Silicon analogue of tolvaptan

Abstract

The present invention addresses the problem of providing a silicon analogue of tolvaptan.　The present invention relates to a compound represented by formula (I) (wherein each symbol is as defined in the description) or a salt thereof. The present invention also relates to a vasopressin receptor antagonist and a pharmaceutical containing the compound or the salt thereof as an active ingredient, and a production method for the compound or the salt thereof.

Description

Silicon analogs of tolvaptan

[0001] This invention relates to a silicon analog obtained by replacing one of the ring member carbon atoms in the seven-membered azacycle portion of tolvaptan, which has vasopressin V2 receptor inhibitory activity, with a silicon atom. Furthermore, this invention relates to a vasopressin receptor inhibitor containing the silicon analog as an active ingredient, and to a pharmaceutical product for preventing and / or treating diseases selected from the group consisting of edema caused by heart failure or cirrhosis, schizophrenia, autism, and depression. Moreover, this invention relates to a method for producing the silicon analog.

[0002] Tolvaptan is given by the following formula:

[0003]

[0004] It is a peripheral vasopressin V2 receptor inhibitor having a benzoaza cycle skeleton represented by (Non-Patent Literature 1). Furthermore, tolvaptan derivatives synthesized during the development of tolvaptan have also been reported to have vasopressin V1a and / or V2 receptor inhibitory activity (Non-Patent Literature 2, Patent Literature 1).

[0005] Since vasopressin V1a receptors are present in the brain, they are involved in human mental function. In other words, it has been suggested that vasopressin V1a receptors may be one of the causes of schizophrenia, autism, depression, etc. (Non-Patent Literature 3). Therefore, the development of vasopressin V1a receptor inhibitors and agonists is expected to elucidate the role of vasopressin receptors in mental function and potentially lead to new treatment strategies for mental illnesses, etc. (Non-Patent Literature 3), and various vasopressin V1a receptor inhibitors and agonists have been reported (Non-Patent Literature 4). Representative examples of vasopressin V1a receptor selective inhibitors include OPC-21268 (Non-Patent Literature 5), SR49059 (Non-Patent Literature 6), and JNJ-17308616 (Non-Patent Literature 7), while examples of vasopressin V1a receptor agonists include selepressin (Non-Patent Literature 8) and isoliquiritigenin (Non-Patent Literature 9).

[0006] However, because vasopressin V1a receptors are located in the brain, there has been a need to develop vasopressin V1a receptor selective inhibitors and agonists with higher central nervous system penetration.

[0007] On the other hand, since Bracza's 1975 report on steroids (Non-Patent Document 10), silicon switches that replace carbon in compounds with silicon have been actively researched (Non-Patent Documents 11, 12). As a result, it is widely recognized that introducing silicon into compounds improves their lipophilicity (Non-Patent Document 13), and changes in physical properties such as solubility and membrane permeability are expected. Changes in biological activity due to increased carbon-silicon (C-Si) bond length are also expected (Non-Patent Document 13).

[0008] Regarding cyclic silicon compounds having five-membered or six-membered rings containing nitrogen as a heteroatom, for example, Dennmark et al. have comprehensively synthesized six-membered cyclic silicon compounds containing nitrogen as a heteroatom, and it has been reported that for some of these compounds, nitrogen-containing six-membered cyclic silicon compounds exhibited improved metabolic stability compared to nitrogen-containing six-membered cyclic carbon compounds (Non-Patent Literature 14). On the other hand, regarding medium-membered cyclic silicon compounds containing nitrogen as a heteroatom, only one example has been reported so far by Doye et al., a seven-membered benzoazacilla cycle using the Buchwald-Hartwig reaction (Non-Patent Literature 15). However, in Doye et al.'s synthesis example, a methyl group is always inserted at the 3-position of the seven-membered benzoazacilla cycle, thus limiting the product. In fact, since there is no methyl group at the 3-position of the benzoazepine moiety of tolvaptan, it is difficult to synthesize silicon analogs of tolvaptan using Doye et al.'s method.

[0009] Special Publication No. 7-76214

[0010] Int. J. Mol. Sci., 2016, 17, 105.J. Med. Chem., 1996, 39, 3547-3555.Japanese Pharmacological Journal, 2009, 134, 3-7.Annual Reports in Medicinal Chemistry, 2009, 44, 129-147.Science, 1995, 252, 572-574.Journal of Clinical Investigation, 1993, 92, 224-231.Psychopharmacology, 2009, 202, 711-718.J. Med. Chem., 2011, 54, 4388-4398.Scientifc Reports, 2021, 11, 23528.Tetrahedron, 1975, 31, 2363-2367.Clin. Cancer Res., 2005, 11, 3009-3016.Bioorg. Med. Chem. Lett., 2016, 26, 1817-1820.J. Med. Chem., 2018, 61, 3779-3798.J. Am. Chem. Soc., 2018, 140, 6668-6684.Chem. Eur. J., 2017, 23, 4197-4202.

[0011] Against this backdrop, the development of vasopressin V1a receptor inhibitors with high central nervous system penetration is an urgent issue. The present invention aims to provide a silicon analogue obtained by replacing one of the ring member carbon atoms of the seven-membered azacycle portion of tolvaptan, which has vasopressin receptor inhibitory activity, with a silicon atom, and to provide a vasopressin receptor inhibitor and a pharmaceutical product containing the silicon analogue as an active ingredient. Furthermore, the present invention also aims to provide a novel method for producing the silicon analogue.

[0012] As a result of diligent research to solve the above problems, the inventors of the present invention have discovered a silicon analog of tolvaptan that exhibits vasopressin receptor inhibitory activity and is highly lipophilic, and have completed the present invention. One embodiment of the present invention is as follows, for example.

[0013] [1] Equation (I):

[0014]

[0015] [wherein, R represents a hydrogen atom, C １－６ alkyl, or a halogen atom; m instances of R １ each independently represent a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ２ represents a hydrogen atom, a halogen atom, hydroxy, amino optionally substituted with 1 or 2 C １－６ alkyl, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ３ represents a hydrogen atom, a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ４ and R ５ each independently represent C １－６ alkyl; m represents an integer of 0 to 2; and n represents 1 or 2. A compound represented by the formula (hereinafter sometimes referred to as "the compound of the present invention", "the compound (I) of the present invention", or "compound (I)") or a salt thereof. [2] R is a hydrogen atom, methyl, or a chlorine atom, R ２ is a hydrogen atom, a halogen atom, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, or C １－４ haloalkoxy, R ３ is a hydrogen atom, a halogen atom, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, or C １－４ haloalkoxy, R ４ and R ５ each independently are C １－４The compound or salt thereof described in [1] above, wherein R is alkyl, m is 0, and n is 1 or 2. [3] R is a hydrogen atom, a methyl atom, or a chlorine atom, ２ However, it is a hydrogen atom or a methyl atom, R ３ However, it is a hydrogen atom, R ４ and R ５ However, each is independent of C １－４ The compound or salt thereof described in [1] above, wherein R is alkyl, m is 0, and n is 1 or 2. [4] R is methyl, R ２ However, it is a hydrogen atom, R ３ However, it is a hydrogen atom, R ４ and R ５ The compound or salt thereof described in [1] above, wherein both are methyl, m is 0, and n is 1. [5] R is a chlorine atom, R ２ However, it is a hydrogen atom, R ３ However, it is a hydrogen atom, R ４ and R ５ [1] above, the compound or a salt thereof, wherein both are methyl, m is 0, and n is 1. [6] A vasopressin receptor antagonist containing the compound or a salt thereof described in any of [1] to [5] above as an active ingredient (hereinafter sometimes referred to as "the vasopressin receptor antagonist of the present invention"). [7] A pharmaceutical product containing the compound or a salt thereof described in any of [1] to [5] above (hereinafter sometimes referred to as "the pharmaceutical product of the present invention"). [8] The pharmaceutical product described in [7] above for the prevention and / or treatment of a disease whose symptoms can be alleviated by vasopressin receptor antagonism. [9] The pharmaceutical product described in [8] above, wherein the disease whose symptoms can be alleviated by vasopressin receptor antagonism is a disease selected from the group consisting of edema caused by heart failure or cirrhosis of the liver, schizophrenia, autism, and depression.

