HK1208676B - Benzazepine derivative and pharmaceutical use thereof - Google Patents

Abstract

The objective of the present invention is to provide a compound which has V2 receptor agonistic activity. A pharmaceutical composition which contains, as an active ingredient, a compound represented by general formula (I) or a pharmacologically acceptable salt thereof. (In general formula (I), R1 represents a group represented by formula (2) or the like; R2 represents a hydrogen atom or a lower alkyl group; R3represents a lower alkyl group which may be substituted by 1-3 fluorine atoms, or a halogen atom; R4 represents a five-membered aromatic monocyclic heterocyclic group, a five-membered non-aromatic monocyclic heterocyclic group or the like (provided that these heterocyclic groups have at least one nitrogen atom and may be substituted by a lower alkyl group); and R5 represents a lower alkyl group, a halogen atom or the like.) (In formula (2), A represents a lower alkylene group which may be substituted by a lower alkyl group, or the like; R6 represents a hydrogen atom or the like; and R7 represents a hydroxyl group, an aromatic heterocyclic group which may be substituted by a lower alkyl group, a carbamoyl group or the like.)

Description

Benzazepine derivatives and medicinal use thereof

Technical Field

The present invention relates to a novel benzazepine derivative useful as a pharmaceutical product and a medical use thereof. The compound has various medical applications as a V2 receptor agonist.

Background

Arginine vasopressin is biosynthesized in the hypothalamus and is a peptide consisting of 9 amino acids secreted from the posterior lobe of the pituitary gland. Receptors for arginine vasopressin are classified into 3 subtypes, V1a, V1b and V2, with V1a receptor being present in the liver, muscle tissue vascular cells, platelets, peripheral tissues and central nervous system, V1b receptor being present in the central nervous system, and V2 receptor being present in kidney collecting duct cells. Arginine vasopressin, when bound to the V2 receptor, promotes the reabsorption of water in the renal collecting ducts, resulting in a decrease in urine volume. Therefore, when arginine vasopressin is insufficient, polyuria symptoms are manifested, and the diseases caused by arginine vasopressin include central diabetes insipidus, nocturia in children, nocturia, overactive bladder, and the like. Therefore, V2 receptor agonists are useful as prophylactic or therapeutic agents for these diseases. Further, since the V2 receptor agonist has an action of releasing factor VIII and von willebrand factor in blood, it can be used for the treatment of bleeding diseases (hemophilia, von willebrand disease, etc.).

Conventionally, as a V2 receptor agonist, desmopressin (a substance in which cysteine at position 1 of arginine vasopressin is deaminated and arginine at position 8 is converted into d-form) has been used as a peptide for the treatment of central diabetes insipidus and nocturia. However, oral formulations of desmopressin have very low bioavailability and require high amounts in order to achieve their effect. In addition, desmopressin preparations are expensive, and side effects due to differences in absorption among individuals may occur, and are not necessarily satisfactory in terms of safety. Therefore, it is desired to develop a drug having a high bioavailability and a small absorption difference.

On the other hand, the metabolic reaction based on cytochrome P-450(CYP) plays a major role in the disappearance of a drug from the body, and it is considered that drugs metabolized by CYPs of the same molecular species are subjected to some metabolic inhibition if they compete with metabolic enzymes thereof. Inhibition of CYP may cause fluctuations in the concentration of the drug in blood and tissues, changes in the therapeutic effect, and the manifestation of serious side effects. Therefore, it is desired to develop a drug having low affinity for CYP and low possibility of inhibiting enzymes.

Heretofore, as compounds having a vasopressin receptor agonistic action, benzoheterocyclic derivatives (patent documents 1 to 3), benzazepine derivatives (patent documents 4 to 5), amide derivatives (patent document 6), and benzodiazepine derivatives (patent document 7) have been reported, and as compounds having a vasopressin receptor antagonistic action, substituted spirocyclic benzazepine derivatives (patent document 8) have been reported, which are structurally different from the compounds of the present invention having a carbonyl group at the 4-position carbon of benzazepine.

Documents of the prior art

Patent document

Patent document 1: international publication No. 95/34540

Patent document 2: japanese laid-open patent publication Hei 09-221476

Patent document 3: japanese patent laid-open publication No. 2000-351768

Patent document 4: international publication No. 97/22591

Patent document 5: japanese patent laid-open No. H11-60488

Patent document 6: japanese laid-open patent publication No. 11-1456

Patent document 7: international publication No. 2006/104008

Patent document 8: international publication No. 2005/37795

Disclosure of Invention

Problems to be solved by the invention

The purpose of the present invention is to provide a compound having a V2 receptor agonistic action, and to provide a prophylactic or therapeutic agent for central diabetes insipidus, nocturia, nocturnal pollakisuria, overactive bladder, hemophilia, or von Willebrand disease based on a V2 receptor agonistic action.

Means for solving the problems

The present inventors consider in view of the above-described aspects that: as means for solving the above problems, compounds having a novel basic structure are effective, and intensive studies have been made on the development of a novel V2 receptor agonist. As a result, they have found that a compound represented by the following general formula (I) and a salt thereof have a very excellent V2 receptor agonistic action, and have completed the present invention.

That is, according to the present invention, there is provided a compound represented by the general formula (I):

[ solution 1]

[ in the formula, R¹Represents hydroxy, lower alkoxy, or the formula:

[ solution 2]

(wherein A is absent or represents a lower alkylene group which may have lower alkyl substitution; R⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic group which may be substituted with a lower alkyl group, a non-aromatic heterocyclic group which may be substituted with an oxy group, or a carbamoyl group which may be substituted with a lower alkyl group); r²Represents a hydrogen atom or a lower alkyl group; r³Represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms or a halogen atom; r⁴Represents a lower alkoxy group which may be substituted by a halogen atom, a 5-membered aromatic monocyclic heterocyclic group or a 5-membered non-aromatic monocyclic heterocyclic group (wherein these heterocyclic groups contain at least one nitrogen atom and may be substituted by a lower alkyl group); r⁵Represents a hydrogen atom, a lower alkyl group or a halogen atom]These compounds are referred to as "compounds of the present invention" in the present specification described below. Various embodiments of the compounds of the present invention are described below.

One embodiment of the present invention is that R in the above general formula (I)¹Is hydroxy, lower alkoxy, or of the formula:

[ solution 3]

[ wherein A is absent or represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic group which may be substituted with a lower alkyl group, a non-aromatic heterocyclic group which may be substituted with an oxy group, or a carbamoyl group which may be substituted with a lower alkyl group. Wherein, except the following cases: a is lower alkylene which may have lower alkyl substitutionAlkyl, and R⁶And R⁷Both are the case of hydrogen atoms; and A is absent, R⁶Is lower alkyl, and R⁷In the case of hydrogen atoms]The compound of (1).

Another embodiment of the present invention is the use of R in the above formula (I)¹Is of the formula:

[ solution 4]

[ wherein A is absent or represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, an oxadiazolyl group which may be substituted with a lower alkyl group, a pyrrolidinyl group which may be substituted with an oxy group, or a carbamoyl group which may be substituted with 1 to 2 lower alkyl groups. Wherein, except the following cases: a is lower alkylene which may have lower alkyl substitution, and R⁶And R⁷Both are the case of hydrogen atoms; and A is absent, R⁶Is lower alkyl, and R⁷In the case of hydrogen atoms]The compound of (1).

Yet another embodiment of the present invention is the use of R in formula (I) above¹Is of the formula:

[ solution 5]

[ wherein A represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom; r⁷Represents a hydroxyl group, an oxadiazolyl group which may have a lower alkyl group substituent, or a carbamoyl group]The compound of (1).

Yet another embodiment of the present invention is the use of R in formula (I) above⁴Is a lower alkoxy group which may have 1 to 3 fluorine atoms substituted, may haveA pyrrolidinyl group substituted with 1 to 4 lower alkyl groups, a pyrazolyl group substituted with 1 to 3 lower alkyl groups, or an oxazolyl group substituted with 1 to 2 lower alkyl groups.

Yet another embodiment of the present invention is the use of R in formula (I) above⁴Is a compound selected from any one of the following groups.

[ solution 6]

[ in the formula, R⁸Represents a hydrogen atom or a lower alkyl group]

Yet another embodiment of the present invention is the use of R in formula (I) above⁴Is a compound selected from any one of the following groups.

[ solution 7]

[ in the formula, R⁸Represents a lower alkyl group]

Yet another embodiment of the present invention is the use of R in formula (I) above⁵A compound which is a methyl group or a fluorine atom.

Yet another embodiment of the present invention is the use of R in formula (I) above³A compound which is a methyl group, a trifluoromethyl group or a chlorine atom.

Yet another embodiment of the present invention is the use of R in formula (I) above¹Is of the formula:

[ solution 8]

[ wherein A represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom; r⁷Represents a hydroxyl group, an oxadiazolyl group which may have a lower alkyl group substituent, or a carbamoyl group]；R²Is a hydrogen atom, R³Is methyl, trifluoromethyl or chlorine atom; r⁴Is selected from the following group

[ solution 9]

[ in the formula, R⁸Represents a lower alkyl group]Any one of the groups; r⁵A compound which is a methyl group or a fluorine atom.

In the present invention, there is also provided a compound represented by the following general formula (II) as an intermediate of the compound of the present invention represented by the above general formula (I).

[ solution 10]

[ in the formula, R²Represents a hydrogen atom or a lower alkyl group; r⁵Represents a hydrogen atom, a methyl group, an ethyl group or a halogen atom; r⁹A protecting group representing a hydrogen atom or a carboxyl group; r¹⁰Represents a hydrogen atom or a protecting group for an amino group. Wherein R is²And R⁵Except for the case where all are hydrogen atoms]

The present invention further provides a pharmaceutical composition comprising the above-mentioned compound of the present invention as an active ingredient. That is, the pharmaceutical composition of the present invention is used for the prevention or treatment of a disease selected from the group consisting of central diabetes insipidus, nocturia, overactive bladder, hemophilia, and von willebrand disease.

Effects of the invention

The compound of the present invention has an excellent V2 receptor agonistic action and is useful as a prophylactic or therapeutic agent for a disease selected from the group consisting of central diabetes insipidus, nocturia, overactive bladder, hemophilia, and von Willebrand disease. The main compound of the present invention has a low inhibitory activity on the drug metabolizing enzymes CYP3a4 and CYP2C9, and further has excellent properties in terms of physical properties as a pharmaceutical product such as solubility and membrane permeability, and kinetics such as plasma clearance and volume of distribution, compared to a compound having a conventionally known V2 receptor agonistic activity, and therefore, is a safe and useful drug exhibiting excellent deviation between various side effects (cytotoxicity, action on hERG and CYP) and drug efficacy.

Detailed Description

The compounds of the present invention are described below.

[ solution 11]

The compound of the present invention is a compound represented by the general formula (I) wherein R is¹、R²、R³、R⁴And R⁵The compound or a pharmacologically acceptable salt thereof is defined as follows.

R¹Represents hydroxy, lower alkoxy or the formula:

[ solution 12]

[ wherein A is absent or represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, mayAn aromatic heterocyclic group which may have a lower alkyl group, a non-aromatic heterocyclic group which may have an oxy group, or a carbamoyl group which may have a lower alkyl group]Among these, R¹Preferably hydroxy, lower alkoxy or of the formula:

[ solution 13]

[ wherein A is absent or represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic group which may be substituted with a lower alkyl group, a non-aromatic heterocyclic group which may be substituted with an oxy group, or a carbamoyl group which may be substituted with a lower alkyl group. Wherein, except the following cases: a is lower alkylene which may have lower alkyl substitution, and R⁶And R⁷Both are the case of hydrogen atoms; and A is absent, R⁶Is lower alkyl, and R⁷In the case of hydrogen atoms]Among them, the following formula is particularly preferred:

[ solution 14]

[ wherein A is absent or represents a lower alkylene group which may be substituted with a lower alkyl group; r⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, an oxadiazolyl group which may be substituted with a lower alkyl group, a pyrrolidinyl group which may be substituted with an oxy group, or a carbamoyl group which may be substituted with 1 to 2 lower alkyl groups. Wherein, except the following cases: a is lower alkylene which may have lower alkyl substitution, and R⁶And R⁷Both are the case of hydrogen atoms; and A is absent, R⁶Is lower alkyl, and R⁷In the case of hydrogen atoms]Wherein A is preferably a group which may haveLower alkyl-substituted lower alkylene, preferably R⁶Is a hydrogen atom, preferably R⁷Is hydroxy, oxadiazolyl which may have lower alkyl substitution, or carbamoyl.

R²Is a hydrogen atom or a lower alkyl group, preferably a hydrogen atom. R³Is a lower alkyl group which may be substituted with 1 to 3 fluorine atoms, or a halogen atom, among which a methyl group, a trifluoromethyl group or a chlorine atom is preferable.

R⁴Is a lower alkoxy group which may be substituted with a halogen atom, a 5-membered aromatic monocyclic heterocyclic group, or a 5-membered non-aromatic monocyclic heterocyclic group (wherein these heterocyclic groups contain at least one nitrogen atom and may be substituted with a lower alkyl group). Among these, R⁴Preferably a group selected from the group consisting of,

[ solution 15]

[ in the formula, R⁸Represents a hydrogen atom or a lower alkyl group]Among them, particularly preferred is a group selected from the group

[ solution 16]

[ in the formula, R⁸Represents a lower alkyl group]。

R⁵Is a hydrogen atom, a lower alkyl group or a halogen atom, among these, a methyl group or a fluorine atom is preferred.

