) as an oil.

Process 8
Preparation of (4-Benzyloxy-3,5-dichlorophenyl)-[8- (tert-butyldimethylsilyloxy) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone 8- (tert -Butyldimethylsilyloxy) -3,4-dihydro-2H-benzo [1,4] oxazine (792 mg) dissolved in chloroform (10 mL) and obtained in Step 3 of Reference Example 8 with pyridine (0.242 mL). 4-Benzyloxy-3,5-dichlorobenzoyl chloride (792 mg) was added. After stirring at room temperature for 1 hour, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 8: 1) to give the title compound (1.28 g) as a white solid.

Step 9
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(8-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (4-benzyloxy-3,5-dichlorophenyl )-[8- (tert-Butyldimethylsilyloxy) -2,3-dihydrobenzo [1,4] oxazin-4-yl] -methanone (545 mg) was dissolved in toluene (2 mL) and trifluoroacetic acid at room temperature. (4 mL) was added. The mixture was heated and stirred at 85 ° C. for 7.5 hours, and then concentrated. The obtained residue was dissolved in tetrahydrofuran and treated with activated carbon. The solvent was evaporated, the residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 1: 1), and crystallized from ethyl ether to obtain the title compound (220 mg) as a yellow solid.

Reference Example 91
Preparation of [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester obtained in Reference Example 3 (3,5-dichloro-4- Hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (1.0067 g) was dissolved in N, N-dimethylformamide (10 mL) and potassium carbonate (0. 6553 g) and ethyl bromoacetate (0.52 mL) were added. After heating and stirring overnight at 70 ° C., ethyl acetate (20 mL) and 10% aqueous citric acid solution (20 mL) were added under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to give the title compound (1.2891 g) as a pale yellow oil.

Reference Example 92
Preparation of [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid [2,6-dichloro-4- (2 , 3-Dihydrobenzo [1,4] oxazine-4-carbonyl) phenoxy] acetic acid ethyl ester (1.2753 g) in methanol (6.5 mL), 2N aqueous sodium hydroxide (3.1 mL) was added, Stir at room temperature for 0.5 hour. Water was added to the reaction solution, washed with ethyl ether, and acidified with 10% aqueous citric acid solution. After extraction with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from methanol to give the title compound (156.4 mg) as white crystals.

Reference Example 93
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone

Process 1
Preparation of 1- (2-nitrophenoxy) -propan-2-one 2-Nitrophenol (2.78 g) was dissolved in N, N-dimethylformamide (20 mL) and potassium carbonate (3.34 g) and bromo at room temperature. Acetone (1.85 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (3.2101 g) as a bright yellow solid.

Process 2
Preparation of 3-methyl-3,4-dihydro-2H-benzo [1,4] oxazine 1- (2-Nitrophenoxy) propan-2-one (501.1 mg) was dissolved in tetrahydrofuran (10 mL). 7.5% Palladium-carbon (49.1 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 3: 1) to obtain the title compound (248.1 mg) as a yellow oil.

Process 3
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(3-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone 3-methyl-3,4-dihydro-2H -Benzo [1,4] oxazine (244.9 mg) and 3,5-dichloro-4-hydroxybenzoyl chloride (370.1 mg) obtained in Step 1 of Reference Example 3 were dissolved in ethyl acetate (7 mL). And stirred at 80 ° C. for 3 hours. Ethyl acetate (15 mL) and water (20 mL) were added to the reaction mixture and the layers were separated, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained solid was crystallized from methanol to give the title compound (320.2 mg) as white crystals.

Reference Example 94
Preparation of N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide

Process 1
Preparation of N-methanesulfonyl-N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide obtained in Reference Example 28 (4 -Amino-3,5-dichlorophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (323 mg) dissolved in N, N-dimethylformamide (5 mL) and 60% hydrogen Sodium chloride (52 mg) was added, and the mixture was stirred at room temperature for 0.5 hr, methanesulfonyl chloride (0.0851 mL) was added, and the mixture was stirred at room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 4: 1) and crystallized from isopropyl ether to give the title compound (78 mg) as a white solid.

Process 2
Preparation of N- [2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide N-methanesulfonyl-N- [2,6-dichloro- 4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl] methanesulfonamide (73 mg) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.168 mL) was dissolved. ) And stirred at room temperature overnight. A 10% aqueous citric acid solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl acetate to give the title compound (48 mg) as a white solid.

Reference Example 95
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone

Process 1
Preparation of tert-butyldimethyl [3- (2-nitrophenoxy) propoxy] silane 2-Nitrophenol (3 g) was dissolved in N, N-dimethylformamide (20 mL) and sodium hydride (1.04 g) was cooled under ice cooling. The mixture was stirred at room temperature for 0.5 hour, and then (3-bromopropoxy) -tert-butyldimethylsilane (5.49 mL) was added under ice cooling, followed by heating and stirring at 90 ° C. overnight. Furthermore, potassium carbonate (1 g) and (3-bromopropoxy) -tert-butyldimethylsilane (2.5 mL) were added, and the mixture was heated and stirred at 90 ° C. for 1.5 hours. A 10% aqueous citric acid solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (6.71 g) as a yellow oil.

Process 2
Preparation of 2- [3- (tert-butyldimethylsilyloxy) propoxy] phenylamine Tert-butyldimethyl [3- (2-nitrophenoxy) propoxy] silane (6.71 g) was dissolved in tetrahydrofuran (50 mL). 7.5% Palladium-carbon (1 g) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to obtain the title compound (5.88 g) as a pale orange oil.

Process 3
Preparation of 4-benzyloxy-N- {2- [3- (tert-butyldimethylsilyloxy) propoxy] phenyl} -3,5-dichlorobenzamide 2- [3- (tert-butyldimethylsilyloxy) propoxy] phenyl Amine (844 mg) was dissolved in chloroform (10 mL), and pyridine (0.314 mL) and 4-benzyloxy-3,5-dichlorobenzoyl chloride (947 mg) obtained in Step 3 of Reference Example 8 were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (1.63 g) as a pale yellow oil. Obtained as a thing.

Process 4
Preparation of 4-benzyloxy-3,5-dichloro-N- [2- (3-hydroxypropoxy) phenyl] benzamide 4-benzyloxy-N- {2- [3- (tert-butyldimethylsilyloxy) propoxy] Phenyl} -3,5-dichlorobenzamide (1.62 g) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 4.33 mL) was added, and the mixture was stirred at room temperature for 1 hr. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from isopropyl ether to give the title compound (1.19 g) as a white solid.

Process 5
Preparation of 4-benzyloxy-3,5-dichloro-N- [2- (3-chloropropoxy) phenyl] benzamide 4-benzyloxy-3,5-dichloro-N- [2- (3-hydroxypropoxy) phenyl Benzamide (1.00 g) was dissolved in pyridine (10 mL), methanesulfonyl chloride (0.225 mL) was added, and the mixture was stirred with heating at 70 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (713 mg) as a beige solid.

Step 6
Preparation of (4-benzyloxy-3,5-dichlorophenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone 4-benzyloxy-3,5 -Dichloro-N- [2- (3-chloropropoxy) phenyl] benzamide (200 mg) was dissolved in N, N-dimethylformamide (3 mL) and 60% sodium hydride (21 mg) and sodium iodide (64 mg) were dissolved. In addition, the mixture was heated and stirred at 60 ° C. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 9: 1) to give the title compound (121 mg) as an oil.

Step 7
Preparation of (3,5-dichloro-4-hydroxyphenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone (4-benzyloxy-3, 5-Dichlorophenyl)-(7,8-dihydro-6H-5-oxa-9-azabenzocyclohepten-9-yl) -methanone (115 mg) was dissolved in tetrahydrofuran (5 mL). 7.5% Palladium-carbon (15 mg) was added to this solution to form a hydrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The solvent was distilled off, and the resulting residue was crystallized from isopropyl ether to give the title compound (69 mg) as a white solid.

¹ H-NMR spectral data of the compounds of Reference Examples ^{1 to} 95 are shown in Tables 1 to 18.
¹ H-NMR spectrum was measured in CDCl ₃ or DMSO-d ₆ using tetramethylsilane as an internal standard, and all δ values were shown in ppm.
The symbols in the table have the following meanings.
s: singlet
d: doublet
t: triplet
dd: double doublet (double doublet)
ddd: double double doublet (double double doublet)
brs: broad singlet
m: multiplet
J: Coupling constant

The powder X-ray diffraction patterns of the crystals of compound [1] are shown in FIGS. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity (cps).
Tables 19 to 22 show diffraction angles (2θ) of diffraction peaks characteristic of each crystal from the powder X-ray diffraction pattern.
A crystal sample of the compound [1] is filled in an aluminum cell, and an X-ray powder diffractometer (RINT2100 Ultima +, manufactured by Rigaku Corporation) is used. X-ray source: Cu-Kα1 line, applied voltage: 40 kV, applied current: 40 mA, The powder X-ray diffraction pattern of each crystal of the present invention was measured at a scanning speed of 5 ° per minute, a scanning width of 0.02 °, and a scanning range of 5 ° to 40 °. Since there is a diffraction peak due to the aluminum cell in the vicinity of 38.20 ° to 38.40 °, the diffraction peak in the vicinity is not listed as a diffraction peak characteristic of each crystal.