[10] Formula (1):

[0016]

[0017] [In the formula, P １ R indicates a protecting group; ３ is a hydrogen atom, a halogen atom, C １－６ Alkyl, C１－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It shows a haloalkoxy; R ４ and R ５ Each of them is independent of C １－６ The compound represented by [ ] or a salt thereof is subjected to a Grubbs-catalyzed ring-closing metathesis reaction, thereby obtaining formula (2):

[0018]

[0019] Formula (I): The process is characterized by including a step of converting the compound represented by (I) (where each symbol in the formula has the same meaning as the definition of each group in formula (1) above) to a salt thereof:

[0020]

[0021] [In the formula, R ３ , R ４ , and R ５ The above formula (1) has the same meaning as the definition of each group; R is a hydrogen atom, C １－６ Represents alkyl or halogen atoms; m R １ Each of these is independently a halogen atom, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It shows a haloalkoxy; R ２ This includes a hydrogen atom, a halogen atom, a hydroxyl group, and one or two carbon atoms. １－６ amino, C which may be substituted with alkyl. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ A method for producing a compound represented by [Formula (I)] or a salt thereof (hereinafter sometimes referred to as "the method of production of the present invention"), where m is an integer from 0 to 2, and n is 1 or 2.

[11] Formula (I):

[0022]

[0023] [In the formula, R is a hydrogen atom, C １－６represents alkyl or a halogen atom; m R １ each independently represent a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ２ represents a hydrogen atom, a halogen atom, hydroxy, amino optionally substituted by 1 or 2 C １－６ alkyl groups, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ３ represents a hydrogen atom, a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ４ and R ５ each independently represent C １－６ alkyl; m represents an integer of 0 to 2; and n represents 1 or 2. A method for treating a disease in a subject, the symptoms of which can be alleviated by vasopressin receptor antagonism, comprising administering a pharmaceutically effective amount of the compound represented by the formula or a pharmaceutically acceptable salt thereof to the subject.

[12] The treatment method according to the above

[11] , wherein the disease whose symptoms can be alleviated by vasopressin receptor antagonism is a disease selected from the group consisting of edema caused by heart failure or liver cirrhosis, schizophrenia, autism, and depression.

[13] Formula (I): for producing a medicament for treating a disease whose symptoms can be alleviated by vasopressin receptor antagonism:

[0024]

[0025] [wherein, R represents a hydrogen atom, C １－６ alkyl, or a halogen atom; m R １ each independently represent a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R２ represents a hydrogen atom, a halogen atom, hydroxy, or an amino group optionally substituted by 1 or 2 C １－６ alkyl groups, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ３ represents a hydrogen atom, a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ４ and R ５ each independently represent C １－６ alkyl; m represents an integer of 0 to 2; and n represents 1 or 2.] or a pharmaceutically acceptable salt thereof.

[14] The use according to the above

[13] , wherein the disease whose symptom can be alleviated by vasopressin receptor antagonistic action is a disease selected from the group consisting of edema caused by heart failure or liver cirrhosis, schizophrenia, autism, and depression.

[15] For use in the treatment of a disease whose symptom can be alleviated by vasopressin receptor antagonistic action, a compound of formula (I):

[0026]

[0027] [wherein, R represents a hydrogen atom, C １－６ alkyl, or a halogen atom; the m R groups １ each independently represent a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ２ represents a hydrogen atom, a halogen atom, hydroxy, or an amino group optionally substituted by 1 or 2 C １－６ alkyl groups, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ３ represents a hydrogen atom, a halogen atom, C １－６ alkyl, C１－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It shows a haloalkoxy; R ４ and R ５ Each of them is independent of C １－６

[16] A compound represented by

[15] or a pharmaceutically acceptable salt thereof, wherein the disease whose symptoms can be relieved by vasopressin receptor antagonism is selected from the group consisting of edema due to heart failure or cirrhosis, schizophrenia, autism, and depression.

[17] A prodrug of a compound described in

[15] or

[16] or a pharmaceutically acceptable salt thereof.

[0028] According to the present invention, it is possible to provide a silicon analog obtained by replacing one of the ring member carbon atoms of the seven-membered azacycle portion of tolvaptan, which has vasopressin receptor inhibitory activity, with a silicon atom, as well as a vasopressin receptor inhibitor and a pharmaceutical product containing the silicon analog as an active ingredient. According to the present invention, by converting tolvaptan into compound (I) of the present invention, which is a silicon analog, or a salt thereof, it is possible to enhance its ability to penetrate the brain. Therefore, compound (I) of the present invention or a salt thereof is particularly useful for treating mental illnesses such as schizophrenia, autism, and depression by acting antagonistically on vasopressin V1a receptors, which are widely distributed in the brain, such as the cerebral cortex and hippocampus. Furthermore, the present invention is also useful in that it can provide an efficient method for producing medium-membered ring silicon compounds containing nitrogen as a heteroatom, for which there has been no synthesis method until now.

[0029] Figure 1 shows the inhibitory activity against the vasopressin V1a receptor by HEK293T cells co-expressing the vasopressin V1a receptor and TRPC3. The vertical axis represents receptor activity. Figure 2 shows the inhibitory activity against the vasopressin V2 receptor by HEK293T cells co-expressing the vasopressin V2 receptor and TRPM2. The vertical axis represents receptor activity. In Figure 3a, the relative values ​​of receptor activity for each concentration of compound (I-2) are shown; b, the relative values ​​of receptor activity for each concentration of compound (II-5) are shown; c, the relative values ​​of receptor activity for each concentration of compound (I-3) are shown; and d, the relative values ​​of receptor activity for each concentration of compound (II-6) are shown.

[0030] The definitions of terms and symbols used herein are given below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the present invention pertains.

[0031] In this specification, numerical ranges represented by "~" or "-" mean numerical ranges where the numbers before and after "~" or "-" are the lower and upper limits, respectively. In this specification, when a numerical range is attached to the element symbol "C" with the numbers before and after "-" to indicate the name of any group, it refers to each of the groups with an integer number of carbon atoms where the numbers before and after "-" are the lower and upper limits, respectively. For example, an alkyl group with 1 to 6 carbon atoms is referred to as "C １－６ It is sometimes written as "alkyl group," but this is -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ These represent each of the above. The same applies to the other elements.

[0032] In this specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0033] In this specification, "C １－６"Alkyl" refers to a linear or branched alkyl group with 1 to 6 carbon atoms. １－６ Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl.

[0034] In this specification, "C １－４ Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0035] In this specification, "C １－６ "Haloalkyl" refers to the aforementioned C １－６ This refers to a group in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms in an alkyl group are substituted with halogens. Specifically, examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc. Among these, C is preferred. １－４ It is a haloalkyl group.

[0036] In this specification, "C １－６ "Alkoxy" refers to the above C １－６ Alkyl refers to a group bonded to an oxygen atom. １－６ Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, and n-hexyloxy.

[0037] In this specification, "C １－４ Examples of "alkoxys" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy.

[0038] In this specification, "C １－６ "Haloalkoxy" refers to the aforementioned C １－６ This refers to a group in which one or more hydrogen atoms in the alkoxy group are substituted with a halogen. Specifically, examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, etc. Among these, C is preferred. １－４ It is a haloalkoxy.

[0039] In this specification, "one or two C １－６ Examples of substituents that may be alkylated include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, and N-methyl-N-hexylamino groups, such as C １－６ Examples include amino groups that may have one or two alkyl groups.

[0040] In this specification, "the salt" means a basic salt or acidic salt produced by treating compound (I) of the present invention with a base or acid when the compound (I) has an acidic group (e.g., a hydroxyl group) or a basic group (e.g., an amino group). Water-soluble salts are preferred. In this specification, "the pharmaceutically acceptable salt" means a salt among the above salts that can be used as a pharmaceutical.