For particularly preferred compounds of the invention, in the general formula (I), R¹Is of the formula:

[ solution 17]

[ wherein A represents a lower alkylene group which may have lower alkyl substitution, R⁶Represents a hydrogen atom, R⁷Represents a hydroxyl group, an oxadiazolyl group which may have a lower alkyl group substituent, or a carbamoyl group]；R²Is a hydrogen atom, R³Is methyl, trifluoromethyl or chlorine atom, R⁴Is a group selected from the group

[ solution 18]

[ in the formula, R⁸Represents a lower alkyl group]，R⁵Is a methyl group or a fluorine atom.

In the present specification, the following definitions are provided.

"lower alkoxy" refers to a group-O- (C1-C3 alkyl), and examples thereof include methoxy, ethoxy, n-propoxy and isopropoxy.

The "lower alkyl group" refers to a linear alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, and an n-propyl group.

The "lower alkylene group" is a linear alkylene group having 1 to 3 carbon atoms, and examples thereof include a methylene group, an ethylene group, and an n-propylene group.

The "aromatic heterocyclic group" refers to a monocyclic to 3-ring aromatic ring group containing at least one heteroatom such as nitrogen, oxygen, sulfur, and the like, and examples thereof include pyridyl, thienyl, furyl, pyrazinyl, pyridazinyl, thiazolyl, pyrimidinyl, pyrazolyl, pyrrolyl, oxazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, imidazolyl, quinolyl, quinazolinyl, purinyl, acridinyl, and the like.

The "non-aromatic heterocyclic group" refers to a non-aromatic cyclic group having 3 to 10 membered rings which may have an unsaturated bond in part and at least one heteroatom such as nitrogen, oxygen, sulfur, and the like, and examples thereof include pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperazinyl, indolyl, 1, 2-dihydroisoquinolinyl, 1,2,3, 4-tetrahydroquinoxalinyl, and the like.

"halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

The "5-membered aromatic or non-aromatic monocyclic heterocyclic group" means a monocyclic group which may have an unsaturated bond and which contains at least one heteroatom such as nitrogen, oxygen, sulfur, and the like, and examples thereof include pyrrolidinyl, thienyl, furyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl and the like.

"pharmacologically acceptable salt" means a salt that retains the biological effectiveness and properties of the compound represented by formula (I) and is not biologically or otherwise undesirable. Such pharmacologically acceptable salts are included within the scope of the present invention. Examples of the pharmacologically acceptable salts include salts with amino acids (for example, salts with lysine, arginine, etc.), alkali metal addition salts (for example, salts with sodium, potassium, etc.), alkaline earth metal addition salts (for example, salts with calcium, magnesium, etc.), organic amine addition salts (for example, salts with diethylamine, diethanolamine, piperazine, etc.), inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.), organic acid addition salts (for example, salts with formic acid, acetic acid, trifluoroacetic acid, etc.), and the like. The formation reaction of these addition salts can be carried out according to a conventional method.

In the case where the compound is converted into the above-mentioned general formula (I) by a reaction based on an enzyme, gastric acid or the like under physiological conditions in vivo, such a compound is included in the scope of the present invention. Examples thereof include: r of a compound represented by the general formula (I)¹In the case of forming a carboxyl group as a hydroxyl group, the carboxyl group is esterified (for example, ethyl esterification, carboxymethyl esterification, pivaloyloxymethylation, etc.) or amidated (for example, methylamidation, etc.). In addition, from R¹Group ofIn the case of a compound having a hydroxyl group, the hydroxyl group may be acylated (for example, acetylation, propionylation, t-butylcarbonylation, etc.), alkoxycarbonylated (for example, methoxycarbonylated, ethoxycarbonylated, t-butoxycarbonylated, etc.), succinylated, or the like.

The following is a description of compounds that are intermediates of the compounds of the present invention.

[ solution 19]

The intermediate compound of the present invention is a compound represented by the above general formula (II) wherein R²Is hydrogen atom or lower alkyl; r⁵Is a hydrogen atom, a methyl group, an ethyl group or a halogen atom; r⁹A protecting group which is a hydrogen atom or a carboxyl group; r¹⁰A protecting group being a hydrogen atom or an amino group (wherein R is²And R⁵Except for the case where both are hydrogen atoms).

Here, the "protecting group for a carboxyl group" refers to a group known as a protecting group for a carboxyl group in general organic synthesis, and may be exemplified by: (1) examples of the lower alkyl group include a linear or branched lower alkyl group having 1 to 4 carbon atoms (e.g., methyl, ethyl, isopropyl, tert-butyl), (2) a halogenated lower alkyl group (e.g., 2-iodoethyl, 2,2, 2-trichloroethyl), (3) a lower alkoxymethyl group (e.g., methoxymethyl, ethoxymethyl, isobutoxymethyl), (4) a lower aliphatic acyloxymethyl group (e.g., butyryloxymethyl, pivaloyloxymethyl), (5) a 1-lower alkoxycarbonyloxyethyl group (e.g., 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl), (6) an aralkyl group (e.g., benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl), (7) benzhydryl, and (8) a benzofuranone group.

The "protecting group for an amino group" is a group generally known as a protecting group for an amino group in organic synthesis, and can be exemplified by: (1) substituted or unsubstituted lower alkanoyl (e.g., formyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl, phenoxyacetyl, thienylacetyl), (2) substituted or unsubstituted lower alkoxycarbonyl (e.g., benzyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), (3) substituted or unsubstituted lower alkyl (e.g., methyl, t-butyl, 2,2, 2-trichloroethyl, trityl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, pivaloyloxymethyl), (4) substituted silyl (e.g., trimethylsilyl, t-butyldimethylsilyl), and (5) substituted or unsubstituted benzylidene (e.g., benzylidene, o-hydroxybenzylidene, p-nitrobenzylidene, m-chlorobenzylidene, 3, 5-di (t-butyl) -4-hydroxybenzylidene), 3, 5-di (t-butyl) benzylidene), and the like.

In the case where 1 or 2 or more asymmetric carbon atoms are present in the compound of the present invention, compounds based on isomers of asymmetric carbon atoms and any combination thereof are also included in the present invention. In addition, in the case where geometric isomers or tautomers exist in the compounds of the present invention, these geometric isomers or tautomers are also included in the present invention. The compound of the present invention also includes solvates with pharmaceutically acceptable solvents such as water, ethanol, and isopropyl alcohol.

The compound represented by the general formula (I) as the compound of the present invention can be produced by a method represented by the following reaction step formula I, a method described in examples, or a method combining known methods.

[ reaction Process formula I ]

[ solution 20]

[ in the formula, R²Represents a hydrogen atom or a lower alkyl group; r³Represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms or a halogen atom; r⁴Represents a lower alkoxy group which may be substituted by a halogen atom,A 5-membered aromatic monocyclic heterocyclic group or a 5-membered non-aromatic monocyclic heterocyclic group (wherein these heterocyclic groups contain at least one nitrogen atom and may have a lower alkyl group as a substituent); r⁵Represents a hydrogen atom, a lower alkyl group or a halogen atom; a is absent or represents lower alkylene which may be substituted with lower alkyl; r⁶Represents a hydrogen atom or a lower alkyl group; r⁷Represents a hydrogen atom, a hydroxyl group, an aromatic heterocyclic group which may be substituted with a lower alkyl group, a non-aromatic heterocyclic group which may be substituted with an oxy group, or a carbamoyl group which may be substituted with a lower alkyl group; r⁹A protecting group representing a carboxyl group]

[ Process I-1]

The compound represented by the general formula (III) is converted into an acid chloride using a chlorinating agent (e.g., thionyl chloride, oxalyl chloride, etc.) in the presence or absence of an additive (e.g., N-dimethylformamide, etc.) in an appropriate solvent (e.g., toluene, dichloromethane, etc.), and then reacted with the compound represented by the general formula (IIa) in an appropriate solvent (e.g., toluene, dichloromethane, tetrahydrofuran, acetonitrile, etc.) using a base (e.g., triethylamine, N-diethylaniline, pyridine, etc.), thereby obtaining the compound represented by the general formula (IV). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours. The compounds represented by the general formula (III) and the general formula (IIa) may be commercially available compounds, but may be produced by the method of the reaction step formulas II to IV described later.

[ Process I-2]

By removing the Protecting group R of the compound represented by the general formula (IV) by the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)", in the following manner⁹To obtain a compound represented by the general formula (V).

[ Process I-3]

The compound represented by the general formula (V) is reacted with the compound represented by the general formula (VI) in an appropriate solvent (e.g., N-dimethylformamide, dichloromethane, tetrahydrofuran, etc.) in the presence or absence of an additive (e.g., diisopropylethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc.) using a condensing agent (e.g., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, etc.), thereby obtaining the compound represented by the general formula (I). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours. The compound represented by the general formula (VI) may be obtained as a commercially available product, but may be produced by a known method.

The compound represented by the general formula (III) used as a starting material in the reaction step formula I can be produced by the methods shown in the following reaction step formulae II and III, the methods described in reference examples, or known methods.

[ reaction Process formula II ]

[ solution 21]

[ in the formula, R³Represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms or a halogen atom; r⁸Represents a lower alkyl group; r¹¹A protecting group representing a carboxyl group; x represents a leaving group such as a halogen atom, trifluoromethanesulfonate or methanesulfonate]

[ Process II-1]

The compound represented by the general formula (VII) is reacted with the compound represented by the general formula (VIII) in an appropriate solvent (for example, N-dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, etc.) using a base (for example, potassium carbonate, sodium carbonate, etc.), thereby obtaining the compound represented by the general formula (IX). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours. The compounds represented by the general formulae (VII) and (VIII) may be commercially available compounds, but they may be produced by a known method.

[ Process II-2]

By removing the Protecting group R of the compound represented by the general formula (IX) by the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"¹¹Thereby obtaining a compound represented by the general formula (IIIa).

[ reaction Process formula III ]

[ solution 22]

[ in the formula, R³Represents a lower alkyl group which may be substituted with 1 to 3 fluorine atoms or a halogen atom; r⁸Represents a lower alkyl group; r¹¹A protecting group representing a carboxyl group; r¹²Indicates that R may react with R at the time of deprotection¹¹A distinct protecting group for a carboxyl group; x represents a leaving group such as a halogen atom, trifluoromethanesulfonate or methanesulfonate]

[ Process III-1]

The compound represented by the general formula (X) is converted into an acid chloride using a chlorinating agent (e.g., thionyl chloride, oxalyl chloride, etc.) in the presence or absence of an additive (e.g., N-dimethylformamide, etc.) in an appropriate solvent (e.g., toluene, dichloromethane, etc.), and then reacted with an alcohol (e.g., methanol, ethanol, isopropanol, benzyl alcohol, etc.) in an appropriate solvent (e.g., toluene, dichloromethane, tetrahydrofuran, acetonitrile, etc.) using a base (e.g., triethylamine, N-diethylaniline, pyridine, etc.), thereby obtaining the compound represented by the general formula (XI). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours. The compound represented by the general formula (X) may be obtained as a commercially available product, but may be produced by a known method.

[ Process III-2]

The compound represented by the general formula (XI) is reacted in an appropriate solvent (e.g., dimethylsulfoxide, N-dimethylformamide, methanol, ethanol, etc.) in the presence or absence of an additive (e.g., 1, 3-bis (triphenylphosphine) propane, 1 '-bis (diphenylphosphino) ferrocene, etc.) using a base (e.g., triethylamine, diisopropylethylamine, cesium carbonate, etc.), a palladium catalyst (e.g., palladium acetate, palladium chloride, [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, tetrakis (triphenylphosphine) palladium, etc.) under a carbon monoxide atmosphere, thereby obtaining the compound represented by the general formula (XII). The reaction temperature is 40 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[ Process III-3]

The Protecting group R of the compound represented by the general formula (XII) is removed by referring to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"¹²To obtain a compound represented by the general formula (XIII).

[ Process III-4]

The compound represented by the general formula (XIII) and the compound represented by the general formula (XIV) are reacted in an appropriate solvent (for example, N-dimethylformamide, dichloromethane, tetrahydrofuran, etc.) in the presence or absence of an additive (for example, diisopropylethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc.) using a condensing agent (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, etc.), thereby obtaining the compound represented by the general formula (XV). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours. The compound represented by the general formula (XIV) may be obtained as a commercially available product, but may be produced by a known method.

[ Process III-5]

The compound represented by the general formula (XV) is reacted with an oxidizing agent (e.g., dess-martin reagent, pyridine-sulfur trioxide complex, etc.) in an appropriate solvent (e.g., dichloromethane, tetrahydrofuran, etc.) in the presence or absence of an additive (dimethyl sulfoxide) to obtain the compound represented by the general formula (XVI). The reaction temperature is 0 ℃ to room temperature, and the reaction time is 30 minutes to 48 hours.