  In general, the diffraction angle (2θ) and peak intensity (cps) of the powder X-ray diffraction pattern may vary depending on the measuring instrument, measurement conditions, and the like. The crystal in the present specification may be a crystal having a value different from the diffraction angle (2θ) and the peak intensity of the diffraction pattern of the powder X-ray described in the present specification as long as it is within a normal error range.

  If the compound [1] is in the form of crystals, it has excellent physical and chemical stability, and therefore has the advantage that the quality can be maintained over a long period of time and the storage becomes easy. In addition, there is an advantage that various pharmaceutical compositions and drug substances can be handled easily during production, and the production cost can be reduced. Therefore, the compound [1] crystal is extremely useful as a medicine.

Reference Test Example 1 Urate transport inhibition test using human URAT1-expressing cells Human URAT1 full-length cDNA was subcloned into the expression vector pcDNA3.1, and the human URAT1 gene was transferred to human fetal kidney-derived cells (HEK293) by the liposomal method using Lipofectamine 2000. Cells). At the same time, HEK293 cells (hereinafter referred to as mock cells) transfected with only the expression vector pcDNA3.1 were also prepared. HEK293 cells or mock cells expressing the human URAT1 gene were selected using geneticin resistance as an index. It was also confirmed that the human URAT1 gene was functionally expressed in the same manner as described below, using as an index the transport of uric acid labeled with ¹⁴ C into cells.

Human URAT1-expressing HEK293 cells or mock cells in Dulbecco's modified Eagle MEM medium (high glucose) containing 10% fetal bovine serum, 0.5 mg / mL geneticin sulfate, 100 units / mL penicillin and 100 μg / mL streptomycin The cells were cultured in an incubator under conditions of 37 ° C. and 5% carbon dioxide gas. Cells were seeded in 96 well plate (poly-D-Lysine coated) at 1 × 10 ⁵ cells / well, and the following uric acid transport inhibition test was performed 24 hours later. The test was conducted under room temperature conditions.

After removing the medium from each well by suction, the cells were washed once with Hank's Balanced Salt Solution (HBSS) and preincubated for 5 minutes in 100 μL / well of HBSS. After aspirating and removing HBSS, an assay buffer (in which NaCl in HBSS was replaced with Na-gluconate) containing reference compounds of various concentrations and a radioligand ( ¹⁴ C-labeled uric acid; final concentration of 50 μM) was added. The addition reaction was performed at 50 μL / well and the uptake reaction was performed for 5 minutes. Immediately after completion of the reaction, the mixture was washed twice with 150 μL / well of ice-cooled HBSS, and Microcinti ™ 20 (PerkinElmer) was added at 50 μL / well. After the cells were lysed by stirring, the radioactivity of each well was measured with a liquid scintillation counter (TOP COUNT, Packard).

Radioactivity showing URAT1-specific uric acid transport (difference in radioactivity between human URAT1-expressing HEK293 cells and mock cells in the absence of reference example compound (DMSO addition)) as 100%, and the uric acid transport rate at each concentration of reference example compound (%) Was calculated, and the concentration of the reference example compound (IC ₅₀ ) at which the uric acid transport rate was inhibited by 50% was determined. The results are shown in Tables 23-24. In Table 23 to Table 24, "+++" indicates that _{an IC 50} value of less than 100nM, "++" the _{IC 50} value of 100nM or less than 1000nM, "+" the _{IC 50} value less than 1000nM to 3000 nM.

Reference Test Example 2 CYP Inhibition Test Using Human Liver Microsomes Human Liver Microsomes (Purchased from Xenotech LLC, Lenexa KS) 20 mg protein / mL 5 μL is suspended in 100 mM potassium phosphate buffer (pH 7.4) 70 μL, and further in DMSO. 0.5 μL of the dissolved reference compound solution was mixed and preincubated at 37 ° C. for 5 minutes. NADPH generating coenzyme solution (β-nicotinamide adenine phosphate: 5.2 mM, D-glucose-6-phosphate: 13.2 mM, magnesium chloride: 13.2 mM, glucose-6-phosphate dehydrogenase: 1.8 U / mL) 25 μL and model substrate dissolved in DMSO (CYP3A4: midazolam 1 mM, CYP2D6: bufuralol 1 mM, CYP2C9: diclofenac 2 mM) 0.5 μL were added to start the reaction. ) Containing 200 μL of acetonitrile, followed by centrifugation (room temperature 3000 rpm, 20 minutes). The amount of metabolite produced from each model substrate in the supernatant was measured using high performance liquid chromatography / mass spectrometry (LC / MS / MS) to determine each CYP enzyme activity. The concentration (IC50) showing 50% inhibition rate was calculated with the enzyme activity at the time of no reference example compound addition (0.5 μL addition of DMSO) as 100%. The results are shown in Tables 25 to 27.

  As is clear from the above Reference Test Example 1 (uric acid transport inhibition test using human URAT1-expressing cells), Compound [1] has an excellent URAT1 activity inhibitory action. Further, as is clear from Reference Test Example 2 (CYP inhibition test), Compound [1] has no or very low CYP inhibitory action.

  For this reason, the compound [1] has an effect of strongly suppressing reabsorption of uric acid, and further, since it does not substantially inhibit CYP, the risk of side effects is very low. It is shown that.

  Therefore, the pharmaceutical composition of the present invention containing compound [1] inhibits URAT1 activity, thereby inhibiting reabsorption of uric acid and lowering blood uric acid level, thereby causing hyperuricemia, gout It is a therapeutic or prophylactic agent for pathological conditions involving uric acid such as nodules, acute gouty arthritis, chronic gouty arthritis, gouty kidneys, urolithiasis, renal dysfunction, coronary artery disease, ischemic heart disease and the like.

  Furthermore, as the causative diseases, complications or highly likely complications of the above-mentioned conditions involving uric acid, for example, gout arthritis, gout kidney, urolithiasis, hypertension or hypertension complications, hyperlipidemia or Hyperlipidemia complications, diabetes or diabetic complications, obesity or obesity complications, secondary uric acid excretion secondary hyperuricemia, renal failure caused by hyperuricemia, cardiovascular disorder, cerebrovascular disorder, etc. There is. Combining the therapeutic or preventive agent for these diseases including hyperuricemia with the pharmaceutical composition of the present invention containing a pharmaceutically effective amount of the compound [1] is effective for treating or preventing these diseases. is there. Further, it is effective to use the pharmaceutical composition of the present invention containing a pharmaceutically effective amount of the compound [1] in combination with a drug that increases blood uric acid level in order to suppress the increase in blood uric acid level. .

  Next, the present invention will be specifically described with reference to the following reference examples, examples and test examples. However, the present invention is not limited to these reference examples, examples, and test examples. In producing the pharmaceutical composition, the mixing order and mixing conditions of the additives can be appropriately changed. It may be done in an order that seems reasonable. When the content of compound [1] per tablet is changed, the weight of each additive can be changed according to the weight of compound [1].

Reference example A
100.0 g of hydroxypropylmethylcellulose 2910 (6 mm ² / s) (TC-5 RW, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (2400.0 g) to prepare a binder solution having a concentration of 4 w / w%. .
Reference example B
100.0 g of hydroxypropylmethylcellulose 2910 (6 mm ² / s) (TC-5 RW, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1566.7 g) to prepare a binder solution having a concentration of 6 w / w%. .

Reference example C
125.0 g of hydroxypropylmethylcellulose 2910 / titanium oxide / macrogol 400 mixture (OPADRY OY-7300, manufactured by Colorcon) was dissolved in 875.0 g of purified water, and a coating solution having a solid content concentration of 12.5 w / w% was obtained. Prepared.

Reference example D
36.0 g of hydroxypropyl methylcellulose 2910 (6 mm ² / s) (TC-5 RW, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (564.0 g) to prepare a binder solution having a concentration of 6 w / w%. .

Reference example E
20.0 g of hydroxypropylmethylcellulose 2910 (6 mm ² / s) (TC-5 RW, manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (313.3 g) to prepare a binder solution having a concentration of 6 w / w%. .

Reference example F
125.0 g of hydroxypropylmethylcellulose 2910 / titanium oxide / macrogol 400 mixture (OPADRY OY-7300, manufactured by Colorcon) was dissolved in 875.0 g of purified water, and a coating solution having a solid content concentration of 12.5 w / w% was obtained. Prepared.

Example 1 (1 mg tablet)
(3-Chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (hereinafter referred to as Compound A) was jet milled (JOM-0101 type, Co., Ltd.) (Made by Seishin Enterprise Co., Ltd.) (pulverization pressure: 0.7 MPa, supply pressure: 0.7 MPa).
25.0 g of compound A, 887.5 g of D-mannitol (D (−)-mannitol fine powder, manufactured by Merck), 750.0 g of crystalline cellulose (Ceulus PH-101, manufactured by Asahi Kasei Chemicals), 1000.0 g Low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) and 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) And mixing (agitator blade: 400 rpm, chopper blade: 1,200 rpm, mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example A is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 60 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder. (1 cu.ft.PK Blender, made by Patterson Kelly) (150 rotations). 37.5 g of magnesium stearate (vegetable, manufactured by Taihei Chemical Industry) is added and further mixed (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 Obtain 4 mm uncoated tablets.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example C using an automatic coating machine (LDCS-3, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) Increased 5.5-6.0 mg from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Obtain film-coated tablets containing 1 mg of compound A per tablet.