[0041] Examples of pharmaceutically acceptable "basic salts" of compound (I) of the present invention include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as ammonium salt and tetramethylammonium salt; organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, and picoline salt; and basic amino acid salts such as lysine salt and arginine salt. Preferably, alkali metal salts (especially sodium salt or potassium salt) or basic amino acid salts are used.

[0042] Examples of pharmaceutically acceptable "acidic salts" of compound (I) of the present invention include hydrohalides such as hydrofluoric acid, hydrochloride, hydrobromide, and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; and organic salts such as acetates, malates, fumarates, succinates, citrates, ascorbic acid, tartrates, oxalates, and maleates. Preferably, hydrohalides (especially hydrochlorides) are used.

[0043] In this specification, “prevention” includes preventing the onset of a disease (i.e., a disease whose symptoms can be alleviated by vasopressin receptor antagonism), delaying the onset of such a disease, and preventing the development of a pathological condition. “Prophylactic effective dose” means a dose of the active ingredient sufficient to achieve the preventive purpose.

[0044] In this specification, “treatment” includes the cure of a disease (i.e., a disease whose symptoms can be alleviated by vasopressin receptor antagonism), the improvement of the pathophysiology of the disease (e.g., one or more symptoms), and the suppression of the progression of the disease (or its severity). “Therapeutic effective dose” means a dose of the active ingredient sufficient to achieve the therapeutic objective. Therefore, “improvement” is a concept encompassed within “treatment.”

[0045] In this specification, "diseases whose symptoms can be alleviated by vasopressin receptor antagonism" means diseases in which a cure, improvement of the condition (e.g., one or more symptoms), or suppression of the progression of the disease (or its severity) can be observed by antagonistically acting on vasopressin V1a and / or V2 receptors. Specifically, such diseases include, for example, edema caused by heart failure or cirrhosis of the liver, schizophrenia, autism, and depression, selected from this group.

[0046] In this specification, "vasopressin receptor antagonist" means a drug that acts antagonistically on vasopressin V1a and / or V2 receptors. Specifically, vasopressin V2 receptor antagonists are drugs that act antagonistically on vasopressin V2 receptors in the kidneys (renal collecting ducts) and exert a diuretic effect by inhibiting water reabsorption by vasopressin (antidiuretic hormone), while vasopressin V1a receptor antagonists are drugs that act antagonistically on vasopressin V1a receptors widely distributed in the brain, such as the cerebral cortex and hippocampus, and improve the pathological condition of diseases selected from the group consisting of schizophrenia, autism, and depression.

[0047] In this specification, "pharmaceutical effective dose" is a concept that encompasses "prophylactic effective dose" and "therapeutic effective dose." In the present invention, "pharmaceutical effective dose" may also mean an amount sufficient to prevent and / or treat a disease selected from the group consisting of edema resulting from heart failure or cirrhosis of the liver, schizophrenia, autism, and depression.

[0048] In this specification, "subject" means a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of active ingredients necessary to prevent and / or treat (or improve) a disease or the pathophysiology of a disease is administered. Examples of such "subjects" include humans and non-human animals, and in particular mammals (e.g., humans, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, etc.).

[0049] In this specification, "Grubbs catalyst" refers to the ruthenium carbene complex developed by Robert Grubbs et al., which is mainly used as a catalyst for olefin metathesis reactions. A typical example of a Grubbs catalyst is shown in the following formula:

[0050]

[0051] The first-generation Grubbs catalyst (Grubbs 1st), represented by the formula below, is dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) and:

[0052]

[0053] One example is dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), which is referred to as a second-generation Grubbs catalyst (Grubbs 2nd).

[0054] [The compound of the present invention (compound (I))] Hereinafter, each group in formula (I) of compound (I) will be described.

[0055] R is a hydrogen atom, C １－６ Represents an alkyl or halogen atom.

[0056] R is preferably a hydrogen atom, a methyl atom, or a chlorine atom, and more preferably a methyl atom or a chlorine atom.

[0057] m R １ Each of these is independently a halogen atom, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６It exhibits haloalkoxy properties.

[0058] R ２ This includes a hydrogen atom, a halogen atom, a hydroxyl group, and one or two carbon atoms. １－６ amino, C which may be substituted with alkyl. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It exhibits haloalkoxy properties.

[0059] R ２ Preferably, a hydrogen atom, a halogen atom, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy, more preferably a hydrogen atom, or a methyl atom, and even more preferably a hydrogen atom.

[0060] R ３ is a hydrogen atom, a halogen atom, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It exhibits haloalkoxy properties.

[0061] R ３ Preferably, a hydrogen atom, a halogen atom, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy, and more preferably a hydrogen atom.

[0062] R ４ and R ５ Each of them is independent of C １－６ It indicates an alkyl group.

[0063] R ４ and R ５ Preferably, each is independently of C １－４ They are alkyl, and more preferably, both are methyl.

[0064] m represents an integer between 0 and 2.

[0065] m is preferably 0 or 1, and more preferably 0.

[0066] n represents either 1 or 2.

[0067] n is preferably 1.

[0068] Suitable compounds (I) include the following: [Compound (IA)] R is a hydrogen atom, a methyl atom, or a chlorine atom; m R １ However, each is independent of the halogen atom, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It is a haloalkoxy; R ２ However, hydrogen atoms, halogen atoms, hydroxyl atoms, one or two C atoms １－６ amino, C which may be substituted with alkyl. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It is a haloalkoxy; R ３ However, hydrogen atoms, halogen atoms, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It is a haloalkoxy; R ４ and R ５ However, each is independent of C １－６ Compound (I) is alkyl; m is an integer between 0 and 2; and n is 1 or 2.

[0069] [Compound (IB)] R is a hydrogen atom, a methyl atom, or a chlorine atom; m R １ However, each is independent of the halogen atom, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It is a haloalkoxy; R ２ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ３ However, hydrogen atoms, halogen atoms, C１－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ４ and R ５ However, each is independent of C １－６ Compound (I) is alkyl; m is an integer between 0 and 2; and n is 1 or 2.

[0070] [Compound (IC)] R is a hydrogen atom, a methyl atom, or a chlorine atom; m R １ However, halogen atoms, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, or C １－６ It is a haloalkoxy; R ２ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ３ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ４ and R ５ However, each is independent of C １－４ Compound (I) is alkyl; m is 0 or 1; and n is 1 or 2.

[0071] [Compound (ID)] R is a hydrogen atom, C １－６ Alkyl or halogen atom; R ２ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ３ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R４ and R ５ However, each is independent of C １－４ Compound (I) is alkyl; m is 0; and n is 1 or 2.

[0072] [Compound (IE)] R is a hydrogen atom, a methyl atom, or a chlorine atom; R ２ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ３ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy; R ４ and R ５ However, each is independent of C １－４ Compound (I) is alkyl; m is 0; and n is 1 or 2.

[0073] [Compound (IF)] R is a hydrogen atom, a methyl atom, or a chlorine atom; R ２ However, it is a hydrogen atom or a methyl atom; R ３ However, it is a hydrogen atom; R ４ and R ５ However, each is independent of C １－４ Compound (I) is alkyl; m is 0; and n is 1 or 2.

[0074] [Compound (IG)] R is methyl, and R ２ However, it is a hydrogen atom, R ３ However, it is a hydrogen atom, R ４ and R ５ Compound (I), in which both are methyl, m is 0, and n is 1.

[0075] [Compound (IH)] R is a chlorine atom, ２ However, it is a hydrogen atom, R ３ However, it is a hydrogen atom, R ４ and R ５Compound (I), in which both are methyl, m is 0, and n is 1.

[0076] Specific examples of suitable compound (I) or its pharmaceutically acceptable salt are the example compounds (compound (I-1) to compound (I-6)) described later, or their pharmaceutically acceptable salts. Among them, the following formula:

[0077]

[0078] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof, is preferred.