[ Process III-6]

The compound represented by the general formula (XVI) is reacted with a chlorinating agent (e.g., hexachloroethane, 1, 2-dibromo-1, 1,2, 2-tetrachloroethane, etc.) and a base (e.g., diisopropylethylamine, pyridine, triethylamine, etc.) in the presence of an additive (triphenylphosphine) in an appropriate solvent (e.g., dichloromethane, acetonitrile, etc.), to obtain the compound represented by the general formula (XVII). The reaction temperature is 0 ℃ to room temperature, and the reaction time is 30 minutes to 5 hours.

[ Process III-7]

The Protecting group R of the compound represented by the general formula (XVII) is removed by referring to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"¹¹Thereby obtaining a compound represented by the general formula (IIIb).

The compound represented by the general formula (IIa) used as a starting material in the reaction step formula I can be produced by the method shown in the following reaction step formulae IV to VI, the method described in the reference example, or a method combining known methods.

[ reaction Process formula IV ]

[ solution 23]

[ in the formula, R²Represents a hydrogen atom or a lower alkyl group; r⁵Represents a lower alkyl group or a halogen atom; r⁹A protecting group representing a carboxyl group; r¹⁰A protecting group representing a nitrogen atom; r¹³Represents cyano or carboxylic acid derivatives (e.g. methyl, ethyl, etc.)]

[ Process IV-1]

With reference to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)", using R¹⁰The nitrogen atom of (2-aminophenyl) methanol is protected to give a compound represented by the general formula (VIII). Incidentally, (2-aminophenyl) methanol is available as a commercially available product.

[ Process IV-2]

The compound represented by the general formula (XVIII) is reacted with manganese (IV) oxide in an appropriate solvent (e.g., dichloromethane, chloroform, acetone, tetrahydrofuran, etc.) to obtain the compound represented by the general formula (XIX). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[ Process IV-3]

The compound represented by the general formula (XIX) is reacted with the compound represented by the general formula (XX) in an appropriate solvent (e.g., N-dimethylformamide, dimethylsulfoxide, etc.) using a base (e.g., potassium carbonate, sodium hydride, etc.), thereby obtaining a compound represented by the general formula (XXI). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours. The compound represented by the general formula (XX) can be produced by the method of the reaction step formula VII described later.

[ Process IV-4]

The compound represented by the general formula (XXI) is reacted with a base (e.g., sodium ethoxide, potassium tert-butoxide, etc.) in an appropriate solvent (e.g., diethyl carbonate, ethanol, etc.) in the presence or absence of an additive (e.g., sodium bromide, lithium bromide, sodium iodide, etc.), to thereby obtain a compound represented by the general formula (XXII).

[ Process IV-5]

The compound represented by the general formula (XXII) is reacted with an acid (e.g., sulfuric acid, hydrochloric acid, etc.) in an appropriate solvent (e.g., acetic acid, water, etc.), to thereby obtain a compound represented by the general formula (XXIII). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 12 hours to 7 days.

[ Process IV-6]

Reference "Protecting Groups in OrgaThe method described in nic Synthesis,3rd Edition, Wiley (1999)' with R⁹Protecting the carboxyl group of the compound represented by the formula (XXIII) to thereby obtain a compound represented by the formula (XXIV).

[ Process IV-7]

With reference to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)", using R¹⁰Protecting the nitrogen atom of the compound represented by the formula (XXIV) to thereby obtain a compound represented by the formula (XXV).

[ Process IV-8]

The compound represented by the general formula (XXV) is reacted in an appropriate solvent (for example, methanol, ethanol, 1, 4-dioxane, etc.) using a palladium catalyst (for example, palladium on carbon, palladium hydroxide on carbon catalyst, etc.) under a hydrogen atmosphere to obtain a compound represented by the general formula (XXVI). The reaction temperature is between room temperature and 60 ℃, and the reaction time is between 1 hour and 48 hours.

[ Process IV-9]

The compound represented by the general formula (XXVI) is reacted with an electrophile (e.g., methyl iodide, methyl bromide, ethyl iodide, N-fluorobenzenesulfonylimide, etc.) in an appropriate solvent (e.g., tetrahydrofuran, diethyl ether, etc.) using a base (e.g., lithium diisopropylamide, N-butyllithium, tert-butyllithium, etc.), thereby obtaining a compound represented by the general formula (XXVII). The reaction temperature is-78 ℃ to 0 ℃, and the reaction time is 30 minutes to 24 hours.

[ Process IV-10]

The Protecting group R of the compound represented by the general formula (XXVII) is removed by referring to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"¹⁰Thereby obtaining a compound represented by the general formula (IIa).

[ reaction Process formula V ]

[ solution 24]

[ in the formula, R⁵Represents a lower alkyl group or a halogen atom; r⁹A protecting group representing a carboxyl group; r¹⁰A protecting group representing a nitrogen atom]

[ Process V-1]

With reference to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)", using R¹⁰Protection of 3, 4-dihydro-1H-benzo [ b]Aza-5 (2H) -one nitrogen atom, to give a compound represented by the general formula (XXVIII). Specifically, 3, 4-dihydro-1H-benzo [ b ]]Aza-5 (2H) -ones can be obtained as commercially available products.

[ Process V-2]

The compound represented by general formula (XXVIII) is reacted with a base (e.g., sodium methoxide, sodium ethoxide, etc.) in an appropriate solvent (e.g., dimethyl carbonate, diethyl carbonate, etc.) to obtain a compound represented by general formula (XXIX). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 5 hours.

[ Process V-3]

The compound represented by general formula (XXIX) is reacted with an electrophile (e.g., methyl iodide, methyl bromide, ethyl iodide, N-fluorobenzenesulfonylimide, etc.) in an appropriate solvent (e.g., tetrahydrofuran, acetone, ethanol, etc.) using a base (e.g., potassium carbonate, cesium carbonate, sodium hydride, etc.), thereby obtaining a compound represented by general formula (XXX). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[ Process V-4]

The compound represented by general formula (XXX) is reacted with a reducing agent (e.g., triethylsilane) in an appropriate solvent (e.g., dichloromethane, tetrahydrofuran, etc.) using an acid (e.g., trifluoroacetic acid, methanesulfonic acid, boron trifluoride diethyl ether complex, etc.), thereby obtaining a compound represented by general formula (XXXI). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[ Process V-5]

The Protecting group R of the compound represented by the general formula (XXXI) is removed by referring to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"¹⁰Thereby obtaining a compound represented by the general formula (IIb).

[ reaction Process formula VI ]

[ solution 25]

[ in the formula, R⁵Represents a hydrogen atom, a lower alkyl group or a halogen atom; r⁹A protecting group representing a carboxyl group; r¹⁰A protecting group representing a nitrogen atom; r¹⁴And R¹⁵Represent mutually different alkyl groups which may have a substituent or aryl groups which may have a substituent]

[ Process VI-1]

The Protecting group R of the compound represented by the general formula (XXXI) is removed by referring to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"⁹Thereby obtaining a compound represented by the general formula (XXXII).

[ Process VI-2]

The compound represented by the general formula (XXXII) and the compound represented by the general formula (XXXIII) are reacted in an appropriate solvent (for example, N-dimethylformamide, dichloromethane, tetrahydrofuran, etc.) in the presence or absence of an additive (diisopropylethylamine, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, etc.), thereby obtaining the compound represented by the general formula (XXXIV). The reaction temperature is 0 ℃ to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours.

[ Process VI-3]

The compound represented by general formula (XXXIV) is obtained by reacting a compound represented by general formula (XXXIV) with an acid (e.g., sulfuric acid, hydrochloric acid, etc.) in an appropriate solvent (e.g., methanol, ethanol, benzyl alcohol, etc.). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 72 hours.

[ Process VI-4]

The Protecting group R of the compound represented by the general formula (XXXV) is removed by referring to the method described in "Protecting Groups in Organic Synthesis,3rd Edition, Wiley (1999)"¹⁰Thereby obtaining a compound represented by the general formula (IIc).

The compound represented by the general formula (XX) used in the reaction step formula IV can be produced by the method represented by the following reaction step formula VII, the method described in the reference example, or a method combining known methods.

[ reaction Process formula VII ]

[ solution 26]

[ in the formula, R²Represents a hydrogen atom or a lower alkyl group; r¹³Represents a cyano group or a carboxylic acid derivative (e.g., methyl ester, ethyl ester, etc.); x represents a leaving group such as a halogen atom, trifluoromethanesulfonate or methanesulfonate]

[ Process VII-1]

The compound represented by the general formula (XXXVI) is reacted with a cyanating agent (e.g., sodium cyanide, potassium cyanide, etc.) in the presence or absence of an additive (e.g., tetrabutylammonium bromide, sodium iodide, 18-crown-6-ether, etc.) in an appropriate solvent (e.g., N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.) to obtain a compound represented by the general formula (XXXVII). The reaction temperature is from room temperature to the boiling point of the solvent, and the reaction time is from 30 minutes to 24 hours.

[ Process VII-2]

The compound represented by the general formula (XXXVII) is reacted with a nucleophile (e.g., thionyl chloride, methylsulfonyl chloride, trifluoromethanesulfonic anhydride, etc.) in an appropriate solvent (e.g., dichloromethane, toluene, etc.) using a base (e.g., triethylamine, diisopropylethylamine, pyridine, etc.), thereby obtaining the compound represented by the general formula (XX). The reaction temperature is 0 ℃ to room temperature, and the reaction time is 30 minutes to 24 hours.

In addition, there are starting materials, intermediates, or compounds used as reagents, which are necessary for producing the compounds of the present invention, and those which are commercially available, but they can also be produced by a known method.

The compound of the present invention and a substituent (for example, hydroxyl group, amino group, carboxyl group, etc.) included in the compound used for producing the compound may be effective for producing the compound by introducing an appropriate Protecting group to the substituent at the stage of a raw material or an intermediate, and the Protecting group described in the above-mentioned "Protecting group in organic Synthesis,3rd Edition, Wiley (1999)" may be appropriately selected and used as necessary.

When the compound of the present invention and the compound used for producing the compound are separated and purified from the reaction solution, a method generally used can be employed. For example, solvent extraction, ion exchange resin, column chromatography using silica gel, alumina or the like as a carrier, High Performance Liquid Chromatography (HPLC) fractionation, thin layer chromatography, scavenger resin, recrystallization or the like can be used, and these separation and purification methods can be carried out alone or in combination. The separation and purification may be performed for each reaction, or may be performed after several reactions have been terminated.

In the case where the compounds in the present specification have asymmetric carbon atoms and optical isomers exist, these optical isomers can be resolved by a usual optical resolution method of racemic compounds, for example, by separate crystallization in the form of recrystallization from a diastereomeric salt of a general optically active compound, or by a conventional method such as chromatography in which a diastereomer is formed by reaction with a general optically active compound. Further, each optical isomer can be separated by High Performance Liquid Chromatography (HPLC) separation using an optically active substance separation column.

The compound of the present invention thus produced can act as a V2 receptor agonist, and therefore can be used as a pharmaceutical composition for the prevention or treatment of central diabetes insipidus, nocturia, nocturnal pollakiuria, overactive bladder, hemophilia, or von willebrand disease. It should be noted that the main compounds of the present invention act selectively on the V2 receptor, and therefore are advantageous in terms of side effects. In addition, the compounds of the present invention have lower inhibitory effects on the drug metabolizing enzymes CYP3a4 and CYP2C9 than the compounds having the V2 receptor agonistic effect known in the past, and further have excellent properties in terms of physical properties as a pharmaceutical product such as solubility and membrane permeability and in terms of kinetics such as plasma clearance and volume of distribution, and thus can be used safely.

As the administration form when the compound of the present invention is used as a pharmaceutical, various administration forms described in the general rules of "japanese pharmacopoeia" preparations can be selected according to the purpose. For example, when the composition is formed into a tablet form, it is generally sufficient to select an orally ingestible ingredient used in this field. Excipients such as lactose, crystalline cellulose, white sugar, potassium phosphate and the like are among such components. Further, various additives commonly used in the field of pharmaceutical preparations, such as a binder, a disintegrant, a lubricant, and an anti-aggregation agent, may be blended as desired.

The amount of the compound of the present invention contained as an active ingredient in the preparation of the present invention is not particularly limited, and may be appropriately selected from a wide range. The dose of the compound of the present invention is suitably determined depending on the administration method, age, sex, and other conditions of the patient, and the degree of the disease, but when orally administered, the 1-day dose of the compound of the present invention is suitably about 1 μ g to 100mg, preferably about 10 μ g to 20mg, and more preferably about 50 μ g to 5mg per 1kg body weight, and can be suitably administered in 1 to 4 divided doses on 1 day. However, the dose and frequency are determined in consideration of the relevant conditions including the degree of symptoms to be treated, the choice of the compound to be administered and the chosen route of administration, and therefore the range and frequency of the dose are not intended to limit the scope of the present invention.

Examples

The contents of the present invention will be described in further detail below with reference to examples, reference examples, and pharmacological test examples, but the technical scope of the present invention is not limited to the descriptions.

Nuclear magnetic resonance in the following examples and reference examples: (¹H-NMR) spectrum, chemical shift values are expressed in terms of the value (ppm) using tetramethylsilane as a standard substance. In the split pattern, a singlet is represented by "s", a doublet by "d", a triplet by "t", a quartet by "q", a quintet by "quin", a multiplet by "m", and a broad peak by "br". Mass spectrometry was performed using electrospray ionization (ESI). In the tables, a methyl group is represented by "Me" and an ethyl group is represented by "Et".