Example 2 (5 mg tablet)
Compound A is pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
125.0 g of compound A, 787.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 750.0 g of crystalline cellulose (Ceulus PH-101, manufactured by Asahi Kasei Chemicals), 1000.0 g Low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) and 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) And mixing (agitator blade: 400 rpm, chopper blade: 1,200 rpm, mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example A is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 60 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder. (1 cu.ft.PK Blender, made by Patterson Kelly) (150 rotations). Add 37.5 g magnesium stearate (vegetable) and mix further (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 Obtain 4 mm uncoated tablets.
The uncoated tablets are coated by spraying the coating solution obtained in Reference Example C using an automatic coating machine (LDCS-3 type, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) 5.5 to 6.0 mg increased from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Film-coated tablets containing 5 mg of compound A per tablet are obtained.

Example 3 (50 mg tablet)
Compound A is pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
Crushed 1250.0 g of Compound A, 412.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 1000.0 g of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) And 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) using a stirring granulator (FS-25, manufactured by Fukae Powtech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, Mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example B was added to the obtained mixed powder and granulated using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 30 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder. (1 cu.ft.PK Blender, made by Patterson Kelly) (150 rotations). Add 37.5 g magnesium stearate (vegetable) and mix further (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 Obtain 4 mm uncoated tablets.
The uncoated tablets are coated by spraying the coating solution obtained in Reference Example C using an automatic coating machine (LDCS-3 type, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) 5.5 to 6.0 mg increased from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Obtain film-coated tablets containing 50 mg of Compound A per tablet.

Example 4 (100 mg tablet)
Compound A is pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
450.0 g of compound A, 148.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 360.0 g of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) And 22.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) were mixed using a stirring granulator (FM-VG-10, manufactured by Pou Lec Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1,200 rpm). , Mixing time: 30 seconds × 2 times) to obtain mixed powder.
The binder solution obtained in Reference Example D is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FM-VG-10, manufactured by POWREC) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, granulation time: 30 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder was sized (rotation speed: 5,900 rpm, screen diameter: 3000 μm) using a screen mill (P-02 type, manufactured by Dalton), and then fluidized bed dryer (MP-01 type, Using Freund Sangyo Co., Ltd. (intake temperature setting: 70 ° C., drying end point: exhaust temperature 38 ° C.), and after drying, using a screen mill (P-02 type, manufactured by Dalton) (Rotation speed: 5,900 rpm, screen diameter: 1000 μm). Two batches of this are prepared (sized granulated powder 1).
Separately from the above, pulverized 250.0 g of Compound A, 82.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 200.0 g of low-substituted hydroxypropylcellulose (LH-21, (Shin-Etsu Chemical Co., Ltd.) and 12.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Industries) were mixed using an agitation granulator (FM-VG-10, manufactured by Pou Lec Co., Ltd.) (agitator blade: 400 rpm, chopper). Blades: 1,200 rpm, mixing time: 30 seconds × 2 times), a mixed powder is obtained.
The binder solution obtained in Reference Example E is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FM-VG-10, manufactured by POWREC) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, granulation time: 30 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder was sized (rotation speed: 5,900 rpm, screen diameter: 3000 μm) using a screen mill (P-02 type, manufactured by Dalton), and then fluidized bed dryer (MP-01 type, Freund Sangyo Co., Ltd.) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 38 ° C.) and after drying, a screen mill (P-02 type, manufactured by Dalton Co.) (Rotation speed: 5,900 rpm, screen diameter: 1000 μm). One batch of this is prepared (sized granulated powder 2).
322.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 149.5 g of crystalline cellulose (Ceulus PH-102, Asahi Kasei) are obtained for the obtained sized powder 2599.0 g (sized particle size 1 + sized particle size 2). Chemicals) is added and mixed using a V-type mixer (V-20, manufactured by Tokuju Kogakusha) (150 revolutions). 34.5 g of magnesium stearate (vegetable, manufactured by Taihei Chemical Industrial Co., Ltd.) is added and further mixed (150 rotations) (tablet powder 1).
1107 g of the tableting powder 1 was tableted with a tableting machine (collect 12HUK type, manufactured by Kikusui Seisakusho) (） size: 9 mmφ-13R, tableting speed: 20-30 rpm, target tablet hardness: 90 N). An uncoated tablet having a thickness of 4.1 to 4.3 mm is obtained.
The uncoated tablets are coated by spraying the coating solution obtained in Reference Example F using an automatic coating machine (HCT-30, manufactured by Freund Corporation) (coating amount: 15 mg, coating end point: pre-dried) Contains 15.5 mg to 16.5 mg of tablet weight afterwards, intake air temperature: 75 ° C., coating liquid spray amount: 5-6 g / min, coating pan rotation speed: 18 rpm) 100 mg of compound A per tablet Film-coated tablets are obtained.

Example 5 (200 mg tablet)
1669.7 g of tableting powder 1 obtained in Example 4 was tableted (tablet size: major axis 16.4 mm, minor axis 7.5 mm, tableting speed) with a tableting machine (collect 12HUK type, manufactured by Kikusui Seisakusho). 20-30 rpm, target tablet hardness: 100 N), and an uncoated tablet having a tablet thickness of 5.1-5.5 mm is obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example F using an automatic coating machine (HCT-30, manufactured by Freund Corporation) (coating amount: 30 mg, coating end point: pre-dried) Contains 30.5-31.5 mg after the tablet weight, intake air temperature: 75 ° C., coating liquid spray amount: 5-6 g / min, coating pan rotation speed: 18 rpm) Contains 200 mg of Compound A per tablet Film-coated tablets are obtained.

Example 6 (1 mg tablet)
(3-Bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (hereinafter referred to as Compound B) was jet milled (JOM-0101 type, Co., Ltd.) (Made by Seishin Enterprise Co., Ltd.) (pulverization pressure: 0.7 MPa, supply pressure: 0.7 MPa).
Milled 25.0 g of compound B, 887.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 750.0 g of crystalline cellulose (Ceulus PH-101, manufactured by Asahi Kasei Chemicals), 1000.0 g Low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) and 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) And mixing (agitator blade: 400 rpm, chopper blade: 1,200 rpm, mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example A is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 60 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder. (1 cu.ft.PK Blender, made by Patterson Kelly) (150 rotations). 37.5 g of magnesium stearate (vegetable, manufactured by Taihei Chemical Industry) is added and further mixed (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 Obtain 4 mm uncoated tablets.
The uncoated tablets are coated by spraying the coating solution obtained in Reference Example C using an automatic coating machine (LDCS-3 type, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) 5.5 to 6.0 mg increased from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Film-coated tablets containing 1 mg of compound B per tablet are obtained.

Example 7 (5 mg tablet)
Compound B is pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (pulverization pressure: 0.7 MPa, supply pressure: 0.7 MPa).
125.0 g of Compound B, 787.5 g of D-mannitol (D (−)-mannitol fine powder, manufactured by Merck), 750.0 g of crystalline cellulose (Celus PH-101, manufactured by Asahi Kasei Chemicals), 1000.0 g Low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) and 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) And mixing (agitator blade: 400 rpm, chopper blade: 1,200 rpm, mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example A is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 60 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder. (1 cu.ft.PK Blender, made by Patterson Kelly) (150 rotations). Add 37.5 g magnesium stearate (vegetable) and mix further (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 Obtain 4 mm uncoated tablets.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example C using an automatic coating machine (LDCS-3, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) Increased 5.5-6.0 mg from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Obtain film-coated tablets containing 5 mg of compound B per tablet.

Example 8 (50 mg tablet)
Compound B is pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (pulverization pressure: 0.7 MPa, supply pressure: 0.7 MPa).
Crushed 1250.0 g of Compound B, 412.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 1000.0 g of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) And 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) using a stirring granulator (FS-25, manufactured by Fukae Powtech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, Mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example B was added to the obtained mixed powder and granulated using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 30 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder. (1 cu.ft.PK Blender, made by Patterson Kelly) (150 rotations). Add 37.5 g magnesium stearate (vegetable) and mix further (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 Obtain 4 mm uncoated tablets.
The uncoated tablets are coated by spraying the coating solution obtained in Reference Example C using an automatic coating machine (LDCS-3 type, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) 5.5 to 6.0 mg increased from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Film-coated tablets containing 50 mg of compound B per tablet are obtained.