[0079] Compound (I) of the present invention, if it has a chiral carbon atom in its molecule, may exist as multiple stereoisomers (i.e., diastereomer isomers, optical isomers) based on that chiral carbon atom. However, the present invention encompasses either any one of these stereoisomers, or a mixture containing any multiple stereoisomers in any proportion. Furthermore, isomers may be generated by conformation or tautomerism, and such isomers or mixtures thereof are also included in Compound (I) of the present invention.

[0080] Compound (I) or a salt thereof of the present invention contains isotopes (for example, ２ H, ３ H, １３ C, １４ C, １５ N, １８ F, １２３ I, １２５ I, １３１ Compounds labeled or substituted with isotopes such as I may be used, and compounds labeled or substituted with isotopes can be used, for example, as tracers (PET tracers) in single-photon emission computed tomography (SPECT) and positron emission tomography (PET), and are useful in fields such as medical diagnosis.

[0081] Compound (I) of the present invention or a salt thereof may be crystalline, and may have a single crystalline form or a mixture of multiple crystalline forms.

[0082] Compound (I) of the present invention or its salts may also include its intramolecular salts, adducts, and solvates thereof. These solvates are compounds in which a solvent molecule is coordinated to compound (I) or its salt, and hydrates are also included. Examples include hydrates, ethanolic dihydrates, and dimethyl sulfoxide dihydrates of compound (I) or its salts.

[0083] Compound (I) of the present invention may be a prodrug.

[0084] A prodrug of compound (I) of the present invention refers to a compound that is converted to compound (I) in the body by a reaction involving enzymes or gastric acid. Examples of prodrugs of compound (I) include, if compound (I) has an amino group, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); and if compound (I) has a hydroxyl group, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated). These compounds can themselves be produced by known methods. Furthermore, the prodrug of compound (I) may be either a hydrate or an unhydrated form. Also, the prodrug of compound (I) may be one that transforms into compound (I) under physiological conditions, as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0085] [Method for Producing Compound (I) or Salt thereof of the Present Invention] Compound (I) or salt thereof of the Present Invention can be produced by applying various known production methods, taking advantage of the characteristics based on its basic skeleton or the type of substituent. Known methods include, for example, those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd edition, ACADEMIC PRESS, INC., 1989, and "Comprehensive Organic Transformations," VCHPublishers Inc., 1989. In such cases, depending on the type of functional group, it may be technically effective in production to protect the functional group with an appropriate protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. Examples of such functional groups include amino groups, hydroxyl groups, sulfanyl groups, carboxyl groups, etc. Examples of protecting groups for these include those described in "Protective Groups in Organic Synthesis (3rd edition, 1999)" by TW Greene and PG Wuts, and these can be appropriately selected and used depending on the reaction conditions. By this method, after introducing the substituent and carrying out the reaction, the protecting group can be removed or converted to a desired group as needed to obtain the desired compound.

[0086] A typical method for producing compound (I) or a salt thereof of the present invention is described below. However, the production method is not limited to the method described below. In addition, unless a specific production method is described, the raw material compounds in each reaction can be readily obtained from the market or produced according to a method that is already known or equivalent.

[0087] (Manufacturing method)

[0088]

[0089] (In the formula, X represents a halogen atom, X １ , X ２ , and X ３Each of these symbols independently represents a leaving group (e.g., a halogen atom, or trifluoromethanesulfonyloxy), and the other symbols have the same meaning as above.

[0090] Step 1: Compound (1) or its salt can be produced by lithiating X of compound (a1) with butyllithium (Step 1-1), and then reacting it with compound (a2) (Step 1-2).

[0091] Step 1-1: Lithiation reaction of compound (a1)

[0092] Examples of solvents include ethers such as tetrahydrofuran, diethyl ether, and dimethoxyethane; aromatic hydrocarbons such as toluene; and aliphatic hydrocarbons such as hexane, with tetrahydrofuran being preferred.

[0093] Examples of butyllithium include n-butyllithium, sec-butyllithium, and tert-butyllithium, with n-butyllithium being preferred.

[0094] The amount of butyllithium used is typically 1 to 1.5 moles per mole of compound (a1), preferably 1 to 1.2 moles.

[0095] The reaction temperature is, for example, -100°C to -40°C, preferably -78°C, and the reaction time is usually 10 minutes to 2 hours.

[0096] Step 1-2: Silyl group introduction reaction

[0097] Examples of solvents include ethers such as tetrahydrofuran, diethyl ether, and dimethoxyethane; aromatic hydrocarbons such as toluene; and aliphatic hydrocarbons such as hexane, with tetrahydrofuran being preferred.

[0098] The amount of compound (a2) used is usually 1 mole to 1.5 moles, preferably 1 mole to 1.2 moles, per mole of compound (a1).

[0099] The reaction temperature is, for example, -100°C to 60°C, preferably -78°C to room temperature, and the reaction time is usually 1 to 24 hours.

[0100] Step 2: The ring-closing metathesis reaction compound (2) or a salt thereof can be produced by subjecting compound (1) or a salt thereof to a ring-closing metathesis reaction in a solvent in the presence of a Grubbs catalyst.

[0101] Examples of solvents include halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as benzene; and aliphatic hydrocarbons such as hexane, with dichloromethane being preferred among them.

[0102] As the Grubbs catalyst, either a first-generation Grubbs catalyst or a second-generation Grubbs catalyst can be used.

[0103] The amount of Grubbs catalyst used is usually 0.01 moles to 0.3 moles, preferably 0.03 moles to 0.2 moles, per mole of compound (1) or its salt.

[0104] The reaction temperature is, for example, 0°C to 50°C, preferably room temperature to 40°C, and the reaction time is usually 0.5 hours to 4 hours.

[0105] Step 3: The catalytic hydrogenation compound (3) or its salt can be produced by subjecting compound (2) or its salt to a catalytic hydrogenation reaction in the presence of a palladium catalyst, under a hydrogen atmosphere, and at atmospheric pressure.

[0106] Examples of solvents include alcohols such as methanol and ethanol; esters such as ethyl acetate; and mixed solvents thereof, with methanol being preferred.

[0107] Examples of palladium catalysts include 5% palladium-carbon (Pd / C), 10% palladium-carbon (Pd / C), and palladium hydroxide (Pd(OH) ２ Examples include ), and among them, 10% palladium-carbon is preferred.

[0108] The reaction temperature is, for example, 0°C to room temperature, preferably room temperature, and the reaction time is usually 4 to 24 hours.

[0109] Step 4: Deprotection reaction compound (4) or its salt is in the solvent, P of compound (3) or its salt １It can be manufactured by deprotecting it.

[0110] P １ Deprotection of P １ Depending on the type, the deprotection can be carried out according to the methods described in "Protective Groups in Organic Synthesis (3rd edition, 1999)" by TW Greene and PG Wuts, or a similar method.

[0111] Step 5: Compound (6) or a salt thereof can be produced by reacting compound (4) or a salt thereof with compound (5) or a salt thereof in a solvent in the presence of a base.

[0112] Examples of solvents include amides such as N,N-dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran (THF) and 1,4-dioxane; halogenated hydrocarbons such as dichloromethane; and aromatic hydrocarbons such as benzene. Among these, dichloromethane is preferred.

[0113] The amount of compound (5) or its salt used is usually 1 to 3 moles, preferably 1.5 to 2.5 moles, per mole of compound (4) or its salt.

[0114] Examples of bases include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; and organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, and N-methylmorpholine, with organic bases such as triethylamine being preferred.

[0115] The amount of base used is usually 1 to 5 moles, preferably 1.5 to 4 moles, per mole of compound (4) or its salt.

[0116] The reaction temperature is, for example, 0°C to 60°C, preferably 0°C to room temperature, and the reaction time is usually 0.5 to 3 hours.

[0117] Step 6: Compound (7) or a salt thereof can be produced by reducing compound (6) or a salt thereof.