[ reference example 1]

(S) -2-methyl-4- (3-methylpyrrolidin-1-yl) benzoic acid methyl ester

Methyl 4-fluoro-2-methylbenzoate (970mg) was dissolved in N-methyl-2-pyrrolidone (20mL), and after (S) -3-methylpyrrolidine hydrochloride (772mg) was added in the presence of potassium carbonate (2.39g), the mixture was stirred at 120 ℃ for 6 hours. The reaction solution was allowed to return to room temperature, ethyl acetate was added thereto, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane: 1/6), whereby the title compound (720mg) was obtained as a colorless oil.

¹H-NMR(400MHz,CDCl₃)7.88(d,J＝8.0Hz,1H),6.34-6.30(m,2H),3.82(s,3H),3.51-3.47(m,1H),3.45-3.39(m,1H),3.36-3.29(m,1H),2.92-2.88(m,1H),2.59(s,3H),2.45-2.32(m,1H),2.17-2.10(m,1H),1.68-1.58(m,1H),1.13(d,J＝8.0Hz,3H).

ESI/MS(m/z)234(M+H)⁺.

[ reference example 2]

(S) -2-methyl-4- (3-methylpyrrolidin-1-yl) benzoic acid

Methyl (S) -2-methyl-4- (3-methylpyrrolidin-1-yl) benzoate (710mg) was dissolved in methanol (7mL), and after adding water (6mL) and lithium hydroxide monohydrate (383mg), the mixture was stirred at 60 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, the mixture was made acidic with a 5% citric acid aqueous solution, and then the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (660mg) as a white solid.

¹H-NMR(400MHz,CDCl₃)12.36(brs,1H),8.00(d,J＝8.0Hz,1H),6.36(d,J＝8.0Hz,1H),6.31(s,1H),3.51-3.48(m,1H),3.47-3.41(m,1H),3.37-3.31(m,1H),2.93-2.89(m,1H),2.62(s,3H),2.42-2.35(m,1H),2.18-2.10(m,1H),1.68-1.59(m,1H),1.13(d,J＝8.0Hz,3H).

ESI/MS(m/z)220(M+H)⁺,218(M-H)^-.

[ reference example 3]

Benzyl 4-bromo-2-methylbenzoate

4-bromo-2-methylbenzoic acid (2.15g) was dissolved in thionyl chloride (5.0mL) and N, N-dimethylformamide (100. mu.L), and stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in methylene chloride (10mL), and benzyl alcohol (1.0mL) and pyridine (1.6mL) were added to stir at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction was performed with dichloromethane. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate 1/0-6/1) to obtain the titled compound (2.65 g).

¹H-NMR(400MHz,CDCl₃)7.82(d,J＝8.4Hz,1H),7.47-7.30(m,7H),5.33(s,2H),2.58(s,3H).

[ reference example 4]

4- [ (benzyloxy) carbonyl]-3-Methylbenzoic acid methyl ester

Benzyl 4-bromo-2-methylbenzoate (4.86g) was dissolved in a mixed solvent of dimethyl sulfoxide (48mL) and methanol (48mL), and after palladium acetate (358mg), 1, 3-bis (diphenylphosphino) propane (657mg) and diisopropylethylamine (5.4mL) were added, the mixture was replaced with carbon monoxide, and the mixture was stirred overnight at 60 ℃. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate 24/1-3/1) to obtain the titled compound (3.91 g).

¹H-NMR(400MHz,CDCl₃)7.97(d,J＝8.1Hz,1H),7.94-7.90(m,1H),7.87(dd,J＝8.1,1.7Hz,1H),7.49-7.43(m,2H),7.43-7.33(m,3H),5.36(s,2H),3.93(s,3H),2.63(s,3H).

ESI/MS(m/z)285(M+H)⁺.

[ reference example 5]

4- [ (benzyloxy) carbonyl]-3-methylbenzoic acid

Methyl 4- [ (benzyloxy) carbonyl ] -3-methylbenzoate (3.03g) was dissolved in a mixed solvent of tetrahydrofuran (30mL) and water (30mL), and lithium hydroxide monohydrate (671mg) was added to stir at room temperature for 2 hours. 1M hydrochloric acid was added to the reaction solution, and the mixture was adjusted to acidic, followed by extraction with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (2.84g) as a white solid.

¹H-NMR(400MHz,DMSO)13.21(s,1H),7.92(d,J＝8.0Hz,1H),7.90-7.77(m,2H),7.53-7.30(m,5H),5.35(s,2H),2.55(s,3H).

ESI/MS(m/z)269(M-H)^-.

[ reference example 6]

4- [ (1-hydroxypropan-2-yl) carbamoyl]-2-methylbenzoic acid benzyl ester

4- [ (benzyloxy) carbonyl ] -3-methylbenzoic acid (1.24g) was dissolved in N, N-dimethylformamide (23mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.76g), 1-hydroxybenzotriazole (1.41g), diisopropylethylamine (3.1mL) and DL-2-amino-1-propanol (730. mu.L) were added and stirred at 40 ℃ overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/ethyl acetate 1/2) to obtain the titled compound (1.07 g).

¹H-NMR(400MHz,CDCl₃)7.90(d,J＝8.1Hz,1H),7.60(s,1H),7.56(d,J＝8.1Hz,1H),7.48-7.29(m,5H),6.71(brs,1H),5.32(s,2H),4.31-4.15(m,1H),3.73(dd,J＝11.1,3.7Hz,1H),3.61(dd,J＝11.1,5.5Hz,1H),3.37(brs,1H),2.56(s,3H),1.25(d,J＝6.8Hz,3H).

ESI/MS(m/z)328(M+H)⁺,326(M-H)^-.

[ reference example 7]

2-methyl-4- [ (1-oxopropan-2-yl) carbamoyl]Benzoic acid benzyl ester

Benzyl 4- [ (1-hydroxypropan-2-yl) carbamoyl ] -2-methylbenzoate (1.07g) was dissolved in methylene chloride (16mL), and dess-martin reagent (2.08g) was added at 0 ℃ and then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction was performed with dichloromethane. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate 1/1-2/5) to obtain the titled compound (846 mg).

¹H-NMR(400MHz,CDCl₃)9.64(s,1H),7.98(d,J＝8.1Hz,1H),7.68(s,1H),7.66-7.59(m,1H),7.48-7.31(m,5H),7.01(brs,1H),5.35(s,2H),4.79-4.62(m,1H),2.63(s,3H),1.49(d,J＝7.4Hz,3H).

ESI/MS(m/z)326(M+H)⁺,324(M-H)^-.

[ reference example 8]

Benzyl 2-methyl-4- (4-methyloxazol-2-yl) benzoate

Triphenylphosphine (2.05g) and hexachloroethane (1.85g) were dissolved in acetonitrile (18mL), and a solution of benzyl 2-methyl-4- [ (1-oxopropan-2-yl) carbamoyl ] benzoate (846mg) in acetonitrile (8mL) was added, followed by stirring at room temperature for 10 minutes. Pyridine (1.3mL) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate 12/1-5/2) to obtain the title compound (691 mg).

¹H-NMR(400MHz,CDCl₃)8.02(d,J＝8.2Hz,1H),7.95-7.90(m,1H),7.89-7.82(m,1H),7.50-7.30(m,6H),5.36(s,2H),2.66(s,3H),2.26(d,J＝1.2Hz,3H).

ESI/MS(m/z)308(M+H)⁺.

[ reference example 9]

2-methyl-4- (4-methyloxazol-2-yl) benzoic acid

Benzyl 2-methyl-4- (4-methyloxazol-2-yl) benzoate (69.0mg) was dissolved in methanol (8mL), and 1M aqueous sodium hydroxide solution (4mL) was added and stirred at 50 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure, and 1M hydrochloric acid was added to the obtained residue to adjust the residue to acidic, and then the precipitated crystal was filtered and washed with water to obtain the title compound (429mg) as a white crystal.

¹H-NMR(400MHz,DMSO)7.97(q,J＝1.2Hz,1H),7.93(d,J＝8.1Hz,1H),7.90-7.86(m,1H),7.86-7.79(m,1H),2.59(s,3H),2.18(d,J＝1.2Hz,3H).

ESI/MS(m/z)218(M+H)⁺,216(M-H)^-.

[ reference example 10]

1-tosyl-2, 3-dihydro-1H-benzo [ b ]]Aza-4-carboxylic acid ethyl ester

(2-aminophenyl) methanol (13.4g) was dissolved in chloroform (400mL) and cooled to 0 ℃. Pyridine (11mL) and p-toluenesulfonyl chloride (24.8g) were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with water, and 6M hydrochloric acid was added thereto to adjust the mixture to acidity, followed by extraction with chloroform. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain N- [2- (hydroxymethyl) phenyl ] -4-methylbenzenesulfonamide.

The above N- [2- (hydroxymethyl) phenyl ] -4-methylbenzenesulfonamide (32.0g) was dissolved in acetone (480mL), and manganese (IV) oxide (75.0g) was added thereto and the mixture was refluxed for 24 hours. The reaction solution was filtered, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give N- (2-formylphenyl) -4-methylbenzenesulfonamide.

The above N- (2-formylphenyl) -4-methylbenzenesulfonamide (24.0g) was dissolved in N, N-dimethylformamide (300mL), ethyl bromobutyrate (36.4g) and potassium carbonate (36.1g) were added, and the mixture was stirred at 80 ℃ for 36 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain ethyl 4- [ N- (2-formylphenyl) -4-methylphenylsulfonamide ] butyrate.

Ethyl 4- [ N- (2-formylphenyl) -4-methylphenylsulfonamide ] butanoate described above was dissolved in diethyl carbonate (480mL), and a 20% sodium ethoxide-ethanol solution (43.1g) was added thereto, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with water, and 6M hydrochloric acid was added thereto to adjust the reaction solution to acidity, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane: 1/10-1/4) to obtain the title compound (18.2g) as a yellowish white oil.

¹H-NMR(400MHz,CDCl₃)6.97-6.87(m,1H),6.61-6.53(m,1H),6.48(d,J＝7.9Hz,1H),3.86(s,1H),3.14-3.00(m,2H),2.86-2.76(m,2H),1.86-1.74(m,2H),1.69-1.60(m,2H).

[ reference example 11]

2, 3-dihydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester

Ethyl 1-tosyl-2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate (18.2g) was dissolved in acetic acid (180mL), sulfuric acid (90mL) and water (9mL) were added, and the mixture was stirred at 90 ℃ for 36 hours. The reaction was cooled to 0 ℃ and diluted with dichloromethane and water. 5M sodium hydroxide was added to the mixed solution, and after neutralization, extraction was performed with methylene chloride. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 2, 3-dihydro-1H-benzo [ b ] azepine-4-carboxylic acid.

The above 2, 3-dihydro-1H-benzo [ b ] azepine-4-carboxylic acid was dissolved in methanol (180mL), and sulfuric acid (10mL) was added dropwise thereto at room temperature, followed by heating and refluxing for 17 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was diluted with water, neutralized with 5M sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane: 1/10-1/4) to obtain the title compound (8.30g) as an off-white solid.

¹H-NMR(400MHz,CDCl₃)7.65(s,1H),7.29-7.23(m,1H),7.13-7.06(m,1H),6.78-6.72(m,1H),6.63-6.57(m,1H),4.55(s,1H),3.80(s,3H),3.42-3.34(m,2H),2.89-2.83(m,2H).

[ reference example 12]

1-tosyl-3, 4-dihydro-1H-benzo [ b ]]Aza-5 (2H) -ones

3, 4-dihydro-1H-benzo [ b ] azepin-5 (2H) -one (10.0g) was dissolved in pyridine (30mL), and p-toluenesulfonyl chloride (13.6g) was added thereto while cooling on ice, and the mixture was stirred at room temperature for 12 hours. Water (60mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 40 minutes. The obtained crystals were filtered and washed with water, followed by drying, to thereby obtain the title compound (18.9g) as a pale yellowish white solid.

¹H-NMR(400MHz,CDCl₃)7.71(ddd,J＝7.8,1.7,0.4Hz,1H),7.59(d,J＝8.3Hz,2H),7.55-7.46(m,2H),7.41-7.35(m,1H),7.23-7.30(m,2H),3.86(t,J＝6.6Hz,2H),2.45-2.39(m,5H),2.00-1.91(m,2H).

ESI/MS(m/z)316(M+H)⁺.

[ reference example 13]

5-oxo-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester

1-tosyl-3, 4-dihydro-1H-benzo [ b ] aza-5 (2H) -one (47.3g) was dissolved in dimethyl carbonate (300mL), and sodium methoxide (48.6g) was added thereto at room temperature, followed by stirring at 70 ℃ for 40 minutes. Thereafter, the reaction mixture was cooled to room temperature and poured into ice water, followed by extraction with ethyl acetate, washing with water and saturated brine, and drying over anhydrous sodium sulfate. Methanol was added to the obtained residue, and the precipitated crystal was filtered to obtain the titled compound (43.8 g).