Example 9 (100 mg tablet)
Compound B is pulverized (jet pressure: 0.7 MPa, supply pressure: 0.7 MPa) with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.).
450.0 g of compound B, 148.5 g of D-mannitol (D (−)-mannitol fine powder, manufactured by Merck), 360.0 g of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) And 22.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) were mixed using a stirring granulator (FM-VG-10, manufactured by Pou Lec) (agitator blade: 400 rpm, chopper blade: 1,200 rpm). , Mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example D is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FM-VG-10, manufactured by POWREC) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, granulation time: 30 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder was sized (rotation speed: 5,900 rpm, screen diameter: 3000 μm) using a screen mill (P-02 type, manufactured by Dalton), and then fluidized bed dryer (MP-01 type, Freund Sangyo Co., Ltd.) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 38 ° C.) and after drying, a screen mill (P-02 type, manufactured by Dalton Co.) (Rotation speed: 5,900 rpm, screen diameter: 1000 μm). Two batches of this are prepared (sized powder 3).
Separately from the above, pulverized 250.0 g of compound B, 82.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 200.0 g of low-substituted hydroxypropylcellulose (LH-21, (Shin-Etsu Chemical Co., Ltd.) and 12.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Industries) were mixed using an agitation granulator (FM-VG-10, manufactured by Pou Lec Co., Ltd.) (agitator blade: 400 rpm, chopper). Blades: 1,200 rpm, mixing time: 30 seconds × 2 times), a mixed powder is obtained.
The binder solution obtained in Reference Example E is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FM-VG-10, manufactured by POWREC) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, granulation time: 30 seconds × 2 times) to obtain a granulated powder.
The obtained granulated powder was sized (rotation speed: 5,900 rpm, screen diameter: 3000 μm) using a screen mill (P-02 type, manufactured by Dalton), and then fluidized bed dryer (MP-01 type, Freund Sangyo Co., Ltd.) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 38 ° C.) and after drying, a screen mill (P-02 type, manufactured by Dalton Co.) (Rotation speed: 5,900 rpm, screen diameter: 1000 μm). One batch is prepared (sized powder 4).
322.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 149.5 g of crystalline cellulose (Ceulus PH-102, Asahi Kasei) are obtained with respect to the obtained sized powder 2599.0 g (sized particle size 3 + sized particle size 4). Chemicals) is added and mixed using a V-type mixer (V-20, manufactured by Tokuju Kogakusha) (150 revolutions). 34.5 g of magnesium stearate (vegetable, manufactured by Taihei Chemical Industry) is added and further mixed (150 rotations) (tablet powder 2).
1107 g of the tableting powder 2 was tableted with a tableting machine (collect 12HUK type, manufactured by Kikusui Seisakusho Co., Ltd.) (杵 size: 9 mmφ-13R, tableting speed: 20-30 rpm, target tablet hardness: 90 N). An uncoated tablet having a thickness of 4.1 to 4.3 mm is obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example F using an automatic coating machine (HCT-30, manufactured by Freund Corporation) (coating amount: 15 mg, coating end point: pre-dried) Contains 15.5 mg to 16.5 mg after tablet weight, intake air temperature: 75 ° C., coating liquid spray amount: 5-6 g / min, coating pan rotation speed: 18 rpm) 100 mg of compound B per tablet Film-coated tablets are obtained.

Example 10 (200 mg tablet)
1679.7 g of tableting powder 2 obtained in Example 9 was tableted (tablet size: major axis 16.4 mm, minor axis 7.5 mm, tableting speed) with a tableting machine (collect 12HUK type, manufactured by Kikusui Seisakusho). 20-30 rpm, target tablet hardness: 100 N), and an uncoated tablet having a tablet thickness of 5.1-5.5 mm is obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example F using an automatic coating machine (HCT-30, manufactured by Freund Corporation) (coating amount: 30 mg, coating end point: pre-dried) Contains 30.5-31.5 mg after tablet weight, intake air temperature: 75 ° C., coating liquid spray rate: 5-6 g / min, coating pan rotation speed: 18 rpm) Contains 200 mg of compound B per tablet Film-coated tablets are obtained.

Example 11 (1 mg tablet)
(3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (hereinafter referred to as compound C) was jet milled (JOM-0101 type, ( (Made by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
25.0 g of compound C, 887.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 750.0 g of crystalline cellulose (Ceulus PH-101, manufactured by Asahi Kasei Chemicals), 1000.0 g Low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) and 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) And mixing (agitator blade: 400 rpm, chopper blade: 1,200 rpm, mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example A is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 60 seconds × 2 times), a granulated powder was obtained.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder, and a V-type mixer (1 cu.ft.PK Blender, manufactured by Patterson Kelly Co.) (150 rotations). 37.5 g of magnesium stearate (vegetable, manufactured by Taihei Chemical Industry) was added and further mixed (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 A 4 mm uncoated tablet was obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example C using an automatic coating machine (LDCS-3, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) Increased 5.5-6.0 mg from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Film-coated tablets containing 1 mg of compound C per tablet were obtained.

Example 12 (5 mg tablet)
Compound C was pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
125.0 g of compound C, 787.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 750.0 g of crystalline cellulose (Ceulus PH-101, manufactured by Asahi Kasei Chemicals), 1000.0 g Low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) and 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Sangyo Co., Ltd.) And mixing (agitator blade: 400 rpm, chopper blade: 1,200 rpm, mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example A is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 60 seconds × 2 times), a granulated powder was obtained.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder, and a V-type mixer (1 cu.ft.PK Blender, manufactured by Patterson Kelly Co.) (150 rotations). 37.5 g of magnesium stearate (vegetable) was added and further mixed (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 A 4 mm uncoated tablet was obtained.
The uncoated tablets are coated by spraying the coating solution obtained in Reference Example C using an automatic coating machine (LDCS-3 type, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) 5.5 to 6.0 mg increased from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Film-coated tablets containing 5 mg of compound C per tablet were obtained.

Example 13 (50 mg tablet)
Compound C was pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
Crushed 1250.0 g of Compound C, 412.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 1000.0 g of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) And 62.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) using a stirring granulator (FS-25, manufactured by Fukae Powtech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, Mixing time: 30 seconds × 2 times), a mixed powder was obtained.
The binder solution obtained in Reference Example B is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FS-25, manufactured by Fukae Pautech Co., Ltd.) (agitator blade: 400 rpm, chopper blade: 1 , 200 rpm, granulation time: 30 seconds × 2 times), a granulated powder was obtained.
The obtained granulated powder is sized (impeller: square, impeller rotational speed: 2,000 rpm, screen diameter: 2972 μm) using a screen mill (QC-197S type, manufactured by Quadro), and then fluidized bed dryer. (FLM-15 type, manufactured by Vector / Freund) (intake air temperature setting: 70 ° C., drying end point: exhaust temperature 37 ° C.), after drying, screen mill (QC-197S type, Quadro) (Impeller: round shape, impeller rotation speed: 2,000 rpm, screen diameter: 1143 μm).
350.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 162.5 g of crystalline cellulose (Ceulus PH-102, manufactured by Asahi Kasei Chemicals) were added to 2825.0 g of the obtained sized powder, and a V-type mixer (1 cu.ft.PK Blender, manufactured by Patterson Kelly Co.) (150 rotations). 37.5 g of magnesium stearate (vegetable) was added and further mixed (150 revolutions).
This was tableted (tablet size: 7 mmφ-10R, tableting speed: 20-30 rpm, target tablet hardness: 65 N) with a tableting machine (XL-100 type, manufactured by Korsch), and the tablet thickness 3.2-3 A 4 mm uncoated tablet was obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example C using an automatic coating machine (LDCS-3, manufactured by Vector / Freund) (coating amount: 5 mg, coating end point: previous) Increased 5.5-6.0 mg from the tablet weight after drying, intake air temperature: 80 ° C. during coating, 70 ° C. during post-drying, coating solution spray amount: 10-15 g / min, coating pan rotation speed: 15 rpm ) Film-coated tablets containing 50 mg of compound C per tablet were obtained.