[0118] The reducing agent is not particularly limited as long as it can reduce nitro groups to amino groups, but for example, compound (7) or a salt thereof can be obtained by catalytic reduction of compound (6) or a salt thereof using a palladium catalyst in a hydrogen atmosphere at atmospheric pressure.

[0119] Examples of solvents include alcohols such as methanol and ethanol; esters such as ethyl acetate; and mixed solvents thereof, with methanol being preferred.

[0120] Examples of palladium catalysts include 5% palladium-carbon (Pd / C), 10% palladium-carbon (Pd / C), and palladium hydroxide (Pd(OH) ２ Examples of palladium catalysts include those listed above, with 10% Pd / C being preferred.

[0121] The reaction temperature is, for example, 0°C to room temperature, preferably room temperature, and the reaction time is usually 4 to 24 hours.

[0122] Step 7: Compound (I) or a salt thereof can be produced by reacting compound (7) or a salt thereof with compound (8) or a salt thereof in a solvent in the presence of a base. This step can be carried out in the same manner as in Step 5.

[0123] Compound (I) of the present invention or its salt produced by the above method can be isolated and purified by known methods, such as extraction, precipitation, distillation, chromatography, fractional recrystallization, and recrystallization. Furthermore, the chemical structure of compound (I) of the present invention or its salt is as follows: １ H-NMR, １３ It can be identified using conventional instrumental analysis methods such as C-NMR, HPLC, and liquid chromatography-mass spectrometry (LC-MS / MS).

[0124] [Vasopressin Receptor Antagonist of the Present Invention] The vasopressin receptor antagonist of the present invention means a drug that contains compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and acts antagonistically on vasopressin receptors, particularly vasopressin V1a and / or V2 receptors.

[0125] The vasopressin receptor antagonist of the present invention may be either a vasopressin receptor antagonist comprising only compound (I) of the present invention or a pharmaceutically acceptable salt thereof, or a vasopressin receptor antagonist comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc.

[0126] [Pharmaceuticals (Pharmaceutical Compositions) of the Present Invention] The pharmaceuticals of the present invention refer to pharmaceuticals (or pharmaceutical compositions) containing compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, these are pharmaceuticals for preventing and / or treating diseases in which symptoms can be alleviated by vasopressin receptor antagonism (for example, diseases selected from the group consisting of edema caused by heart failure or cirrhosis of the liver, schizophrenia, autism, and depression).

[0127] The pharmaceutical product of the present invention may be either a pharmaceutical product comprising only compound (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc. The pharmaceutical product of the present invention can be administered in a pharmaceutically effective amount to a target (for example, a mammal such as a mouse, rat, hamster, rabbit, cattle, dog, cow, sheep, monkey, or human).

[0128] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), solubilizers (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), and suspending agents (e.g., stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate). Surfactants such as phosphorus; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), buffering agents (e.g., buffers such as phosphates, acetates, carbonates, and citrates), analgesics (e.g., benzyl alcohol) Examples of additives include cellulose, preservatives (e.g., parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, etc.), colorants (e.g., water-soluble food tar dyes (e.g., food colorants such as Food Red No. 2 and 3, Food Yellow No. 4 and 5, Food Blue No. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble food tar dyes), natural pigments (e.g., β-carotene, chlorophyll, red iron oxide, etc.)), and flavoring and deodorizing agents.

[0129] The pharmaceutical (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then processing the mixture according to known manufacturing methods to produce, for example, oral preparations such as tablets, granules, capsules, and dry syrups, or parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip preparations), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, and liposome preparations. Furthermore, if necessary, it can also be prepared as a lyophilized preparation for immediate use.

[0130] Parenteral formulations may be packaged in ampoules, vials, or syringes with needles. All parenteral formulations should be sterile, as is common knowledge and practice in the art.

[0131] The injectable formulation may be designed for local and systemic administration. Compound (I) or a pharmaceutically acceptable salt thereof may be administered as a single dose or divided into several smaller doses administered at time intervals. It should be noted that the dosage of the pharmacopoeia of the present invention may vary depending on the site of parenteral administration, the age, weight, general health status, sex, severity of the condition, type of disease, type of concomitant medications, etc. Accordingly, the dosage and content ranges described herein are intended to be representative and not to limit the scope or implementation of the claimed formulation.

[0132] The content of compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the pharmaceutical (pharmaceutical composition) of the present invention varies depending on the form of the formulation, but is usually in the range of about 0.0001% to 90% by weight, preferably in the range of about 0.001% to 50% by weight, and more preferably in the range of about 0.01% to 20% by weight, with the entire formulation being 100% by weight.

[0133] The daily dose of compound (I) of the present invention or a pharmaceutically acceptable salt thereof, for example, in humans, when administered orally to an adult patient (weighing approximately 60 kg), is typically 0.1 mg to 1000 mg, preferably 1 mg to 500 mg, of the active ingredient compound (I), administered once to several times a day. Also, in humans, when administered parenterally to an adult patient (weighing approximately 60 kg), is typically 0.01 mg to 500 mg, preferably 0.1 mg to 100 mg, of the active ingredient compound (I), administered once to several times a day. The timing of administration is not limited to before, after, or between meals. The duration of administration is not particularly limited.

[0134] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent antagonistic activity against vasopressin receptors (particularly vasopressin V1a and / or V2 receptors). Therefore, pharmaceuticals containing Compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient are useful for the prevention and / or treatment of diseases whose symptoms can be alleviated by vasopressin receptor antagonism (for example, diseases selected from the group consisting of edema caused by heart failure or cirrhosis, schizophrenia, autism, and depression).

[0135] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof is preferably administered in combination with other drugs (concomitant drugs) for the prevention and / or treatment of diseases (for example, diseases selected from the group consisting of edema due to heart failure or cirrhosis, schizophrenia, autism, and depression), provided that the efficacy of the compound is not impaired. The concomitant drugs are not particularly limited, as long as they are one or more known drugs that have been conventionally used to treat diseases selected from the group consisting of edema due to heart failure or cirrhosis, schizophrenia, autism, and depression.

[0136] Examples of medications used to treat edema caused by heart failure or cirrhosis include loop diuretics such as azosemide, furosemide, and torasemide; thiazide diuretics such as hydrochlorothiazide, trichlormethiazide, and bentylhydrochlorothiazide; potassium-sparing diuretics such as amiloride, triamterene, spironolactone, and eplerenone; and sodium-glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin, dapagliflozin, and empagliflozin.

[0137] Examples of medications used to treat schizophrenia include antipsychotics such as chlorpromazine, fluphenazine, levomepromazine, haloperidol, pipemperone hydrochloride, sulpiride, aripiprazole, risperidone, olanzapine, quetiapine fumarate, and clozapine; anxiolytics such as tizolam, diazepam, and alprazolam; hypnotics such as nitrazepam, flunitrazepam, and brotizolam; and antidepressants such as aminotributyrine, fluvoxamine, milnacipran, and clomipramine.

[0138] Examples of medications used to treat autism include antiepileptic drugs such as carbamazepine and sodium valproate; central nervous system stimulants such as methylphenidate; mood stabilizers such as risperidone; and serotonin reuptake inhibitors such as paroxetine and fluvoxamine.

[0139] Examples of medications used to treat depression include aminotributyrine, fluvoxamine, milnacipran, and clomipramine.

[0140] When using concomitant drugs, the timing of administration is not limited; they may be administered simultaneously to the target patient, or with a time difference. In the case of time-difference administration, the pharmaceutical agent of the present invention may be administered first, followed by the concomitant drug, or vice versa. The administration methods may be the same or different. Furthermore, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered as a single formulation containing the concomitant drug in combination.

[0141] The dosage of concomitant medications can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of compound (I) of the present invention or its pharmaceutically acceptable salt, etc., with the concomitant medication can be appropriately selected according to the target population (age, weight, general health status, sex, severity of illness, etc.), route of administration, type of disease, type of concomitant medication, etc.