¹H-NMR(400MHz,CDCl₃)11.9(brs,1H),7.81-7.10(m,8H),4.10(t,J＝6.4Hz,2H),3.75-3.69(m,3H),2.57-2.17(m,5H).

[ reference example 14]

4-methyl-5-oxo-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (racemization)

Methyl 5-oxo-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (100mg) was dissolved in acetone (2mL), and potassium carbonate (74.1mg) and methyl iodide (33. mu.L) were added to the solution, followed by refluxing with heating for 1.5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate 4/1-2/1) to give the title compound (99.2mg) as a white solid.

¹H-NMR(400MHz,CDCl₃)7.55(d,J＝8.4Hz,2H),7.46-7.31(m,4H),7.28-7.21(m,2H),4.08-3.99(m,1H),3.87-3.77(m,1H),3.61(s,3H),2.47-2.31(m,4H),1.89-1.78(m,1H),1.31(s,3H).

ESI/MS(m/z)388(M+H)⁺.

Here, "racemic" means: for example of the formula

[ solution 27]

When the quaternary carbon atom is an asymmetric carbon atom, a racemic compound is present at the quaternary carbon atom. In addition, the same compounds and the following compounds obtained using a raw material in which the quaternary carbon atom at the 4-position is likewise racemic are labeled at the end of their nomenclature (racemic).

[ example 1]

4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (rac)

Methyl 4-methyl-5-oxo-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 74.0mg) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (29. mu.L), triethylsilane (120. mu.L), methanesulfonic acid (19. mu.L), and boron trifluoride diethyl ether complex (36. mu.L) were added thereto under ice bath, followed by direct stirring for 30 minutes and stirring at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate 9/1-1/1) to give the titled compound (34.2 mg).

¹H-NMR(400MHz,CDCl₃)7.62(d,J＝8.3Hz,2H),7.33-7.06(m,6H),4.14-3.37(m,5H),2.69(d,J＝13.8Hz,1H),2.53-2.37(m,4H),2.21-2.09(m,1H)1.83-1.54(m,1H),1.12(brs,3H).

ESI/MS(m/z)374(M+H)⁺.

[ example 2]

4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Aza-4-carboxylic acid methyl ester (rac)

Methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 434mg) was dissolved in methanol (12mL), magnesium (283mg) was added, and the mixture was stirred at 60 ℃ for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate 3/2), whereby the title compound (255mg) was obtained as a yellow oil.

¹H-NMR(400MHz,CDCl₃)7.09(dd,J＝7.4,1.6Hz,1H),7.04(td,J＝7.4,1.6Hz,1H),6.81(td,J＝7.4,1.2Hz,1H),6.67(dd,J＝7.4,1.2Hz,1H),3.71(brs,1H),3.62(s,3H),3.18-3.05(m,3H),2.79(d,J＝13.7Hz,1H),2.26(dddd,J＝13.9,7.0,2.6,1.1Hz,1H),1.70(ddd,J＝13.9,9.1,3.2Hz,1H),1.24(s,3H).

ESI/MS(m/z)220(M+H)⁺.

[ example 3]

4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid (rac)

Methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 4.82g) was dissolved in a mixed solvent of tetrahydrofuran (35mL) and methanol (35mL), 1M sodium hydroxide (37mL) was added, and the mixture was stirred at 50 ℃ for 11 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the obtained residue to conduct extraction with ethyl acetate. After the aqueous phase was acidified by addition of 6M hydrochloric acid, the mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (3.92g) as a white solid.

¹H-NMR(400MHz,CDCl₃)7.62(d,J＝8.3Hz,2H),7.27-7.12(m,6H),3.98-3.49(m,2H),2.71(d,J＝14.0Hz,1H),2.49(d,J＝14.0Hz,1H),2.43(s,3H),2.19-2.13(m,1H),1.78-1.71(m,1H),1.16(brs,3H).

ESI/MS(m/z)360(M+H)⁺,358(M-H)^-.

[ reference example 15]

N- [ (R) -2-hydroxy-1-phenylethyl group]-4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b] Aza-4-carboxamides (chiral A)

[ reference example 16]

N- [ (R) -2-hydroxy-1-phenylethyl group]-4-methyl-1-tosyl-2, 3,4, 5-tetrakishydro-1H-benzo [ b] Aza-4-carboxamides (chiral B)

4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] azepine-4-carboxylic acid (rac: 1.00g) was dissolved in N, N-dimethylformamide (20mL), and 1-hydroxybenzotriazole (563mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (800mg), and (R) - (-) -2-phenylglycinol (572mg) were added to stir at room temperature for 3 hours. Water was added, extraction was performed with ethyl acetate, and then the organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate 1/1), thereby obtaining the title compound as a colorless oil [ reference example 15 (chiral a): 526mg, reference example 16 (chiral B): 629mg ].

Reference example 15 (chiral a):¹H-NMR(400MHz,CDCl₃)7.59(d,J＝8.3Hz,2H),7.32-7.23(m,9H),7.17(td,J＝7.4,1.4Hz,1H),7.09(dd,J＝7.4,1.4Hz,1H),6.96(brs,1H),6.16(d,J＝6.9Hz,1H),4.94-4.90(m,1H),3.88-3.74(m,1H),3.81(dd,J＝5.3,5.3Hz,2H),3.63-3.49(m,1H),2.64(d,J＝14.3Hz,1H),2.52(d,J＝14.3Hz,1H),2.40(s,3H),2.29-2.23(m,1H),1.72-1.65(m,1H),1.12(brs,3H).

ESI/MS(m/z)479(M+H)⁺,477(M-H)^-.

reference example 16 (chiral B):¹H-NMR(400MHz,CDCl₃)7.62(d,J＝8.3Hz,2H),7.37-7.20(m,9H),7.17(d,J＝8.0Hz,2H),7.12(dd,J＝7.0,1.8Hz,1H),6.16(d,J＝6.9Hz,1H),4.96-4.92(m,1H),3.78-3.74(m,4H),2.64(d,J＝14.1Hz,1H),2.59-2.53(m,1H),2.42(s,3H),2.27-2.22(m,1H),1.70-1.62(m,1H),1.11(brs,3H).

ESI/MS(m/z)479(M+H)⁺,477(M-H)^-.

here, "chiral a" means: for example of the formula

[ solution 28]

When the quaternary carbon atom is an asymmetric carbon atom, the highly polar optically active isomer is present at the quaternary carbon atom. In addition, the same compounds and the following compounds obtained using, as a starting material, a highly polar isomer that is also optically active at the quaternary carbon atom are labeled at the end of their nomenclature (chiral a).

Here, "chiral B" means: for example of the formula

[ solution 29]

When the quaternary carbon atom is an asymmetric carbon atom, the optically active low-polarity isomer is present at the quaternary carbon atom. In addition, the same compounds and the following compounds obtained by using, as a raw material, a low-polar isomer that is also optically active at the quaternary carbon atom are labeled at the end of their nomenclature (chiral B).

[ example 4]

4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (chiral A)

N- [ (R) -2-hydroxy-1-phenylethyl ] -4-methyl-1-toluenesulfonyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxamide (chiral A: 526mg) was dissolved in methanol (11mL), concentrated sulfuric acid (2.2mL) was added, and the mixture was stirred at 80 ℃ for 11 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the obtained residue to conduct extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate 2/1), whereby the title compound (434mg) was obtained as a colorless oil.

¹H-NMR(400MHz,CDCl₃)7.62(d,J＝8.3Hz,2H),7.28-7.25(m,2H),7.23-7.14(m,3H),7.12-7.08(m,1H),4.00-3.87(m,1H),3.64-3.48(m,1H),3.53(s,3H),2.69(d,J＝13.8Hz,1H),2.47(d,J＝13.8Hz,1H),2.43(s,3H),2.18-2.13(m,1H),1.76-1.70(m,1H),1.12(brs,3H).

ESI/MS(m/z)374(M+H)⁺.

[ example 5]

4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Aza-4-carboxylic acid methyl ester (chiral A)

The same procedure as in example 2 was repeated except for using methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of using methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) to give the titled compound.

¹H-NMR(400MHz,CDCl₃)7.09(dd,J＝7.4,1.4Hz,1H),7.04(td,J＝7.4,1.4Hz,1H),6.81(td,J＝7.4,1.4Hz,1H),6.67(dd,J＝7.4,1.4Hz,1H),3.71(brs,1H),3.62(s,3H),3.18-3.05(m,3H),2.79(d,J＝13.7Hz,1H),2.26(dddd,J＝13.9,7.0,2.6,1.1Hz,1H),1.70(ddd,J＝13.9,9.1,3.2Hz,1H),1.24(s,3H).

ESI/MS(m/z)220(M+H)⁺.

[ reference example 17]

1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Aza-4-carboxylic acid ethyl ester (rac)

Ethyl 1-tosyl-2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate (631mg) was dissolved in ethanol (8mL), 10% palladium on carbon (63.0mg) was added, and the mixture was stirred at 50 ℃ for 14.5 hours under a hydrogen atmosphere. After palladium on carbon was subjected to celite filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (634mg) as a white solid.

¹H-NMR(400MHz,CDCl₃)7.66-7.58(m,2H),7.31-7.23(m,3H),7.22-7.12(m,3H),4.20-3.96(m,2H),3.65-3.38(m,1H),2.75-2.57(m,2H),2.55-2.45(m,1H),2.42(s,3H),2.15-1.96(m,3H),1.19(t,J＝7.1Hz,3H).

[ example 6]

4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid ethyl ester (rac)

Ethyl 1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 1.00g) was dissolved in tetrahydrofuran (25mL) and cooled to-78 ℃. After a 2M lithium diisopropylamine-tetrahydrofuran solution (1.7mL) was added dropwise at-78 ℃, the mixture was stirred for 30 minutes. A tetrahydrofuran solution (10mL) of N-fluorobenzenesulfonylimide (1.27g) was added dropwise at the same temperature, and the mixture was stirred for 10 minutes, then heated to-40 ℃ and further stirred for 10 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane: 1/6), whereby the title compound (936mg) was obtained as a white solid.

¹H-NMR(400MHz,CDCl₃)7.66-7.61(m,2H),7.31-7.19(m,5H),7.16-7.11(m,1H),4.25-4.16(m,2H),3.63-3.41(m,1H),3.01-2.80(m,2H),2.56-2.37(m,4H),2.15-2.03(m,2H),1.30-1.25(m,3H).

ESI/MS(m/z)392(M+H)⁺.

[ example 7]

4-fluoro-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (rac)

The same procedure as in example 2 was repeated except for using ethyl 4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.65-7.60(m,2H),6.88(td,J＝7.9,1.2Hz,1H),6.78(dd,J＝7.9,1.2Hz,1H),3.82(s,3H),3.45-3.06(m,4H),2.28-2.46(m,1H),2.24-2.11(m,1H).

ESI/MS(m/z)224(M+H)⁺.

[ example 8]

4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid (rac)

The same procedure as in example 3 was repeated except for using ethyl 4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), thereby obtaining the titled compound.

1H-NMR(400MHz,CDCl₃)7.63(d,J＝8.3Hz,2H),7.32-7.21(m,5H),7.17-7.12(m,1H),4.23(d,J＝13.7Hz,1H),3.55-3.42(m,1H),3.05-2.87(m,2H),2.63-2.39(m,4H),2.16-2.09(m,1H).

ESI/MS(m/z)364(M+H)⁺.

[ reference example 18]

4-fluoro-N- [ (R) -2-hydroxy-1-phenylethyl]-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Nitrogen is present in Hetero-4-carboxamides (chiral A)

[ reference example 19]

4-fluoro-N- [ (R) -2-hydroxy-1-phenylethyl]-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Nitrogen is present in Hetero-4-carboxamides (chiral B)

The same procedures as in reference examples 15 and 16 were carried out using 4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ B ] aza-4-carboxylic acid (racemic) instead of 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ B ] aza-4-carboxylic acid (racemic), thereby obtaining the titled compound [ reference example 18 (chiral A) and reference example 19 (chiral B) ].

Reference example 18 (chiral A))：¹H-NMR(400MHz,CDCl₃)7.59(d,J＝8.3Hz,2H),7.46-7.17(m,10H),7.07-7.02(m,1H),7.01-6.94(m,1H),5.07-5.01(m,1H),4.35(d,J＝14.8Hz,1H),3.92-3.86(m,2H),3.48-3.36(m,1H),2.91-2.73(m,1H),2.69-2.47(m,3H),2.39(s,3H),2.08-1.92(m,1H).

ESI/MS(m/z)483(M+H)⁺.

Reference example 19 (chiral B):¹H-NMR(400MHz,CDCl₃)7.58(d,J＝8.3Hz,2H),7.44(dd,J＝7.8,1.4Hz,1H),7.39-7.21(m,9H),7.12(dd,J＝7.4,1.5Hz,1H),7.00-6.97(m,1H),5.06-5.02(m,1H),4.32(dt,J＝14.8,4.0Hz,1H),3.92-3.89(m,2H),3.39(dd,J＝13.8,13.8Hz,1H),2.91-2.72(m,2H),2.58-2.41(m,1H),2.41(s,3H),2.03(dd,J＝6.6,5.8Hz,1H),1.94-1.87(m,1H).