Example 14 (100 mg tablet)
Compound C was pulverized with a jet mill (JOM-0101 type, manufactured by Seishin Enterprise Co., Ltd.) (grinding pressure: 0.7 MPa, supply pressure: 0.7 MPa).
450.0 g of compound C, 148.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 360.0 g of low-substituted hydroxypropylcellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) And 22.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation) were mixed using a stirring granulator (FM-VG-10, manufactured by Pou Lec) (agitator blade: 400 rpm, chopper blade: 1,200 rpm). , Mixing time: 30 seconds × 2 times) to obtain a mixed powder.
The binder solution obtained in Reference Example D is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FM-VG-10, manufactured by POWREC) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, granulation time: 30 seconds × 2 times), a granulated powder was obtained.
The obtained granulated powder was sized (rotation speed: 5,900 rpm, screen diameter: 3000 μm) using a screen mill (P-02 type, manufactured by Dalton), and then fluidized bed dryer (MP-01 type, Using Freund Sangyo Co., Ltd. (intake temperature setting: 70 ° C., drying end point: exhaust temperature 38 ° C.), and after drying, using a screen mill (P-02, manufactured by Dalton) (Rotational speed: 5,900 rpm, screen diameter: 1000 μm). Two batches of this were prepared (sized powder 5).
Separately from the above, pulverized 250.0 g of compound C, 82.5 g of D-mannitol (D (-)-mannitol fine powder, manufactured by Merck), 200.0 g of low-substituted hydroxypropylcellulose (LH-21, (Shin-Etsu Chemical Co., Ltd.) and 12.5 g of light anhydrous silicic acid (Adsolider 101, manufactured by Freund Industries) were mixed using an agitation granulator (FM-VG-10, manufactured by Pou Lec Co., Ltd.) (agitator blade: 400 rpm, chopper). Blades: 1,200 rpm, mixing time: 30 seconds × 2 times), a mixed powder was obtained.
The binder solution obtained in Reference Example E is added to the obtained mixed powder, and granulation is performed using an agitation granulator (FM-VG-10, manufactured by POWREC) (agitator blade: 400 rpm, chopper blade: 1,200 rpm, granulation time: 30 seconds × 2 times), a granulated powder was obtained.
The obtained granulated powder was sized (rotation speed: 5,900 rpm, screen diameter: 3000 μm) using a screen mill (P-02 type, manufactured by Dalton), and then fluidized bed dryer (MP-01 type, Using Freund Sangyo Co., Ltd. (intake temperature setting: 70 ° C., drying end point: exhaust temperature 38 ° C.), and after drying, using a screen mill (P-02 type, manufactured by Dalton) (Rotational speed: 5,900 rpm, screen diameter: 1000 μm). One batch of this was prepared (sized granulated powder 6).
322.0 g of crospovidone (Kollidon CL, manufactured by BASF) and 149.5 g of crystalline cellulose (Ceulus PH-102, Asahi Kasei) are obtained with respect to the obtained sized powder 2599.0 g (sized particle size 5 + sized particle size 6). Chemicals) was added and mixed using a V-type mixer (V-20, manufactured by Tokuju Kogakusha Co., Ltd.) (150 revolutions). 34.5 g of magnesium stearate (vegetable, manufactured by Taihei Chemical Industrial Co., Ltd.) was added and further mixed (150 rotations) (tablet powder 3).
1107 g of the tableting powder 3 was tableted with a tableting machine (collect 12HUK type, manufactured by Kikusui Seisakusho Co., Ltd.) (杵 size: 9 mmφ-13R, tableting speed: 20-30 rpm, target tablet hardness: 90 N) An uncoated tablet having a thickness of 4.1 to 4.3 mm was obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example F using an automatic coating machine (HCT-30, manufactured by Freund Corporation) (coating amount: 15 mg, coating end point: pre-dried) Contains 15.5 mg to 16.5 mg from the weight of the later tablet, intake air temperature: 75 ° C., coating liquid spray amount: 5-6 g / min, coating pan rotation speed: 18 rpm) 100 mg of compound C per tablet A film-coated tablet was obtained.

Example 15 (200 mg tablet)
1679.7 g of the tableting powder 3 obtained in Example 14 was tableted with a tableting machine (collect 12HUK type, manufactured by Kikusui Seisakusho Co., Ltd.) (杵 size: major axis 16.4 mm, minor axis 7.5 mm, tableting speed) 20-30 rpm, target tablet hardness: 100 N), and uncoated tablets with a tablet thickness of 5.1-5.5 mm were obtained.
The uncoated tablets are coated by spraying the coating liquid obtained in Reference Example F using an automatic coating machine (HCT-30, manufactured by Freund Corporation) (coating amount: 30 mg, coating end point: pre-dried) Contains 30.5-31.5 mg from the tablet weight later, intake air temperature: 75 ° C., coating liquid spray amount: 5-6 g / min, coating pan rotation speed: 18 rpm) Contains 200 mg of Compound C per tablet A film-coated tablet was obtained.

  For the compounds of Reference Examples 4 to 95, tablets can be produced in the same manner as in Examples 1 to 15 above.

Test Example 1 (Evaluation of stability in combination with additives)
Compound A is physically mixed with various additives shown in Table 28 in a mortar (for mixing ratios, see Table 28), and the resulting powder mixture is placed in a glass sample bottle in an amount of about 5 mm in layer thickness. .
This glass sample bottle is placed in a desiccator adjusted to 75% RH (relative humidity) without a lid, and the desiccator is stored in a thermostat set to 60 ° C. for 2 weeks.
After completion of storage, a 60 v / v% acetonitrile aqueous solution is added as Compound A to 0.5 mg / mL, and dissolution treatment by ultrasonic irradiation and filtration treatment are performed. Each sample is measured by high performance liquid chromatography, and the stability is evaluated based on changes from the start of storage. Table 29 shows the measurement conditions by high performance liquid chromatography.

  In the preparation of Compound A and various additives, by not using a basic additive (particularly calcium silicate), it is possible to provide a preparation that can ensure the stability of Compound A over time during storage.

Test example 2 (dissolution test 1)
About the tablet prepared according to prescription shown in Table 30, the dissolution characteristic is evaluated by a dissolution test (refer to Table 31 for dissolution test conditions).
After lightly mixing any of A, B and C in the tablet preparation bowl, granulation is carried out by adding a solution of D which has been adjusted to a concentration of 5 w / w% in advance using purified water. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, the sizing is carried out with a 500 μm sieve, and E and F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending low-substituted hydroxypropyl cellulose, a preparation in which compound A is eluted quickly can be provided.

Test example 3 (dissolution test 2)
About the tablet prepared according to the prescription shown in Table 32, the dissolution characteristic is evaluated by a dissolution test (refer to Table 33 for dissolution test conditions).
After mixing A, B and C lightly in a tablet preparation bowl, a solution of D adjusted to a concentration of 5 w / w% with purified water in advance is added thereto and granulation is carried out. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, the sizing is carried out with a 500 μm sieve, and E and F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending an appropriate amount of low-substituted hydroxypropylcellulose, it is possible to provide a preparation in which compound A is eluted quickly while suppressing the addition amount of low-substituted hydroxypropylcellulose.

Test example 4 (dissolution test 3)
About the tablet prepared according to prescription shown in Table 34, the dissolution characteristic is evaluated by a dissolution test (refer to Table 35 for dissolution test conditions).
After mixing A, B and C lightly in a tablet preparation bowl, a solution of D adjusted to a concentration of 5 w / w% with purified water in advance is added thereto and granulation is carried out. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, sizing is carried out with a 500 μm sieve, and any of E and then F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending crospovidone, it is possible to provide a preparation in which Compound A elutes quickly.

Test Example 5 (dissolution test 4)
About the tablet prepared according to prescription shown in the following table (Table 36), the dissolution characteristic is evaluated by a dissolution test (refer to Table 37 for dissolution test conditions).
After A, B and C are lightly mixed in a tablet preparation bowl, a solution of D adjusted to a concentration of 5 w / w% with purified water in advance is added thereto and granulation is performed. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, the sizing is carried out with a 500 μm sieve, and E and F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending an appropriate amount of crospovidone, it is possible to provide a preparation in which compound A is eluted quickly while suppressing the amount of crospovidone added.

Test Example 6 (Evaluation of stability in blending with additives)
Compound B is physically mixed with various additives shown in Table 38 in a mortar (mixing ratio is shown in Table 38), and the resulting powder mixture is put into a glass sample bottle in an amount of about 5 mm in layer thickness. .
This glass sample bottle is placed in a desiccator adjusted to 75% RH (relative humidity) without a lid, and the desiccator is stored in a thermostat set to 60 ° C. for 2 weeks.
After the storage, 60 v / v% acetonitrile aqueous solution is added as Compound B so as to be 0.5 mg / mL, and dissolution treatment by ultrasonic irradiation and filtration treatment are performed. Each sample is measured by high performance liquid chromatography, and the stability is evaluated based on changes from the start of storage. Table 39 shows the measurement conditions by high performance liquid chromatography.

  In the preparation of Compound B and various additives, by not using a basic additive (especially calcium silicate), it is possible to provide a preparation that can ensure stability over time of Compound B during storage.

Test example 7 (dissolution test 5)
About the tablet prepared according to prescription shown in Table 40, the dissolution characteristic is evaluated by a dissolution test (refer to Table 41 for dissolution test conditions).
After lightly mixing any of A, B and C in the tablet preparation bowl, granulation is carried out by adding a solution of D which has been adjusted to a concentration of 5 w / w% in advance using purified water. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, the sizing is carried out with a 500 μm sieve, and E and F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending low-substituted hydroxypropylcellulose, a preparation in which Compound B elutes quickly can be provided.

Test Example 8 (Dissolution test 6)
About the tablet prepared according to the prescription shown in Table 42, the dissolution characteristic is evaluated by a dissolution test (refer to Table 43 for dissolution test conditions).
After mixing A, B and C lightly in a tablet preparation bowl, a solution of D adjusted to a concentration of 5 w / w% with purified water in advance is added thereto and granulation is carried out. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, the sizing is carried out with a 500 μm sieve, and E and F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending an appropriate amount of low-substituted hydroxypropylcellulose, it is possible to provide a preparation in which Compound B elutes quickly while suppressing the addition amount of low-substituted hydroxypropylcellulose.

Test Example 9 (Dissolution test 7)
For tablets prepared according to the formulation shown in Table 44, the dissolution characteristics are evaluated by dissolution test (see Table 45 for dissolution test conditions).
After mixing A, B and C lightly in a tablet preparation bowl, a solution of D adjusted to a concentration of 5 w / w% with purified water in advance is added thereto and granulation is carried out. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, sizing is carried out with a 500 μm sieve, and any of E and then F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending crospovidone, it is possible to provide a preparation in which Compound B elutes quickly.