[0142] The mass ratio of compound (I) of the present invention or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[0143] Furthermore, concomitant agents that complement and / or enhance the therapeutic effect of compound (I) of the present invention or a pharmaceutically acceptable salt thereof include those that have not been discovered to date but may be discovered in the future, based on the mechanism described above.

[0144] Furthermore, in order to complement and / or enhance the prophylactic and / or therapeutic effects of compound (I) of the present invention or its pharmaceutically acceptable salt, it is also effective to use it in combination with dietary therapy, supportive therapy, etc.

[0145] The pharmaceutical or pharmaceutical composition of the present invention may be provided in the form of a kit along with instructions on how to administer it. The drug contained in the kit is supplied in a container made of a material that effectively maintains the activity of the components of the pharmaceutical or pharmaceutical composition for a long period of time, does not adsorb to the inside of the container, and does not alter the components. For example, the sealed glass ampoule may contain a buffer sealed in the presence of a neutral, unreactive gas such as nitrogen gas. Instructions for use may also be attached to the kit. The instructions for use of this kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and supplied to the user.

[0146] The present invention will be described in detail below based on reference examples, examples, test examples, and formulation examples. However, the present invention is not limited to the examples, test examples, and formulation examples, and may be modified without departing from the scope of the present invention.

[0147] The percentages indicate mol / mol% for yields, and weight% for all other values ​​unless otherwise specified. Room temperature refers to a temperature range of 15°C to 30°C unless otherwise specified. Other abbreviations used in this text have the following meanings. Boc: tert-butoxycarbonyl n-BuLi: n-butyllithium THF: tetrahydrofuran AcOEt: ethyl acetate DMSO: dimethyl sulfoxide Grubbs 1st: dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) Grubbs 2nd: dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) Pd / C: palladium-carbon PPA: polyphosphate LiAlH4: lithium aluminum hydride RuClH(CO)[PPh3]3: carbonylchlorohydridetris(triphenylphosphine)ruthenium(II) CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide PBS: phosphate-buffered saline HBSS: Hanks equilibrium salt solution BSA: bovine serum albumin LC-MS: liquid chromatography-mass spectrometry HRMS: High resolution mass spectrometry

[0148] Nuclear magnetic resonance (NMR) spectroscopy was performed using JEOL ECS 300, JEOL JNM-ECS 400, or JEOL JNMLA 500.

[0149] High-resolution mass spectrometry (HRMS) was performed using a JEOL JMS-S3000.

[0150] Unless otherwise specified, the raw material compounds used in the following reference examples, examples, and test examples are known compounds, synthesized and identified according to known methods or similar methods, or used as commercially available products. Furthermore, unless otherwise specified, the reagents and equipment used in the following reference examples, examples, and test examples are commercially available.

[0151] Reference Example 1: Synthesis of tert-butyl (E)-(2-bromophenyl)(prop-1-en-1-yl)carbamate (compound (S2))

[0152]

[0153] A solution of tert-butylallyl(2-bromophenyl)carbamate (compound (S1)) (1.56 g, 5.03 mmol) and RuClH(CO)[PPh3]3 (24 mg, 0.25 mmol) in dichloromethane (500 mL) was heated under reflux for 17 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 30 / 1) to obtain compound (S2) (61%, 952 mg, 3.05 mmol) as a white solid. 1 H NMR (301 MHz, DMSO-d6, 130 ℃) δ 7.68 (dd, J = 7.9, 1.4 Hz, 1H), 7.41 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H), 7.29-7.22 (m, 2H), 6.88 (dq, J = 14.3, 1.6 Hz, 1H), 4.20 (qd, J = 9.3, 5.0 Hz, 1H), 1.54 (dd, J = 6.7, 1.6 Hz, 3H), 1.34 (s, 9H); 13 C NMR (126 MHz, DMSO-d6, 130 ℃) δ 150.5, 137.6, 132.6, 130.4, 129.0, 128.2, 128.1, 122.5, 104.7, 80.2, 27.3, 13.8; HRMS (ESI) calcd for C 14 H 18 NO2Br: 334.0413 ([M+Na] + ), found 334.0419 ([M+Na] + ); mp: 52-56 ℃.

[0154] Reference Example 2: Synthesis of tert-butyl (E)-(2-(allyldimethylsilyl)phenyl)(prop-1-en-1-yl)carbamate (compound (1a))

[0155]

[0156] To a solution of compound (S2) (1.19 g, 3.81 mmol) in THF (38 mL), a solution of n-BuLi in n-hexane (1.6 M, 2.38 mL, 3.81 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour, then allylchlorodimethylsilane (0.58 mL, 4.2 mmol) was added dropwise, and the mixture was stirred at the same temperature for 17 hours. The reaction mixture was diluted with water, and the organic compound was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 20 / 1 to 10 / 1) to obtain compound (1a) (93%, 1.17 g, 3.52 mmol) as a colorless, transparent oil. 1 H NMR (301 MHz, DMSO-d6, 130 ℃) δ 7.59 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 7.5, 1.7 Hz 1H), 7.35 (dd, J =7.2, 7.2 Hz, 1H), 7.01-6.94 (m, 2H), 5.72 (dq, J = 10.3, 7.6 Hz, 1H), 4.84 (d, J = 5.8 Hz, 1H), 4.79 (s, 1H), 4.10 (td, J = 13.8, 6.7 Hz, 1H), 1.73 (d, J = 7.6 Hz, 2H), 1.57 (dd, J = 6.7, 0.8 Hz 3H), 1.37 (s, 9H), 0.23 (s, 6H); 13 C NMR (126 MHz, DMSO-d6) δ 151.2, 143.6, 136.8, 134.7, 133.7, 130.5, 129.3, 128.6, 126.0, 112.4, 105.1, 79.7, 27.4, 27.1(rotamer mixture), 22.5, 13.3, -3.3, -3.4; HRMS (ESI) calcd for C 19 H 29 NO2Si: 354.1860 ([M+Na] + ), found 354.1858 ([M+Na] + ).

[0157] Reference Example 3: Synthesis of tert-butyl allyl (2-(allyldimethylsilyl)phenyl)carbamate (compound (1b))

[0158]

[0159] To a solution of compound (S1) (1.87 g, 5.99 mmol) in THF (38 mL), a solution of n-BuLi in n-hexane (3.74 ml, 5.99 mmol) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour, then allylchlorodimethylsilane (1.0 ml, 6.6 mmol) was added dropwise, and the mixture was stirred at the same temperature for 17 hours. The reaction mixture was diluted with water, and the organic compound was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 20 / 1 to 10 / 1) to obtain compound (1b) (87%, 1.73 g, 5.23 mmol) as a colorless, transparent oil. 1 H NMR (500 MHz, DMSO-d6, 130 ℃) δ 7.54 (d, J = 7.4 Hz, 1H), 7.37 (dd, J = 7.5, 7.5 Hz, 1H), 7.29 (dd, J = 7.5, 7.5 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 5.98-5.90 (m, 1H), 5.77 (td, J = 17.0, 8.8 Hz, 1H), 5.14-5.07 (m, 2H), 4.87-4.83 (m, 2H), 3.98 (s, 2H), 1.79 (d, J = 8.0 Hz, 2H), 1.38 (s, 9H), 0.28 (s, 6H); 13 C NMR (126 MHz, DMSO-d6, 130 ℃) δ 153.6, 146.9, 136.3, 134.9, 134.0, 133.3, 129.0, 128.5, 125.8, 116.6, 112.7, 78.7, 53.1, 27.4, 22.8, -3.0; HRMS (ESI) calcd for C 19 H 29 NO2Si: 354.1860 ([M+Na] +), found 354.1854 ([M+Na] + ).