ESI/MS(m/z)483(M+H)⁺.

[ example 9]

4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (chiral A)

The same procedure as in example 4 was repeated except for using 4-fluoro-N- [ (R) -2-hydroxy-1-phenylethyl ] -1-toluenesulfonyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxamide (chirality a) instead of using N- [ (R) -2-hydroxy-1-phenylethyl ] -4-methyl-1-toluenesulfonyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxamide (chirality a) to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.64(d,J＝8.3Hz,2H),7.31-7.19(m,5H),7.13(dd,J＝5.1,2.5Hz,1H),4.25-4.07(m,1H),3.77(s,3H),3.61-3.42(m,1H),3.09-2.80(m,2H),2.57-2.39(m,4H),2.15-2.04(m,1H).

ESI/MS(m/z)378(M+H)⁺.

[ example 10]

4-fluoro-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (chiral A)

The same procedure as in example 2 was repeated except for using methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) and methyl 4-fluoro-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.65-7.60(m,2H),6.88(td,J＝7.9,1.2Hz,1H),6.78(dd,J＝7.9,1.2Hz,1H),3.82(s,3H),3.45-3.06(m,4H),2.28-2.46(m,1H),2.24-2.11(m,1H).

ESI/MS(m/z)224(M+H)⁺.

[ example 11]

4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid ethyl ester (rac)

The reaction was carried out in the same manner as in example 6 using methyl iodide instead of N-fluorobenzenesulfonylimide, thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.62(d,J＝8.3Hz,2H),7.31-7.08(m,6H),4.08-3.86(m,3H),3.71-3.41(m,1H),2.67(d,J＝13.9Hz,1H),2.52-2.39(m,4H),2.21-2.10(m,1H),1.82-1.63(m,1H),1.21-1.02(m,6H).

ESI/MS(m/z)388(M+H)⁺.

[ example 12]

4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid ethyl ester (rac)

The same procedure as in example 2 was repeated except for using ethyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.12-7.06(m,1H),7.03(td,J＝7.5,1.4Hz,1H),6.81(td,J＝7.5,1.4Hz,1H),6.67(dd,J＝7.5,1.4Hz,1H),4.06(q,J＝7.2Hz,2H),3.71(brs,1H),3.20-3.63(m,3H),2.79(d,J＝13.8Hz,1H),2.31-2.22(m,1H),1.74-1.64(m,1H),1.24(s,3H),1.19(t,J＝7.2Hz,3H).

ESI/MS(m/z)234(M+H)⁺.

[ reference example 20]

1- (tert-butoxycarbonyl) -2, 3-dihydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester

Methyl 2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate (114g) was dissolved in tetrahydrofuran (1.2L), and 4-dimethylaminopyridine (6.85g) and di-tert-butyl dicarbonate (490g) were added to the solution, followed by stirring at 80 ℃ for 5 hours. Thereafter, 4-dimethylaminopyridine (68.5g) and di-tert-butyl dicarbonate (184g) were further added thereto, and the mixture was stirred at 80 ℃ for 15 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the organic phase was washed with a 20% citric acid aqueous solution, a saturated sodium bicarbonate aqueous solution, and saturated brine in this order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane: 1/6), whereby the title compound (141g) was obtained as a pale yellow solid.

¹H-NMR(400MHz,CDCl₃)7.67(s,1H),7.41-7.27(m,3H),7.19(t,J＝8.0Hz,1H),3.82(s,3H),3.65(s,2H),2.89(t,J＝4.0Hz,2H),1.47(s,9H).

ESI/MS(m/z)304(M+H)⁺.

[ reference example 21]

1- (tert-butoxycarbonyl) -2,3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester

The reaction was carried out in the same manner as in reference example 17 using methyl 1- (tert-butoxycarbonyl) -2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate instead of ethyl 1-tosyl-2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.26-7.12(m,4H),4.45-4.25(m,1H),3.69(s,3H),3.00-2.10(m,4H),2.10-2.00(m,2H),1.53-1.36(m,9H).

ESI/MS(m/z)306(M+H)⁺.

[ example 13]

1- (tert-butoxycarbonyl) -4-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (Xiaoxiao) Rotary)

Instead of ethyl 1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate, methyl 1- (tert-butoxycarbonyl) -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate was used; the reaction was carried out in the same manner as in example 6 using iodoethane instead of N-fluorobenzenesulfonylimide, thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.21-7.08(m,4H),4.30(s,1H),3.59(s,3H),3.00-2.83(m,3H),2.23-2.18(m,1H),1.69-1.37(m,12H),0.85(t,J＝8.0Hz,3H).

ESI/MS(m/z)334(M+H)⁺.

[ example 14]

1- (tert-butoxycarbonyl) -4-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid (rac)

The same procedure as in example 3 was repeated except for using methyl 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) and methyl 1- (tert-butoxycarbonyl) -4-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.26-7.10(m,4H),4.29-2.83(m,4H),2.20-2.16(m,1H),1.68-1.37(m,12H),0.91-0.87(m,3H).

ESI/MS(m/z)320(M+H)⁺,318(M-H)^-.

[ reference example 22]

4-BYl-4- { [ (R) -2-hydroxy-1-phenylethyl]Carbamoyl } -2,3,4, 5-tetrahydro-1H-benzo [ b ]] Aza-1-carboxylic acid tert-butyl ester (chiral A)

[ reference example 23]

4-Ethyl-4- { [ (R) -2-hydroxy-1-phenylethyl]Carbamoyl } -2,3,4, 5-tetrahydro-1H-benzo [ b ]] Aza-1-carboxylic acid tert-butyl ester (chiral B)

The same procedures as in reference examples 15 and 16 were repeated except for using 1- (tert-butoxycarbonyl) -4-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ B ] aza-4-carboxylic acid (racemic) instead of 4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ B ] aza-4-carboxylic acid (racemic), thereby obtaining the titled compound [ reference example 22 (chiral a) and reference example 23 (chiral B) ].

Reference example 22 (chiral a):¹H-NMR(400MHz,CDCl₃)7.33-6.93(m,9H),6.31(s,1H),4.98(s,1H),4.30-3.83(m,3H),2.96-2.27(m,4H),1.68-1.37(m,13H),0.95-0.91(m,3H).

ESI/MS(m/z)439(M+H)⁺,437(M-H)^-.

reference example 23 (chiral B):¹H-NMR(400MHz,CDCl₃)7.35-7.14(m,9H),6.25(brs,1H),4.97-4.94(m,1H),4.36-4.23(m,1H),3.77-3.70(m,2H),3.00-2.95(m,2H),2.38-2.20(m,2H),1.71-1.53(m,3H),1.37(s,9H),0.86(t,J＝7.7Hz,3H).

ESI/MS(m/z)439(M+H)⁺,437(M-H)^-.

[ example 15]

4-ethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ]]Aza-4-carboxylic acid methyl ester (chiral A)

The reaction was carried out in the same manner as in example 4 using tert-butyl 4-ethyl-4- { [ (R) -2-hydroxy-1-phenylethyl ] carbamoyl } -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-1-carboxylate (chirality A) instead of N- [ (R) -2-hydroxy-1-phenylethyl ] -4-methyl-1-tosyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxamide (chirality A), thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.09(d,J＝8.0Hz,1H),7.03(t,J＝8.0Hz,1H),6.80(t,J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),3.72(brs,1H),3.61(s,3H),3.22-2.83(m,4H),2.28-2.22(m,1H),1.76-1.51(m,3H),0.85(t,J＝8.0Hz,3H).

ESI/MS(m/z)234(M+H)⁺.

[ reference example 24]

(S) -3-cyano-2-methylpropyl methanesulfonate

(R) -3-bromo-2-methyl-1-propanol (30.1g) was dissolved in dimethyl sulfoxide (130mL), and sodium cyanide (10.1g) was added and stirred at 60 ℃ for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with methylene chloride 4 times. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain (S) -4-hydroxy-3-methylbutyronitrile.

(S) -4-hydroxy-3-methylbutyronitrile described above was dissolved in methylene chloride (400mL), and triethylamine (44mL) and methanesulfonyl chloride (18.4mL) were added at 0 ℃ and the mixture was stirred at 0 ℃ for 30 minutes. 1M hydrochloric acid was added to the reaction solution to adjust the reaction solution to acidity, and then extraction was performed with methylene chloride. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (29.9g) as a colorless oil.

¹H-NMR(400MHz,CDCl₃)4.25(dd,J＝10.3,4.7Hz,1H),4.08(dd,J＝10.3,7.5Hz,1H),3.06(s,3H),2.57-2.41(m,2H),2.41-2.25(m,1H),1.18(d,J＝6.9Hz,3H).

[ reference example 25]

(S) -N- (3-cyano-2-methylpropyl) -N- (2-formylphenyl) -4-methylbenzenesulfonamide

N- (2-formylphenyl) -4-methylbenzenesulfonamide (33.0g) and (S) -3-cyano-2-methylpropyl methanesulfonate (23.3g) were dissolved in N, N-dimethylformamide (480mL), and lithium bromide (15.6g) and potassium carbonate (24.9g) were added to stir at 70 ℃ for 18 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate 3/1-1/2) to obtain the title compound (23.5g) as a yellow oil.

¹H-NMR(400MHz,CDCl₃)10.45-10.38(m,1H),8.04(dd,J＝7.1,2.3Hz,1H),7.56-7.45(m,2H),7.43-7.39(m,2H),7.28(d,J＝8.3Hz,2H),6.82-6.71(m,1H),3.85-3.64(m,1H),3.50-3.21(m,1H),2.62-2.39(m,1H),2.45(s,3H),2.35(dd,J＝6.4,2.4Hz,1H),2.13-1.95(m,1H),1.20-1.04(m,3H).

ESI/MS(m/z)357(M+H)⁺.

[ reference example 26]

(S) -3-methyl-1-tosyl-2, 3-dihydro-1H-benzo [ b)]Aza-4-carbonitriles

(S) -N- (3-cyano-2-methylpropyl) -N- (2-formylphenyl) -4-methylbenzenesulfonamide (17.7g) was dissolved in diethyl carbonate (830mL), and a 20% sodium ethoxide-ethanol solution (24mL) was added thereto, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane: 1/9-1/1) to obtain the titled compound (9.00 g).

¹H-NMR(400MHz,CDCl₃)7.65(dd,J＝8.0,1.0Hz,1H),7.46-7.33(m,1H),7.42(d,J＝8.4Hz,2H),7.29(td,J＝7.5,1.0Hz,1H),7.21-7.18(m,3H),6.71(d,J＝1.8Hz,1H),4.40(dd,J＝13.5,4.2Hz,1H),3.23-3.01(m,2H),2.39(s,3H),1.21(d,J＝6.6Hz,3H).

ESI/MS(m/z)339(M+H)⁺,337(M-H)^-.

[ reference example 27]

(S) -3-methyl-2, 3-dihydro-1H-benzo [ b ]]Aza-4-carboxylic acid methyl ester

The reaction was carried out in the same manner as in reference example 11 using (S) -3-methyl-1-toluenesulfonyl-2, 3-dihydro-1H-benzo [ b ] aza-4-carbonitrile instead of ethyl 1-toluenesulfonyl-2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate to give the titled compound.

¹H-NMR(400MHz,CDCl₃)7.62(s,1H),7.27(dd,J＝7.8,1.6Hz,1H),7.11(ddd,J＝8.3,7.2,1.6Hz,1H),6.73(ddd,J＝7.8,7.2,1.2Hz,1H),6.69-6.61(m,1H),4.57(brs,1H),3.80(s,3H),3.42-3.25(m,2H),3.04(d,J＝12.8Hz,1H),1.15(d,J＝6.8Hz,3H).

ESI/MS(m/z)218(M+H)⁺.

[ example 16]

(3S) -1- (tert-Butoxycarbonyl) -3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (racemization)

Methyl (S) -3-methyl-2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate (305mg) was dissolved in tetrahydrofuran (3mL), and di-tert-butyl dicarbonate (1.1mL) and 4-dimethylaminopyridine (305mg) were added to the solution, and the mixture was refluxed for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane: 1/4-1/2) to obtain (3S) -1- (tert-butoxycarbonyl) -3-methyl 2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylic acid methyl ester.

The above-mentioned methyl (3S) -1- (tert-butoxycarbonyl) -3-methyl 2, 3-dihydro-1H-benzo [ b ] aza-4-carboxylate was dissolved in ethanol (4mL), and 10% palladium on carbon (30.0mg) was added. After the inside of the reaction vessel was replaced with hydrogen, the mixture was stirred at 50 ℃ for 4 hours. After the inside of the reaction vessel was replaced with argon, the reaction solution was filtered through celite and washed with ethyl acetate. After water was added to the filtrate to separate the phases, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (251 mg).

¹H-NMR(400MHz,CDCl₃)7.29-7.01(m,4H),4.54-3.91(m,1H),3.82-3.40(m,3H),3.27-2.07(m,5H),1.60-1.30(m,9H),1.13-0.79(m,3H).