Test Example 10 (elution test 8)
The dissolution characteristics of the tablets prepared according to the formulation shown in the following table (Table 46) are evaluated by dissolution test (see Table 47 for dissolution test conditions).
After A, B and C are lightly mixed in a tablet preparation bowl, a solution of D adjusted to a concentration of 5 w / w% with purified water in advance is added thereto and granulation is performed. The obtained granulated powder is passed through a sieve having an opening of 710 μm, and then dried at 60 ° C. for 2 hours. After the drying, the sizing is carried out with a 500 μm sieve, and E and F are sequentially mixed with the obtained sized powder. The obtained tableting powder is pressure-compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

  By blending an appropriate amount of crospovidone, it is possible to provide a preparation in which compound B is rapidly eluted while suppressing the amount of crospovidone added.

Test Example 11 (Evaluation of stability in blending with additives)
Compound C is physically mixed in the mortar with various additives shown in Table 48 (see Table 48 for the mixing ratio), and the resulting mixed powder is put in a glass sample bottle in an amount of about 5 mm in layer thickness. It was.
This glass sample bottle was placed in a desiccator conditioned to 75% RH (relative humidity) without a lid, and the desiccator was stored in a thermostat set at 60 ° C. for 2 weeks.
After the completion of storage, 60 v / v% acetonitrile aqueous solution was added as Compound C to 0.5 mg / mL, and dissolution treatment by ultrasonic irradiation and filtration treatment were performed. Each sample was measured by high performance liquid chromatography, and the stability was evaluated based on changes from the start of storage. Table 49 shows the measurement conditions by high performance liquid chromatography.
In Table 48, the area percentage of the decomposed product represents the ratio of the peak area of the decomposed product to the sum of the areas of all peaks detected by high performance liquid chromatography.

From Table 48,
(1) Compound C exhibits good stability in combination with additives other than calcium silicate,
(2) It has been clarified that Compound C has a new peak that is considered to be caused by a decomposition product of Compound C in the combination with calcium silicate.
As described above, in the preparation of Compound C and various additives, by not using a basic additive (especially calcium silicate), it is possible to provide a preparation that can ensure stability over time of Compound C during storage.

Test Example 12 (Dissolution test 9)
About the tablet prepared according to prescription shown in Table 50, the dissolution characteristic was evaluated by the dissolution test (refer Table 51 for the dissolution test conditions). The results of the dissolution test are shown in Table 52.
After lightly mixing any one of A, B and C in the tablet preparation bowl, granulation was carried out by adding a solution of D previously adjusted to a concentration of 5 w / w% using purified water. The obtained granulated powder was passed through a sieve having an aperture of 710 μm, and dried at 60 ° C. for 2 hours. After the drying, sizing was performed with a 500 μm sieve, and E and F were sequentially mixed with the obtained sized powder. The obtained tableting powder was pressurized and compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

As shown in Table 52, the formulation blended with low-substituted hydroxypropylcellulose showed the quickest dissolution at 0 to 30 minutes.
As mentioned above, the formulation from which the compound C elutes quickly can be provided by containing a low substituted hydroxypropyl cellulose.

Test Example 13 (Dissolution test 10)
The dissolution characteristics of the tablets prepared according to the formulation shown in Table 53 were evaluated by dissolution test (see Table 54 for dissolution test conditions). The results of the dissolution test are shown in Table 55.
After A, B and C were lightly mixed in a tablet preparation pot, granulation was carried out by adding a solution of D previously adjusted to a concentration of 5 w / w% using purified water. The obtained granulated powder was passed through a sieve having an aperture of 710 μm, and dried at 60 ° C. for 2 hours. After the drying, sizing was performed with a 500 μm sieve, and E and F were sequentially mixed with the obtained sized powder. The obtained tableting powder was pressurized and compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

As shown in Table 55, the formulation containing 40.0 mg of low-substituted hydroxypropylcellulose showed a clear dissolution at 0 to 30 minutes compared to the formulations containing 20.0 mg and 30.0 mg, In addition, even when compared with a formulation containing 50.0 mg, which is 10 mg more, almost the same dissolution characteristics were exhibited.
As mentioned above, compound C elutes rapidly, suppressing the addition amount of low substituted hydroxypropyl cellulose by mix | blending 40.0 mg (27.0 w / w% in mass ratio in a tablet) of low substituted hydroxypropyl cellulose. A formulation can be provided.

Test Example 14 (dissolution test 11)
The dissolution characteristics of the tablets prepared according to the formulation shown in Table 56 were evaluated by dissolution test (see Table 57 for dissolution test conditions). The results of the dissolution test are shown in Table 58.
After A, B and C were lightly mixed in a tablet preparation pot, granulation was carried out by adding a solution of D previously adjusted to a concentration of 5 w / w% using purified water. The obtained granulated powder was passed through a sieve having an aperture of 710 μm, and dried at 60 ° C. for 2 hours. After completion of drying, sizing was performed with a 500 μm sieve, and any of E and then F were sequentially mixed with the obtained sized powder. The obtained tableting powder was pressurized and compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

As shown in Table 58, the formulation containing crospovidone showed the quickest dissolution of Compound C in 0 to 30 minutes.
As mentioned above, the formulation from which compound C elutes quickly can be provided by containing crospovidone.

Test Example 15 (dissolution test 12)
The dissolution characteristics of the tablets prepared according to the formulation shown in the table below (Table 59) were evaluated by dissolution test (see Table 60 for dissolution test conditions). The results of the dissolution test are shown in Table 61.
After A, B and C were lightly mixed in a tablet preparation pot, granulation was carried out by adding a solution of D previously adjusted to a concentration of 5 w / w% using purified water. The obtained granulated powder was passed through a sieve having an aperture of 710 μm, and dried at 60 ° C. for 2 hours. After the drying, sizing was performed with a 500 μm sieve, and E and F were sequentially mixed with the obtained sized powder. The obtained tableting powder was pressurized and compressed (target value: 100 N) with a constant speed strain type universal testing machine (SC-50CJ type, JT Toshi) to prepare tablets.

As shown in Table 61, the formulation containing 13.7 mg of crospovidone showed clear elution at 0 to 30 minutes compared to the formulation containing 6.5 mg and no formulation, and further doubled the amount. Compared to the formulation containing 25.0 mg in the vicinity, the dissolution characteristics were almost the same.
From the above, by incorporating 13.7 mg of crospovidone (mass ratio in the tablet: 10.0 w / w%), a preparation in which compound C dissolves quickly can be provided while suppressing the amount of crospovidone added.

  The pharmaceutical composition of the present invention has excellent stability over time and dissolution (disintegration) of the active ingredient, hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, It is useful for treatment or prevention of pathological conditions involving uric acid such as renal dysfunction, coronary artery disease, ischemic heart disease and the like.

X-ray powder diffraction pattern of (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 1). X-ray powder diffraction pattern of (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 2). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 3). X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 4). X-ray powder diffraction pattern of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-diiodophenyl) -methanone (Reference Example 5). X-ray powder diffraction pattern of (3,5-difluoro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 6). X-ray powder diffraction pattern of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3,5-dimethylphenyl) -methanone (Reference Example 7). (3,5-Dichloro-4-hydroxyphenyl)-(1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [1,4] thiazin-4-yl) -methanone (Reference Example 10) X-ray diffraction pattern. X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 12). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(5-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 14). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(8-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 15). X-ray powder of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Reference Example 16) Diffraction pattern. X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 17). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(7-methoxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 18). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 19). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(7-hydroxy-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 20). X-ray powder diffraction pattern of 4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-sulfonic acid diethylamide (Reference Example 21). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(3,4-dihydro-2H-quinolin-1-yl) -methanone (Reference Example 26). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) -methanone (Reference Example 27). X-ray powder diffraction pattern of (3-chloro-4-hydroxy-5-nitrophenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 31). X-ray powder diffraction of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydropyrido [3,2-b] [1,4] oxazin-4-yl) -methanone (Reference Example 36) pattern. X-ray powder diffraction pattern of (3,5-dichloro-2-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 38). X-ray powder diffraction pattern of (2,3-dihydrobenzo [1,4] oxazin-4-yl)-(4-hydroxy-3-trifluoromethylphenyl) -methanone (Reference Example 39). X-ray powder diffraction pattern of (3-chloro-4-hydroxy-5-methoxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 40). X-ray powder diffraction pattern of (4-chloro-3-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 41). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 44). X-ray powder diffraction pattern of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 50). X-ray powder diffraction pattern of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dichloro-4-hydroxyphenyl) -methanone (Reference Example 51). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-hydroxymethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 56) . X-ray powder diffraction of (3,5-dichloro-4-hydroxyphenyl)-(6,8-dimethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 66) pattern. X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 67). X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(6-nitro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 69). X-ray powder diffraction pattern of 1- [4- (3,5-dichloro-4-hydroxybenzoyl) -3,4-dihydro-2H-quinoxalin-1-yl] -ethanone (Reference Example 73). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2-methyl-2,3-dihydroindol-1-yl) -methanone (Reference Example 76). X-ray powder diffraction pattern of (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl) -methanone (Reference Example 77). X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(6-fluoro-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 79). X-ray powder of (3,5-dibromo-4-hydroxyphenyl)-(2,3-dihydronaphtho [2,1-b] [1,4] oxazin-1-yl) -methanone (Reference Example 80) Diffraction pattern. X-ray powder diffraction pattern of (3,5-dibromo-4-hydroxyphenyl)-(6-methyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 81). X-ray powder diffraction pattern of (6-chloro-2,3-dihydrobenzo [1,4] oxazin-4-yl)-(3,5-dibromo-4-hydroxyphenyl) -methanone (Reference Example 82). Powder X-ray diffraction of (3,5-dichloro-4-hydroxyphenyl)-(6-trifluoromethyl-2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone (Reference Example 85) pattern. X-ray powder diffraction pattern of acetic acid 2,6-dichloro-4- (2,3-dihydrobenzo [1,4] oxazine-4-carbonyl) phenyl ester (Reference Example 87).