[0160] Reference Example 4: Synthesis of tert-butyl (Z)-6,6-dimethyl-5,6-dihydrobenzo[b][1,4]azasilocine-1(2H)-carboxylate (compound (2b))

[0161]

[0162] To a solution of compound (1b) (1.66 g, 5.01 mmol) obtained in Reference Example 3 in dichloromethane (50 mL), Grubbs 1st (208 mg, 0.253 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 20 / 1) to obtain compound (2b) (89%, 1.35 g, 4.46 mmol) as a colorless oil. 1 H NMR (500 MHz, DMSO-d6, 130 ℃) δ 7.44 (d, J = 6.9 Hz, 1H), 7.37 (dd, J = 7.5, 7.5 Hz, 1H), 7.26 (dd, J = 7.2, 7.2 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 5.69 (dtd, J = 19.6, 9.2, 1.7 Hz, 1H), 5.10 (dt, J =10.3, 4.6 1H), 4.16 (br, 2H), 1.76 (d, J = 7.4 Hz, 2H), 1.33 (s, 9H), 0.24 (s, 6H); 13 C NMR (126 MHz, DMSO-d6, 130 ℃) δ: 154.8, 147.5, 138.8, 134.9, 130.8, 129.9, 128.1, 127.3, 122.0, 79.7, 49.1, 28.7, 18.7, -1.3; HRMS (ESI) calcd for C 17 H 25 NO2Si: 326.1547 ([M+Na] + ), found 326.1547 ([M+Na] + ).

[0163] Reference Example 5: Synthesis of (6,6-dimethyl-3,4,5,6-tetrahydrobenzo[b][1,4]azasilocin-1(2H)-yl)(4-nitrophenyl)methanone (compound (6b))

[0164]

[0165] In Example 1(2), described later, compound (2b) was used instead of compound (2a). Otherwise, compound (6b) was obtained as a yellow amorphous material by the same method as in Examples 1(2) to (4). 1 H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H), 7.48-7.46 (m, 1H), 7.41-7.39 (m, 2H), 7.24-7.21 (m, 2H), 6.94-6.92 (m, 1H), 4.93-4.87 (m, 1H), 3.17-3.12 (m, 1H), 2.10-2.00 (m, 1H), 1.84-1.75 (m, 2H), 1.65 (td, J = 11.3, 3.1 Hz, 1H), 1.44-1.35 (m, 1H), 0.90 (td, J = 10.0, 5.2 Hz, 1H), 0.30 (s, 3H), 0.08 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 168.4, 147.7, 145.9, 142.7, 141.3, 135.6, 130.3, 129.6, 129.4, 127.6, 122.7, 50.3, 24.9, 22.4, 13.5, -0.5, -2.0; HRMS (ESI) calcd for C 19 H 22 N2O3Si: 377.1292 ([M+Na] + ), found 377.1287 ([M+Na] + ); mp: 87-90 ℃.

[0166] Reference Example 6: Synthesis of 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (compound (11a))

[0167] (1) Synthesis of (Z)-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one oxime (compound (9a))

[0168]

[0169] A solution of 4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one (1.18 g, 6.78 mol) and 2-hydroxyisoindorin-1,3-dione (1.66 g, 10.2 mmol) in 20 ml of water was stirred at 90°C for 48 hours. The mixture was then cooled to room temperature, AcOEt was added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 10 / 1) to obtain compound (9a) (52%, 671 mg, 3.56 mmol) as a white solid.

[0170] (2) Synthesis of 5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-one (compound (10a))

[0171]

[0172] The mixture of compound (9a) (671 mg, 3.56 mmol) obtained in (1) above and PPA (3.6 ml) was stirred at 120 °C for 2 hours. The reaction mixture was then cooled to room temperature, AcOEt was added, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product of compound (10a).

[0173] (3) Synthesis of 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (compound (11a))

[0174]

[0175] To a solution of compound (10a) obtained in (2) above in dried THF (32 mL) and diethyl ether (8 mL), LiAlH4 (407 mg, 10.7 mmol) was added, and the mixture was heated under reflux for 16 hours. The reaction mixture was then stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture and extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to obtain compound (11a) (39%, 252 mg, 1.39 mmol in two steps) as a pale yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.96-6.91 (m, 1H), 6.73 (d, J = 7.8 Hz, 1H), 3.66 (br ,s, 1H), 3.09-3.07 (m, 2H), 1.93 (tt, J = 8.5, 3.0 Hz, 2H), 1.71-1.68 (m, 2H), 1.45 (s, 6H); 13 C NMR (101 MHz, CDCl3) δ 150.0, 139.3, 127.1, 126.4, 120.9, 120.8, 48.8, 40.3, 38.5, 29.0, 27.0; HRMS (ESI) calcd for C 12 H 17 N: 176.1434 ([M+H] + ), found 176.1432 ([M+H] + ).

[0176] Reference Example 7: Synthesis of (5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)(4-nitrophenyl)methanone (compound (12a))

[0177]

[0178] In Example 1 (4), described later, compound (11a) obtained in Reference Example 6 was used instead of compound (4a). Otherwise, compound (12a) was obtained as a yellow solid by the same method as in Example 1 (4). 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 6.8, 2.0 Hz, 2H), 7.46 (dd, J = 7.9, 1.3 Hz, 1H), 7.40 (dd, J = 7.0, 2.1 Hz, 2H), 7.16 (ddd, J =7.7, 7.7, 1.4 Hz, 1H), 6.86 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H), 6.50 (dd, J = 7.8, 1.5 Hz, 1H), 5.04-4.99 (m, 1H), 2.83 (t, J = 12.7 Hz, 1H), 2.35-2.27 (m, 1H), 1.92-1.80 (m, 2H), 1.68-1.61 (m, 1H), 1.51 (s, 3H), 1.50 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 166.3, 147.7, 144.0, 142.0, 142.0, 129.7, 129.6, 127.8, 126.8, 122.7, 47.9, 39.8, 38.4, 32.0, 24.6 (one HRMS (ESI): calcd for C 19 H 20 N2O3: 325.1547 ([M+H] + ), found 325.1545([M+H] + ); mp: 138-142 ℃.

[0179] Reference Example 8: Synthesis of (4-nitrophenyl)(2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)methanone (compound (12b))

[0180]

[0181] In Example 1 (4), described later, 2,3,4,5-tetrahydro-1H-1-benzoazepine was used instead of compound (4a). Otherwise, compound (12b) was obtained as a yellow solid by the same method as in Example 1 (4). 1H-NMR (301 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.10 (dd, J =7.6, 7.6 Hz, 1H), 6.90 (dd, J =7.6, 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.00-4.95 (m, 1H), 3.06-2.78 (m, 3H), 2.13-1.97 (m, 3H), 1.54 (t, J = 13.8 Hz, 1H); 13 C-NMR (101 MHz, CDCl3) δ 166.9, 147.8, 142.8, 142.5, 139.3, 130.3, 128.8, 128.2, 127.8, 127.2, 122.9, 47.7, 34.9, 29.5, 26.2; HRMS (ESI): calcd for C 17 H 16 N2O3: 297.1234 ([M+H] + ), found 297.1232 ([M+H] + ); mp: 152-153 ℃.

[0182] Reference Example 9: Synthesis of (4-nitrophenyl)(3,4,5,6-tetrahydrobenzo[b]azosin-1(2H)-yl)methanone (compound (12c))

[0183]

[0184] In Example 1 (4), described later, 1,2,3,4,5,6-hexahydro-1-benzoazosine was used instead of compound (4a), and purification by column chromatography was not performed. Otherwise, compound (12c) was obtained as the crude product by the same method as in Example 1 (4).