[ example 17]

(3S) -1- (tert-Butoxycarbonyl) -3, 4-dimethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester Base ester (racemic)

Methyl (3S) -1- (tert-butoxycarbonyl) -3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (251mg) was dissolved in tetrahydrofuran (5mL) and cooled to-78 ℃. Lithium diisopropylamine (1.8M tetrahydrofuran solution) (870. mu.L) was added dropwise and stirred for 30 minutes. Methyl iodide (98. mu.L) was added thereto, and the mixture was stirred at-40 ℃ for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate/hexane: 1/10-1/4) to obtain the titled compound (219 mg).

¹H-NMR(400MHz,CDCl₃)7.25-7.04(m,4H),4.22-4.04(m,1H),3.74(s,3H),3.23(d,J＝13.2Hz,1H),2.71-2.35(m,3H),1.60-1.31(m,9H),0.85-0.69(m,3H).

[ example 18]

(3S) -3, 4-dimethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (rac)

Methyl (3S) -1- (tert-butoxycarbonyl) -3, 4-dimethyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 219mg) was dissolved in dichloromethane (4.4mL), and trifluoroacetic acid (730. mu.L) was added to stir at room temperature for 1 hour. The reaction solution was cooled to 0 ℃ and diluted with dichloromethane and water. After the mixed solution was neutralized by adding 5M sodium hydroxide, extraction was performed with methylene chloride. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (144 mg).

ESI/MS(m/z)234(M+H)⁺.

[ example 19]

(3S) -3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester

Methyl (3S) -1- (tert-butoxycarbonyl) -3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 913mg) was dissolved in dichloromethane (9mL), and trifluoroacetic acid (3mL) was added to stir at room temperature for 1 hour. The reaction solution was cooled to 0 ℃ and diluted with dichloromethane and water. After the mixed solution was neutralized by adding 5M sodium hydroxide, extraction was performed with methylene chloride. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (560 mg).

ESI/MS(m/z)220(M+H)⁺.

[ example 20]

(3R) -4-fluoro-3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid methyl ester (rac)

Methyl (3S) -1- (tert-butoxycarbonyl) -3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 571mg) was dissolved in tetrahydrofuran (7mL) and cooled to-78 ℃. After a 2M lithium diisopropylamine-tetrahydrofuran solution (1.8mL) was added dropwise at-78 ℃, the mixture was stirred for 30 minutes. A tetrahydrofuran solution (2mL) of N-fluorobenzenesulfonylimide (1.13g) was added dropwise at the same temperature, and the mixture was stirred for 10 minutes, then heated to-40 ℃ and further stirred for 10 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane ═ 1/4), whereby methyl (3R) -1- (tert-butoxycarbonyl) -4-fluoro-3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 463mg) was obtained.

Methyl (3R) -1- (tert-butoxycarbonyl) -4-fluoro-3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 456mg) above was dissolved in dichloromethane (5mL), and trifluoroacetic acid (1.7mL) was added to stir at room temperature for 1 hour. The reaction solution was cooled to 0 ℃ and diluted with dichloromethane and water. After the mixed solution was neutralized by adding 5M sodium hydroxide, extraction was performed with methylene chloride. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (259 mg).

ESI/MS(m/z)238(M+H)⁺.

[ example 21]

4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl]-2,3,4, 5-tetrahydro-1H-benzene And [ b ]]Aza-4-carboxylic acid methyl ester (rac)

2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoic acid (507mg) was suspended in thionyl chloride (5mL), and after stirring at 50 ℃ for 30 minutes, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (8mL), and a solution of methyl 4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 466mg) and pyridine (430. mu.L) in methylene chloride (2mL) was added to stir at room temperature for 3 hours. Water was added to the reaction mixture, extraction was performed with dichloromethane, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate 2/1-1/1) to obtain the title compound (848mg) as a yellow oil.

¹H-NMR(400MHz,CDCl₃)7.84-7.42(m,2H),7.16-5.56(m,6H),6.27-6.19(m,1H),4.85-4.61(m,1H),3.79-3.44(m,4H),3.13-2.80(m,3H),2.53-2.29(m,6H),1.99-1.93(m,1H),1.43(brs,2H),1.06(brs,1H).

ESI/MS(m/z)418(M+H)⁺.

[ example 22]

4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl]-2,3,4, 5-tetrahydro-1H-benzene And [ b ]]Aza-4-carboxylic acid (rac)

Methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2(3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (rac: 848mg) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and methanol (5mL), 5M sodium hydroxide (2mL) was added, stirring at 50 deg.C for 3.5 hr, concentrating the reaction solution under reduced pressure, adding water to the obtained residue, extracting with ethyl acetate, adding 6M hydrochloric acid to the water phase, adjusting to acidity, after extraction with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (819mg) as a white solid.

¹H-NMR(400MHz,CDCl₃)7.84-7.45(m,2H),7.21-6.55(m,6H),6.27-6.20(m,1H),4.87-4.61(m,1H),3.75-2.82(m,4H),2.53-2.28(m,6H),2.01-1.95(m,1H),1.50(brs,2H),1.10(brs,1H).

ESI/MS(m/z)404(M+H)⁺,402(M-H)^-.

[ example 23]

N- (2-amino-2-oxoethyl) -N, 4-dimethyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzene Formyl radical]-2,3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxamides (rac)

4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylic acid (rac: 20.0mg) was dissolved in methylene chloride (1.5mL), and 1-hydroxybenzotriazole (13.4mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (19.0mg), and N-methylglycinamide hydrochloride (12.4mg) were added to stir at room temperature for 17.5 hours. Water was added thereto, the mixture was extracted with dichloromethane, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography (chloroform/methanol 10/1), whereby the title compound (2.00mg) was obtained as a white solid.

¹H-NMR(400MHz,CDCl₃)7.84-7.44(m,2H),7.19-6.76(m,4H),7.11(dd,J＝8.2,2.0Hz,1H),6.60(d,J＝7.4Hz,1H),6.27-6.19(m,1H),5.56(brs,1H),5.33(brs,1H),4.96-4.82(m,1H),4.56-4.49(m,1H),4.18-3.94(m,2H),3.61-3.15(m,5H),2.93-2.88(m,1H),2.52-2.33(m,6H),1.95-1.89(m,1H),1.56(brs,2H),1.26(brs,1H).

ESI/MS(m/z)474(M+H)⁺,472(M-H)^-.

With reference to the procedure of example 21, a compound was synthesized according to the following reaction scheme. The synthesized compounds and data are shown in tables 1 and 2.

[ solution 30]

[ Table 1]

[ Table 2]

[ example 44]

4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl]-2,3,4, 5-tetrahydro-1H-benzene And [ b ]]Aza-4-carboxylic acid (chiral A)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) was used, and the reaction was carried out in the same manner as in example 22 to obtain the title compound.

¹H-NMR(400MHz,CDCl₃)7.84-7.45(m,2H),7.21-6.55(m,6H),6.27-6.20(m,1H),4.87-4.61(m,1H),3.75-2.82(m,4H),2.53-2.28(m,6H),2.01-1.95(m,1H),1.50(brs,2H),1.10(brs,1H).

ESI/MS(m/z)404(M+H)⁺,402(M-H)^-.

[ example 45]

4-methyl-1- [ 2-methyl-4- (pyrrolidin-1-yl) benzoyl]-2,3,4, 5-tetrahydro-1H-benzo [ b]Nitrogen is present in Hetero-4-carboxylic acid (chiral A)

The same procedure as in example 22 was repeated except for using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of using methyl 4-methyl-1- [ 2-methyl-4- (pyrrolidin-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) to obtain the titled compound.

ESI/MS(m/z)393(M+H)⁺,391(M-H)^-.

[ example 46]

4-methyl-1- [ 2-methyl-4- (4-methyloxazol-2-yl) benzoyl]-2,3,4, 5-tetrahydro-1H-benzo [ b] Aza-4-carboxylic acid (rac)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), ethyl 4-methyl-1- [ 2-methyl-4 (4-methyloxazol-2-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) was used, and the reaction was carried out in the same manner as in example 22 to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.78(s,1H),7.50-7.37(m,2H),7.22-6.80(m,4H),6.62-6.57(m,1H),4.86-4.61(m,1H),3.49-3.47(m,1H),3.29-2.83(m,2H),2.53(s,3H),2.34-2.27(m,1H),2.20(d,J＝1.2Hz,2H),2.10(s,1H),2.02-1.96(m,1H),1.50(brs,2H),1.10(brs,1H).

ESI/MS(m/z)405(M+H)⁺,403(M-H)^-.

[ example 47]

1- [ 2-chloro-4- (3-methyl-1H-pyrazol-1-yl) benzoyl]-4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [b]Aza-4-carboxylic acid (chiral A)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), methyl 1- [ 2-chloro-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) was used, and the reaction was carried out in the same manner as in example 22 to obtain the title compound.

¹H-NMR(400MHz,CDCl₃)7.84-7.70(m,1H),7.64-7.60(m,1H),7.52-6.83(m,6H),6.30-6.21(m,1H),4.80-4.59(m,1H),3.51-2.77(m,3H),2.47-1.95(m,5H),1.62-1.07(m,3H).

ESI/MS(m/z)424(M+H)⁺,422(M-H)^-.

[ example 48]

1- [ 2-chloro-4- (3-fluoropropoxy) benzoyl]-4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4- Formic acid (racemic)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), ethyl 1- [ 2-chloro-4- (3-fluoropropoxy) benzoyl ] -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) was used, and the reaction was carried out in the same manner as in example 22 to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.38-6.78(m,6H),6.54(d,J＝8.5Hz,1H),4.83-4.51(m,3H),4.16-3.97(m,2H),3.76-3.48(m,1H),3.28-2.77(m,2H),2.44-2.21(m,1H),2.13(quin,J＝5.9Hz,1H),2.07(quin,J＝5.9Hz,1H),2.02-1.95(m,1H),1.47(brs,2H),1.08(brs,1H).

ESI/MS(m/z)420(M+H)⁺,419(M-H)^-.

[ example 49]

1- [ 2-chloro-4- (pyrrolidin-1-yl) benzoyl) -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza- 4-Carboxylic acid (racemic)

The same procedure as in example 22 was repeated except for using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) and methyl 1- [ 2-chloro-4- (pyrrolidin-1-yl) benzoyl ] -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.19(d,J＝7.3Hz,1H),7.07-6.92(m,2H),6.85-6.81(m,1H),6.75(d,J＝8.5Hz,1H),6.36(d,J＝2.3Hz,1H),6.11(dd,J＝8.5,2.3Hz,1H),4.84-4.78(m,1H),4.63-4.57(m,1H),3.52-3.49(m,1H),3.18-3.15(m,4H),3.10-3.08(m,1H),2.41-2.23(m,2H),1.95(ddd,J＝6.6,3.3,3.3Hz,4H),1.46(brs,2H),1.09(brs,1H).

ESI/MS(m/z)413(M+H)⁺,411(M-H)^-.

[ example 50]

1- (2-chloro-4-propoxybenzoyl) -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4-carboxylic acid (racemization)

The reaction was carried out in the same manner as in example 22 using methyl 1- (2-chloro-4-propoxybenzoyl) -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.20(d,J＝7.5Hz,1H),7.13-6.81(m,4H),6.77(d,J＝2.5Hz,1H),6.53(dd,J＝8.5,2.5Hz,1H),4.82-4.58(m,1H),3.80(t,J＝6.6Hz,2H),3.50(d,J＝13.7Hz,1H),3.27-3.04(m,2H),2.45-2.24(m,1H),2.02-1.94(m,1H),1.73(sext,J＝7.2Hz,2H),1.47(brs,2H),1.08(brs,1H),0.98(t,J＝7.2Hz,3H).

ESI/MS(m/z)402(M+H)⁺,400(M-H)^-.

[ example 51]

1- [ 2-chloro-4- (oxazol-2-yl) benzoyl]-4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza-4- Formic acid (racemic)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), methyl 1- [ 2-chloro-4- (oxazol-2-yl) benzoyl ] -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) was used, and the reaction was carried out in the same manner as in example 22 to obtain the title compound.

¹H-NMR(400MHz,CDCl₃)7.95(brs,1H),7.71-7.68(m,1H),7.68(s,1H),7.22(s,1H),7.22-7.00(m,3H),6.98-6.89(m,2H),4.83-4.62(m,1H),3.54-3.50(m,1H),3.31-3.08(m,2H),2.49-2.29(m,1H),2.06-1.98(m,1H),1.49(brs,2H),1.09(brs,1H).

ESI/MS(m/z)411(M+H)⁺,409(M-H)^-.

[ example 52]

1- [ 2-chloro-4- (1H-pyrazol-1-yl) benzoyl]-4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b]Aza- 4-Carboxylic acid (racemic)

The same procedure as in example 22 was repeated except for using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of using methyl 1- [ 2-chloro-4- (1H-pyrazol-1-yl) benzoyl ] -4-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)7.83(d,J＝2.5Hz,1H),7.68(d,J＝1.7Hz,1H),7.67-7.65(m,1H),7.38-7.34(m,1H),7.21-6.86(m,5H),6.44(dd,J＝2.5,1.7Hz,1),4.84-4.61(m,1H),3.53-3.50(m,1H),3.32-3.07(m,2H),2.48-2.24(m,1H),2.05-1.98(m,1H),1.49(brs,2H),1.09(brs,1H).

ESI/MS(m/z)410(M+H)⁺,408(M-H)^-.