Claims (36)

A nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives, wherein the nitrogen-containing fused ring A pharmaceutical composition wherein the compound or a pharmaceutically acceptable salt thereof is not in contact with a basic additive.

[Where:
R ¹ , R ² and R ³ are the same or different,
1) a hydrogen atom, or 2) a group selected from the following group A, or 3) saturated or unsaturated having 3 to 14 carbon atoms together with the carbon atom to which R ¹ and R ² are bonded Or the carbocycle may be substituted with one or more substituents selected from group A below, or 4) R ² and R ³ are bonded to each other A saturated or unsaturated carbocycle having 3 to 14 carbon atoms together with the carbon atom to be substituted (the carbocycle may be substituted with one or more substituents selected from the following group A). May form;
Y is
1) -CO-,
2) -CS-, or 3) -S (= O) _2-
Is;
X ¹ is,
1) a nitrogen atom, or 2) CR ⁴ (wherein R ⁴ is
(A) a hydrogen atom, or (b) a group selected from group A below, or (c) R ³ and R ⁴ are saturated with 3 to 14 carbon atoms together with the carbon atom to which they are bonded. Alternatively, an unsaturated carbocycle (the carbocycle may be substituted with one or more substituents selected from the same or different groups selected from group A below) may be formed. )
Is;
X ² is,
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CR ⁹ R ¹⁰ — (wherein R ⁹ and R ¹⁰ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁹ and R ¹⁰ Together may form an oxo group. )
Is;
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different groups selected from the following group B, or (c) the same carbon atom R ¹¹ and R ^{12 to} be bonded together form an oxo group, or (d) two of n R ¹¹ and R ¹² bonded to the same or adjacent two carbon atoms are the carbon atoms And a saturated or unsaturated carbocycle having 3 to 14 carbon atoms (the carbocycle may be substituted with one or more substituents selected from the following group A). May be. )
And ring A is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following group A), or 2) A saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group A; May be.)
It is.
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ is as defined above, and R ²² is a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² is as defined above),
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) are
1 ') a halogen atom,
2 ′) a hydroxyl group,
3 ′) a C _1-6 alkoxy group,
4 ′) — NR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′ and R ¹⁹ ′ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen containing R ¹⁸ ′ and R ¹⁹ ′ together with a nitrogen atom to which they are bonded to form a single ring A saturated heterocyclic ring may be formed. ),
^{5 ') - CONR 18' R} 19 '( ^{wherein, R 18'} and ^{R 19} 'has the same meaning as defined above),.
6 ′)-COR ²⁰ ′ (wherein R ²⁰ ′ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7 ′) — NR ²¹ ′ COR ²⁰ ′ (wherein R ²⁰ ′ has the same meaning as described above, and R ²¹ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8 ′) — NR ²¹ ′ CONR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′, R ¹⁹ ′ and R ²¹ ′ are as defined above),
9 ′) — NR ²¹ ′ S (═O) ₂ R ²² ′ (wherein R ²¹ ′ has the same meaning as described above, and R ²² ′ is a C _1-6 alkyl group), and 10 ′. ^{_{) -S (= O) 2 R}} 22 '( ^{wherein, R 22'} has the same meaning as defined above.)
May be substituted with one or more substituents selected from the same or different,
In addition, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) is further one or more substitutions selected from the C _1-6 alkyl group and the above 1 ′) to 10 ′). It may be substituted with a group. ] A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives, the basic additive comprising: A pharmaceutical composition containing not more than 1 part by weight of a basic additive with respect to 1 part by weight of a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.

[Each symbol in the formula is as defined in claim 1.] ]   The pharmaceutical composition according to claim 1, wherein all of the additives are not basic additives.   Basic additives are alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal silicate The pharmaceutical composition according to any one of claims 1 to 3, which is selected from a salt and an alkaline earth metal silicate.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the basic additive is selected from alkali metal silicates and alkaline earth metal silicates.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the basic additive is calcium silicate. One or more pharmaceutically acceptable additives selected from the group consisting of the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and an acidic additive and a neutral additive. A pharmaceutical composition containing no basic additive or basic with respect to 1 part by weight of a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof: A pharmaceutical composition containing less than 1 part by weight of an additive.

[Each symbol in the formula is as defined in claim 1.] ] A nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising one or more pharmaceutically acceptable additives, all of the additives Is a pharmaceutical composition selected from the group consisting of acidic additives and neutral additives.

[Each symbol in the formula is as defined in claim 1.] ]   The additive contained is D-mannitol, crystalline cellulose, low substituted hydroxypropyl cellulose, light anhydrous silicic acid, crospovidone, magnesium stearate, lactose, corn starch, croscarmellose sodium, carmellose, carmellose sodium, carme The pharmaceutical according to any one of claims 1 to 8, which is one or more selected from the group consisting of calcium calcium, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, titanium oxide, and macrogol. Composition.   The pharmaceutical composition according to any one of claims 1 to 9, comprising low-substituted hydroxypropylcellulose.   The pharmaceutical composition according to any one of claims 1 to 9, comprising crospovidone.   The pharmaceutical composition according to any one of claims 1 to 9, comprising low-substituted hydroxypropylcellulose and crospovidone.   The pharmaceutical composition according to any one of claims 1 to 9, comprising D-mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, hydroxypropylmethylcellulose, crospovidone and magnesium stearate. A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and a low-substituted hydroxypropylcellulose.

[Each symbol in the formula is as defined in claim 1.] ] A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and crospovidone.

[Each symbol in the formula is as defined in claim 1.] ] A pharmaceutical composition comprising a nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, a low-substituted hydroxypropylcellulose and crospovidone.

[Each symbol in the formula is as defined in claim 1.] ]   The pharmaceutical composition according to any one of claims 1 to 16, which is a tablet.   The pharmaceutical composition according to claim 17, which is coated with a coating agent.   The pharmaceutical composition according to claim 18, wherein the coating agent comprises hydroxypropylmethylcellulose, titanium oxide and macrogol.   The pharmaceutical composition according to any one of claims 1 to 19, which is a URAT1 activity inhibitor.   The pharmaceutical composition according to any one of claims 1 to 19, which is a blood uric acid level-lowering agent.   The pharmaceutical composition according to any one of claims 1 to 19, which is a therapeutic or prophylactic agent for a disease state involving uric acid.   23. The pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gout kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease The pharmaceutical composition as described.   The pharmaceutical composition according to any one of claims 1 to 19, which does not substantially inhibit CYP. The pharmaceutical composition according to any one of claims 1 to 24, wherein the nitrogen-containing condensed ring compound represented by the general formula [1] is a nitrogen-containing condensed ring compound represented by the following general formula [2]. .