[ example 53]

4-methyl-1- [4- (3-methyl-1H-pyrazol-1-yl) -2- (trifluoromethyl) benzoyl]-2,3,4, 5-tetrahydro- 1H-benzo [ b]Aza-4-carboxylic acid (chiral A)

The reaction was carried out in the same manner as in example 22 using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) instead of methyl 4-methyl-1- [4- (3-methyl-1H-pyrazol-1-yl) -2- (trifluoromethyl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a), thereby obtaining the titled compound.

¹H-NMR(400MHz,CDCl₃)8.07-7.90(m,1H),7.76-7.75(m,1H),7.61-7.48(m,1H),7.37-6.87(m,4H),6.79-6.72(m,1H),6.33-6.24(m,1H),4.81-4.60(m,1H),3.47-2.82(m,3H),2.39-1.97(m,5H),1.64-1.09(m,3H).

ESI/MS(m/z)458(M+H)⁺,456(M-H)^-.

[ example 54]

4-fluoro-1- [ 2-methyl-4- (pyrrolidin-1-yl) benzoyl]-2,3,4, 5-tetrahydro-1H-benzo [ b]Aza- 4-Carboxylic acid (chiral A)

The same procedure as in example 22 was repeated except for using methyl 4-fluoro-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) instead of using methyl 4-methyl-1- [ 2-methyl-4- (pyrrolidin-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (chiral a) to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.24-7.16(m,1H),7.14-6.94(m,2H),6.76-6.47(m,2H),6.37-6.23(m,1H),6.09-5.94(m,1H),5.03-4.82(m,1H),3.78-2.86(m,7H),2.71-2.38(m,4H),2.29-2.13(m,1H),2.09-1.84(m,4H).

ESI/MS(m/z)397(M+H)⁺.

[ example 55]

(3S) -3, 4-dimethyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl]-2,3,4, 5-tet hydro-1H-benzo [ b]Aza-4-carboxylic acid (rac)

Instead of using 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylic acid methyl ester (rac), in addition, the same procedure as in example 22 was repeated using (3S) -3, 4-dimethyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazolo-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylic acid methyl ester (racemic), thereby obtaining the titled compound.

ESI/MS(m/z)418(M+H)⁺,416(M-H)^-.

[ example 56]

(3S) -1- [ 2-chloro-4- (pyrrolidin-1-yl) benzoyl]-3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b] Aza-4-carboxylic acid (rac)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), methyl (3S) -1- [ 2-chloro-4- (pyrrolidin-1-yl) benzoyl ] -3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) was used, and the reaction was carried out in the same manner as in example 22 to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.18(d,J＝7.3Hz,1H),7.08-6.93(m,2H),6.90-6.72(m,2H),6.38-6.36(m,1H),6.15-6.09(m,1H),6.15-6.09(m,1H),4.96(d,J＝12.0Hz,1H),3.40-3.29(m,1H),3.18-3.15(m,4H),2.96-2.90(m,1H),2.50-2.42(m,2H),2.23-2.17(m,1H),1.97-1.93(m,4H),1.17-1.04(m,3H).

ESI/MS(m/z)413(M+H)⁺,411(M-H)^-.

[ example 57]

(3R) -1- [ 2-chloro-4- (pyrrolidin-1-yl) benzoyl]-4-fluoro-3-methyl-2, 3,4, 5-tetrahydro-1H-benzene And [ b ]]Aza-4-carboxylic acid (rac)

Instead of using methyl 4-methyl-1- [ 2-methyl-4- (3-methyl-1H-pyrazol-1-yl) benzoyl ] -2,3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic), methyl (3R) -1- [ 2-chloro-4- (pyrrolidin-1-yl) benzoyl ] -4-fluoro-3-methyl-2, 3,4, 5-tetrahydro-1H-benzo [ b ] aza-4-carboxylate (racemic) was used, and the reaction was carried out in the same manner as in example 22 to obtain the titled compound.

¹H-NMR(400MHz,CDCl₃)7.14(d,J＝7.0Hz,1H),7.09-7.02(m,2H),6.88(d,J＝7.3Hz,1H),6.76(d,J＝8.4Hz,1H),6.35(d,J＝2.2Hz,1H),6.12(dd,J＝8.4,2.2Hz,1H),4.81-4.77(m,1H),3.71(dd,J＝44.3,14.7Hz,1H),3.20-3.14(m,5H),2.89-2.74(m,2H),1.95(ddd,J＝6.7,3.6,3.6Hz,4H),1.06(d,J＝6.2Hz,3H).

ESI/MS(m/z)431(M+H)⁺,429(M-H)^-.

With reference to the procedure of example 22, a compound was synthesized according to the following reaction scheme. The synthesized compounds and data are shown in table 3.

[ solution 31]

[ Table 3]

With reference to the procedure of example 23, a compound was synthesized according to the following reaction scheme. The synthesized compounds are shown in tables 4 to 6, and the data are shown in tables 7 to 9.

[ solution 32]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

Pharmacological test

(1) Preparation of human V2 receptor-expressing cells

A DNA fragment comprising the human V2 receptor coding region is inserted into an expression vector for a vertebrate cell. The gene is introduced into animal cells, and the human V2 receptor is expressed on the cell surface. Since the expression vector can express the neo gene that functions as a marker for G418 tolerance, cells stably expressing the human V2 receptor can be selectively obtained by culturing in a G418-containing medium.

(2) cAMP production assay in V2 receptor expressing cells

The human V2 receptor-expressing cells prepared by the above method were collected, resuspended in culture buffer (F-12 medium, 20mM HEPES), and 5. mu.l of the cells were dispensed into 384-well plates at a density of 15,000 cells/well. To each well was added a compound solution diluted with an assay buffer (F-12 medium, 20mM HEPES, 1mM IBMX) or 8-AVP ((Arg)⁸) Vasopressin) solution 5 μ l (10 μ l/well) (final concentration: 15,000 cells/well, 500 μ M IBMX, 1% dimethyl sulfoxide). After incubation at room temperature for 30 minutes, the amount of cAMP production was measured using a commercially available HTRF cAMP kit (Cisbio) according to the described experimental procedure. To determine the EC of the test compound₅₀Emax value, using Excel Fit. The Emax value of the test compound was calculated by taking the maximum reaction based on 8-AVP as 100%, and the EC value was taken as the value showing 50% of the reaction from the concentration-reaction curve of the test compound₅₀Value, EC obtained₅₀Emax is shown in Table 10.

As a result, it was found that all the compounds of the examples subjected to this test had V2 receptor agonist activity.

[ Table 10]

(3) Rat PK assay

As experimental animals, 7-8 week-old male Sprague-Dawely (Crj: CD (SD)) IGS (Charles River, Japan) rats were used. Overnight fasted rats were used. After the test compound was dissolved in DMSO, PEG and physiological saline were added and prepared at a concentration of 0.5mg/mL (20/20/60, v/v/v), and administered into the tail vein at a dose of 0.5 mg/kg. Blood was collected from the jugular vein with a heparin-treated syringe at a time within 6 to 8 hours after administration, and the collected blood was centrifuged to obtain plasma. Drug concentrations in plasma were determined using LC/MS/MS. The sample for LC/MS/MS measurement used a supernatant obtained by adding an internal standard substance and acetonitrile to plasma and removing proteins. PK parameters were resolved using a non-compartmental model. Clearance rate (CL)_p) Dividing the dose by AUC_0-∞And then calculated. Volume of distribution (Vd)_ss) Is to CL_pMultiplied by the Mean Residence Time (MRT). The resulting CLp and Vdss are shown in table 11.

As a result, it was found that all the compounds of the examples subjected to this test had good plasma clearance and volume of distribution, and were excellent in kinetics.

[ Table 11]

Comparative compound 1 is the compound of example 4 (compound: N- (2-hydroxyethyl) - (R) -1- (2-chloro-4-pyrazol-1-ylbenzoyl) -3-methyl-1, 2,3, 5-tetrahydrobenzo [ e ] -1, 4-diaza-4-carboxamide) described in international publication No. 2006/104008.

(4) Cytochrome P450(3A4) enzyme inhibition assay

Using a 96-well plate, a substrate of midazolam (2.5. mu.M), a test compound (0.21 to 50. mu.M), a human liver microsomal protein concentration of 0.1mg protein/mL, and a 1.55mM NADP content⁺3.3mM glucose-6-phosphate, 3.3mM MgCl₂And 0.4 units/ml glucose-6-phosphate dehydrogenase 0.1M phosphate buffer (pH 7.4) total amount of 500 u l to prepare a reaction solution, at 37 degrees C culture for 10 minutes, adding 4 times of cold acetonitrile to stop the reaction, thereafter, centrifugal separation (5000g × 10 minutes × 4 degrees C), collecting the supernatant, using LC/MS/MS measurement of metabolite production, relative to the value of not containing the test compounds to calculate each concentration of inhibition rate, determined the metabolite production of 50% test compounds concentration point fluctuation ( degrees ポイント) and the use of the two test compounds concentrations and inhibition rate to determine IC₅₀. The resulting IC₅₀The values are shown in Table 12.

(5) Cytochrome P450(2C9) enzyme inhibition assay

Using a 96-well plate, sulfaphenazole (10. mu.M) as a substrate, a test compound (0.21 to 50. mu.M), human liver microsomal protein concentration 0.1mg protein/mL, and a concentration of 1.55mM NADP⁺3.3mM glucose-6-phosphate, 3.3mM MgCl₂And 0.4 units/ml glucose-6-phosphate dehydrogenase 0.1M phosphate buffer (pH 7.4) total amount of 500 u l to prepare a reaction solution, at 37 degrees C culture for 10 minutes, adding 4 times of cold acetonitrile to stop the reaction, thereafter, centrifugal separation (5000g × 10 minutes × 4 degrees C), collecting the supernatant, using LC/MS/MS measurement of metabolite production, relative to the value of not containing the test compounds to calculate each concentration of inhibition rate, determined the metabolite production of 50% test compounds concentration point fluctuation ( degrees ポイント) and the use of these two test compound concentrations and inhibition rate to determine IC₅₀. The resulting IC₅₀The values are shown in Table 12.

As a result, it was found that all the compounds of the examples subjected to this test showed low inhibitory effects on the drug metabolizing enzymes CYP3a4 and CYP2C 9.

[ Table 12]

Comparative compound 2 is the compound of example 32 (compound: 2- [ (5R) -1- (2-chloro-4-pyrrolidin-1-ylbenzoyl) -2,3,4, 5-tetrahydrobenzazepin-5-yl ] -N-isopropylacetamide) described in International publication No. 97/22591.

Industrial applicability

The compound of the present invention has a V2 receptor agonistic action, and therefore is useful as a prophylactic or therapeutic agent for central diabetes insipidus, nocturia, overactive bladder, hemophilia, or von willebrand disease.

Claims (8)

1. A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof,

[ solution 1]

In the general formula (I), R¹Represents the formula:

[ solution 2]

Wherein A represents a linear alkylene group having 1 to 3 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms; r⁶Represents a hydrogen atom; r⁷An oxadiazolyl group which represents a hydroxyl group or which may have a linear alkyl group having 1 to 3 carbon atoms;

R²represents a hydrogen atom; r³Represents a straight-chain alkyl group having 1 to 3 carbon atoms which may be substituted with 1 to 3 fluorine atoms, or a halogen atom;

R⁴represents any one group selected from the following group:

in the formula, R⁸Represents a hydrogen atom or a straight chain alkyl group having 1 to 3 carbon atoms,

R⁵represents a straight chain alkyl group having 1 to 3 carbon atoms or a halogen atom.

2. The compound of claim 1, wherein R⁴Is represented by the following formula,

[ solution 7]

In the formula, R⁸Represents a straight chain alkyl group having 1 to 3 carbon atoms.

3. The compound according to claim 1, wherein in the formula (I), R is⁵Is a methyl group or a fluorine atom.

4. The compound according to claim 1, wherein in the formula (I), R is³Is methyl, trifluoromethyl or chlorine atom.

5. The compound according to claim 1, wherein in the formula (I), R is¹Is of the formula:

[ solution 8]

Wherein A represents a linear alkylene group having 1 to 3 carbon atoms which may be substituted with a linear alkyl group having 1 to 3 carbon atoms; r⁶Represents a hydrogen atom; r⁷An oxadiazolyl group which represents a hydroxyl group or which may have a linear alkyl group having 1 to 3 carbon atoms;

R²is a hydrogen atom; r³Is methyl, trifluoromethyl or chlorine atom;

R⁴is represented by the following formula,

[ solution 9]

In the formula, R⁸Represents a straight-chain alkyl group having 1 to 3 carbon atoms;

R⁵is a methyl group or a fluorine atom.

6. A compound represented by the general formula (II),

[ solution 10]

In the formula, R²Represents a hydrogen atom; r⁵Represents a methyl group, an ethyl group or a halogen atom; r⁹A protecting group representing a hydrogen atom or a carboxyl group; r¹⁰Represents a hydrogen atom or a protecting group for an amino group.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 as an active ingredient.

8. The pharmaceutical composition of claim 7, wherein the composition is used for the prevention or treatment of a disease selected from the group consisting of central diabetes insipidus, nocturia, nocturnal pollakiuria, overactive bladder, hemophilia and von willebrand disease.