[Wherein R ¹ , R ² , R ³ , Y, X ¹ , X ³ and X ⁴ are as defined in claim 1,
Ring A ′ is
1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is substituted with one or more substituents selected from the following group C), or 2) nitrogen A saturated or unsaturated heterocyclic group having at least one heteroatom selected from an atom, an oxygen atom and a sulfur atom (the heterocyclic group is substituted with one or more substituents selected from the following group C; ing.)
Wherein the ring A ′ is substituted with at least one —OR ¹³ ′ (R ¹³ ′ is defined in group C below);
X ² '
1) oxygen atom,
2) —N (R ⁵ ) — (wherein R ⁵ is
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
3) —N (COR ⁶ ) — (wherein R ⁶ is
(A) a hydroxyl group,
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
(C) C _1-6 alkoxy group (The C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii) which are the same or different).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
(D) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms which may be substituted with one or more substituents selected from the following group A;
(E) a cycloalkylalkoxy group optionally substituted by one or more substituents selected from the following group A,
(F) an aralkyl group optionally substituted with one or more substituents selected from the following group A, or (g) substituted with one or more substituents selected from the following group A. A good aralkoxy group. ),
4) —N (S (═O) ₂ R ⁶ ) — (wherein R ⁶ is as defined above),
5) -N (CONR ⁷ R ⁸ )-(wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ⁷ and R ⁸ Are nitrogen-containing saturated heterocycles consisting of a single ring together with the nitrogen atom to which they are bonded (the heterocycle may be substituted with one or more substituents selected from the following group A, or the same or different. ) May be formed. ),
6) sulfur atom,
7) -S (= O)-,
8) —S (═O) ₂ —, or 9) —CH ₂ —.
It is.
(However, when X ² ′ is —CH ₂ —,
-X ³ -X ⁴ -is
-(CR ¹¹ R ¹² ) n- (wherein n is an integer of 1 to 3 and n R ¹¹ and R ¹² are the same or different,
(A) a hydrogen atom, or
(B) R ¹¹ and R ¹² bonded to the same carbon atom together form an oxo group, or (c) n two R ¹¹ and R ¹² are bonded to the same or adjacent two carbon atoms. The two bonded together with the carbon atom are a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring is substituted with one or more substituents selected from the following group A; May be formed). )
Is;
R ¹³ ′ is a hydrogen atom; and ring A ′ is further substituted with at least one halogen atom;
However, when R ¹¹ and R ¹² are both hydrogen atoms and n is 2, R ¹ , R ² and R ³ are all hydrogen atoms. )
[Group A]
1) a halogen atom,
2) —OR ¹³ (wherein R ¹³ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group which may be substituted with one or different substituents selected from the following group B, or (c) —COR ¹⁴ (wherein R ¹⁴ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
7) —COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
8) —NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B below, or (c) R ¹⁵ and R ¹⁶ A nitrogen-containing saturated heterocycle comprising a single ring together with the nitrogen atom to which they are bonded (the heterocycle is substituted with one or more substituents selected from the following (i) and (ii)): May be.
(I) a substituent selected from Group B below,
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ) May be formed. ),
9) -CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
10) —NR ¹⁷ COR ¹⁴ (wherein R ¹⁴ has the same meaning as described above, and R ¹⁷ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more substituents selected from the same or different groups selected from Group B below. ),
11) —NR ¹⁷ S (═O) ₂ R ¹⁴ (wherein R ¹⁴ and R ¹⁷ are as defined above),
12) —NR ¹⁷ CONR ¹⁵ R ¹⁶ (wherein R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined above),
13) —SR ¹³ (wherein R ¹³ has the same meaning as described above),
14) —S (═O) R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
15) —S (═O) ₂ R ¹⁴ (wherein R ¹⁴ has the same meaning as described above),
16) —S (═O) ₂ NR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above),
17) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
19) Aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the following group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the following group B; ),
20) Cyano group, and 21) Nitro group [Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C _1-6 alkoxy group,
4) -NR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen-containing saturated heterocycle comprising R ¹⁸ and R ¹⁹ together with a nitrogen atom to which they are bonded to form a monocycle. A ring may be formed. ),
5) -CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ and R ¹⁹ are as defined above),
6) -COR ²⁰ (wherein R ²⁰ represents
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7) —NR ²¹ COR ²⁰ (wherein R ²⁰ has the same meaning as described above, and R ²¹ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8) —NR ²¹ CONR ¹⁸ R ¹⁹ (wherein R ¹⁸ , R ¹⁹ and R ²¹ are as defined above),
9) —NR ²¹ S (═O) ₂ R ²² (wherein R ²¹ is as defined above, and R ²² is a C _1-6 alkyl group), and 10) —S (═O ₂ R ²² (wherein R ²² is as defined above),
Here, the C _1-6 alkyl group and the C _1-6 alkoxy group in the above 3) to 10) are
1 ') a halogen atom,
2 ′) a hydroxyl group,
3 ′) a C _1-6 alkoxy group,
4 ′) — NR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′ and R ¹⁹ ′ are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group, or (c) a nitrogen containing R ¹⁸ ′ and R ¹⁹ ′ together with a nitrogen atom to which they are bonded to form a single ring A saturated heterocyclic ring may be formed. ),
^{5 ') - CONR 18' R} 19 '( ^{wherein, R 18'} and ^{R 19} 'has the same meaning as defined above),.
6 ′)-COR ²⁰ ′ (wherein R ²⁰ ′ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C _1-6 alkyl group, or (d) a C _1-6 alkoxy group. ),
7 ′) — NR ²¹ ′ COR ²⁰ ′ (wherein R ²⁰ ′ has the same meaning as described above, and R ²¹ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group. ),
8 ′) — NR ²¹ ′ CONR ¹⁸ ′ R ¹⁹ ′ (wherein R ¹⁸ ′, R ¹⁹ ′ and R ²¹ ′ are as defined above),
9 ′) — NR ²¹ ′ S (═O) ₂ R ²² ′ (wherein R ²¹ ′ has the same meaning as described above, and R ²² ′ is a C _1-6 alkyl group), and 10 ′. ^{_{) -S (= O) 2 R}} 22 '( ^{wherein, R 22'} has the same meaning as defined above.)
May be substituted with one or more substituents selected from the same or different,
In addition, the nitrogen-containing saturated heterocyclic ring consisting of a single ring in the above 4), 5) and 8) is further one or more substitutions selected from the C _1-6 alkyl group and the above 1 ′) to 10 ′). It may be substituted with a group.
[Group C]
1) a halogen atom,
2) —OR ¹³ ′ (wherein R ¹³ ′ is
(A) a hydrogen atom,
(B) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from Group B, or (c) —COR ¹⁴ ′ (wherein R ¹⁴ ′ is
a) a hydrogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B;
d) C _1-6 alkoxy group (the C _1-6 alkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
e) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
f) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
g) Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following (i) and (ii).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ), Or h) an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ). ). ),
3) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B;
4) Cycloalkylalkoxy group (The cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
5) Aralkyl group (The aralkyl group may be substituted by one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
6) Aralkoxy group (The aralkoxy group may be substituted with one or more substituents which are the same or different and are selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
7) —COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
8) -NR ¹⁵ 'R ¹⁶ ' (wherein R ¹⁵ 'and R ¹⁶ ' are the same or different,
(A) a hydrogen atom, or (b) a C _1-6 alkyl group that may be substituted with one or more of the same or different substituents selected from the group B, or (c) R ¹⁵ ′ and R ¹⁶ 'is a nitrogen-containing saturated heterocycle consisting of a single ring together with the nitrogen atom to which they are bonded (wherein the heterocycle is one or more substituents selected from the following (i) and (ii): May be substituted.
(I) a substituent selected from the group B;
(Ii) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ) May be formed. ),
9) —NR ¹⁷ ′ COR ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above, and R ¹⁷ ′ represents
(A) a hydrogen atom, or (b) a C _1-6 alkyl group which may be substituted with one or more substituents selected from the same or different group B. ),
_{^{10) -NR 17 'S (=}} O) 2 R 14' ( ^{wherein, R 14} 'and ^{R 17'} has the same meaning as defined above.)
11) —NR ¹⁷ ′ CONR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′, R ¹⁶ ′ and R ¹⁷ ′ are as defined above),
12) —SR ¹³ ′ (wherein R ¹³ ′ has the same meaning as described above),
13) —S (═O) R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
14) —S (═O) ₂ R ¹⁴ ′ (wherein R ¹⁴ ′ has the same meaning as described above),
15) —S (═O) ₂ NR ¹⁵ ′ R ¹⁶ ′ (wherein R ¹⁵ ′ and R ¹⁶ ′ are as defined above),
16) A saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (a) and (b)).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
17) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following (a) and (b)) It may be substituted with one or more substituents.
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
18) Aryloxy group (The aryloxy group may be substituted with one or more substituents selected from the following (a) and (b).
(A) a substituent selected from the group B;
(B) a C _1-6 alkyl group which may be substituted with one or more same or different substituents selected from the group B; ),
19) cyano group, and 20) nitro group]   The nitrogen-containing fused ring compound represented by the general formula [1] is (3-chloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone, 26. A pharmaceutical composition according to any one of claims 1 to 25.   The nitrogen-containing fused ring compound represented by the general formula [1] is (3-bromo-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone, 26. A pharmaceutical composition according to any one of claims 1 to 25.   The nitrogen-containing condensed ring compound represented by the general formula [1] is (3,5-dichloro-4-hydroxyphenyl)-(2,3-dihydrobenzo [1,4] oxazin-4-yl) -methanone. 26. A pharmaceutical composition according to any one of claims 1 to 25. One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for stabilizing a salt to be obtained, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not contacted with a basic additive.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof In which the basic additive is not blended, or 1 part by weight of the basic additive is added to 1 part by weight of the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof. Stabilization method blended in less than part.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives selected from the group consisting of acidic additives and neutral additives are added to the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof. The basic additive is not added, or the basic additive is added in an amount of less than 1 part by weight to 1 part by weight of the nitrogen-containing condensed ring compound or pharmaceutically acceptable salt thereof. A method for stabilizing a ring compound or a pharmaceutically acceptable salt thereof.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives are blended in the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for stabilizing a salt, wherein all of the additives are selected from the group consisting of acidic additives and neutral additives.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for preserving the salt, wherein the nitrogen-containing fused ring compound or a pharmaceutically acceptable salt thereof is not contacted with a basic additive.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives are blended with the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof In which the basic additive is not added, or the basic additive is less than 1 part by weight with respect to 1 part by weight of the nitrogen-containing fused ring compound or pharmaceutically acceptable salt thereof. Storage method to be blended in.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives selected from the group consisting of acidic additives and neutral additives are added to the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof. The basic additive is not added, or the basic additive is added in an amount of less than 1 part by weight to 1 part by weight of the nitrogen-containing condensed ring compound or pharmaceutically acceptable salt thereof. A method for preserving a ring compound or a pharmaceutically acceptable salt thereof.

[Each symbol in the formula is as defined in claim 1.] ] One or more pharmaceutically acceptable additives are blended in the nitrogen-containing fused ring compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, and the nitrogen-containing fused ring compound or the pharmaceutically acceptable salt thereof A method for preserving a salt, wherein all of the additives are selected from the group consisting of an acidic additive and a neutral additive.

[Each symbol in the formula is as defined in claim 1.] ]

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