[0185] Example 1: Synthesis of N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azacilepin-1-carbonyl)phenyl)benzamide (compound (I-1))

[0186] (1) Synthesis of tert-butyl 5,5-dimethyl-4,5-dihydro-1H-benzo[b][1,4]azacilepin-1-carboxylate (compound (2a))

[0187]

[0188] To a solution of compound (1a) (1.06 g, 3.20 mmol) obtained in Reference Example 2 in dichloromethane (640 mL), Grubbs 2nd (272 mg, 0.32 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 20 / 1) to obtain compound (2a) (80%, 740 mg, 2.56 mmol) as a colorless, transparent oil. 1 H NMR(500 MHz, DMSO-d6, 130 ℃) δ 7.41 (d, J = 7.4 Hz, 1H), 7.32 (dd, J = 7.5, 7.5 Hz, 1H), 7.23 (dd, J = 7.5, 7.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 7.4 Hz, 1H), 5.46 (td, J = 12.6, 6.3 Hz, 1H), 1.47 (d, J = 5.7 Hz, 2H), 1.38 (s, 9H), 0.26 (s, 6H); 13 HRMS (ESI) calcd for C 16 H 23 NO2Si: 312.1390 ​​([M+Na] + ), found 312.1389 ([M+Na] + ).

[0189] (2) Synthesis of tert-butyl 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azacilepin-1-carboxylate (compound (3a))

[0190]

[0191] To a methanol (5 mL) solution of compound (2a) (154 mg, 0.50 mmol) obtained in (1) above, 10% Pd / C (7.7 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 17 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound (3a) as a colorless, transparent oil.

[0192] (3) Synthesis of 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azacilepin (compound (4a))

[0193]

[0194] To a 5 mL solution of compound (3a) obtained in (2) above, Amberlyst® 15 (1.54 g) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound (4a).

[0195] (4) Synthesis of (5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azacilepin-1-yl)(4-nitrophenyl)methanone (compound (6a))

[0196]

[0197] To a solution of compound (4a) obtained in (3) above and triethylamine (0.28 ml, 2.0 mmol) in dichloromethane (5 ml), p-nitrobenzoyl chloride (5a) (186 mg, 1.0 mmol) was slowly added, and the mixture was stirred at 0 °C for 15 minutes, followed by 1 hour at room temperature. Water was added to the reaction mixture, liquid-liquid separation was performed, the organic layer was washed three times with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 10:1) to obtain compound (6a) (61%, 106 mg, 0.31 mmol) as yellow plate-like crystals. 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 9.2 Hz, 2H), 7.55 (dd, J = 7.4, 1.1 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.20 (dd, J = 7.5, 7.5 Hz, 1H), 7.04 (dd, J = 9.2, 7.4 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 4.86 (d, J = 13.7 Hz, 1H), 2.88 (t, J = 11.7 Hz, 1H), 2.28-2.23 (m, 1H), 2.05-2.02 (m, 1H), 1.00 (dt, J = 14.3, 4.6 Hz, 1H), 0.81 (td, J = 13.2, 5.2 Hz, 1H), 0.40 (s, 3H), 0.36 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 167.3, 149.7, 147.9, 142.1, 137.4, 135.5, 130.4, 130.0, 128.2, 127.3, 122.8, 52.8, 24.4, 14.2, -2.3, -2.8; HRMS (ESI) calcd for C 18 H 20 N2O3Si: 363.1135 ([M+Na] + ), found 363.1130 ([M+Na] + ); mp: 141-142 ℃.

[0198] (5) Synthesis of (4-aminophenyl)(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azacilepin-1-yl)methanone (7a)

[0199]

[0200] To a methanol (5.8 mL) solution of compound (6a) (100 mg, 0.29 mmol) obtained in (4) above, 10% Pd / C (10 mg, 10 wt%) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 17 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound (7a) as a brown powder.

[0201] (6) Synthesis of N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azacilepin-1-carbonyl)phenyl)benzamide (compound (I-1))

[0202]

[0203] To a solution of compound (7a) obtained in (5) above and triethylamine (0.40 ml, 2.9 mmol) in dichloromethane (5.8 ml), benzoyl chloride (8a) (85 μL, 0.73 mol) was slowly added, and the mixture was stirred at 0 °C for 15 minutes, then at room temperature for 1 hour. Water was added to the reaction mixture, liquid-liquid separation was performed, the organic layer was washed three times with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 3:1) to obtain compound (I-1) (55%, 66.2 mg, 0.16 mmol) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H), 7.43 (d, J = 8.7 Hz, 3H), 7.35-7.31 (m, 2H), 7.18-7.11 (m, 3H), 7.04 (dd, J =11.5, 7.3 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.85 (d, J = 13.3 Hz, 1H), 2.78 (t, J = 12.1 Hz, 1H), 2.14 (q, J = 11.8 Hz, 1H), 1.95-1.92 (m, 1H), 0.94 (q, J = 4.9 Hz, 1H), 0.76 (dt, J = 18.9, 6.6 Hz, 1H), 0.38 (s, 3H), 0.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.6, 166.0, 150.7, 139.5, 136.9, 135.0, 134.6, 131.7, 130.8, 130.2, 130.1, 128.5, 128.0, 127.2, 126.6, 118.7, 52.5, 24.3, 14.0, -2.5, -3.0; HRMS (ESI) calcd for C 25 H 26 N2O2Si: 415.1842 ([M+H] + ), found 415.1828 ([M+H] + ); m.p.: 208-212 ℃

[0204] Example 2: Synthesis of N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azasilepin-1-carbonyl)phenyl)-2-methylbenzamide (Compound (I-2))

[0205]

[0206] In (6) of Example 1, 2-methylbenzoyl chloride (8b) was used in place of benzoyl chloride (8a). Except for that, the same procedure as in Example 1 was followed to obtain Compound (I-2) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.55 (dd, J = 7.1, 1.6 Hz, 1H), 7.40-7.31 (m, 4H), 7.23-7.17 (m, 5H), 7.10 (ddd, J = 7.7, 7.7, 1.5 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 4.88 (d, J = 13.3 Hz, 1H), 2.81 (t, J = 11.4 Hz, 1H), 2.44 (s, 3H), 2.24-2.15 (m, 1H), 2.00 (dd, J = 12.4, 4.6 Hz, 1H), 0.98 (td, J = 9.4, 4.6 Hz, 1H), 0.83-0.76 (m, 1H), 0.40 (s, 3H), 0.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.3, 168.1, 150.8, 139.2, 137.0, 136.4, 136.0, 135.1, 131.2, 131.1, 130.5, 130.4, 130.2, 128.0, 126.6, 126.6, 125.8, 118.1, 52.6, 24.4, 19.8, 14.1, -2.5, -2.9; HRMS (ESI) calcd for C 26 H 28 N2O2Si: 429.1998 ([M+H] + ), found 429.1984 ([M+H] + ); m.p.: 208-212 °C.

[0207] Example 3: Synthesis of 2-chloro-N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]azasilepin-1-carbonyl)phenyl)benzamide (Compound (I-3))

[0208]

[0209] In (6) of Example 1, 2-chlorobenzoyl chloride (8c) was used instead of benzoyl chloride (8a). Except for that, the same procedure as in Example 1 was followed to obtain Compound (I-3) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.3, 1.4 Hz, 1H), 7.40 (d, J = 7.3 Hz, 2H), 7.25 (d, J = 3.7 Hz, 3H), 7.19-7.14 (m, 4H), 7.11 (d, J = 8.7 Hz, 2H), 6.99 (ddd, J =7.8, 7.8, 1.4 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 4.86 (d, J = 13.3 Hz, 1H), 2.82 (t, J = 11.7 Hz, 1H), 2.25-2.21 (m, 1H), 2.02 (br, s, 1H), 0.98 (td, J = 14.7, 4.1 Hz, 1H), 0.81 (td, J = 11.5, 5.0 Hz, 1H), 0.38 (s, 3H), 0.30 (s, 3H); 13 C-NMR (101 MHz, CDCl3) δ 169.2, 168.0, 150.3, 138.9, 137.0, 135.8, 135.1, 135.1, 131.4, 130.8, 130.1, 130.1, 129.8, 129.2, 128.0, 127.4, 126.7, 126.6, 52.6, 24.3, 14.1, -2.4, -2.9; HRMS (APCI) calcd for C 25 H 25 ClN2O2Si: 449.1452 ([M+H] + ), found 449.1453 ([M+H] + ); mp: 154-158 ℃.

[0210] Example 4: N-(4-(6,6-ジメチル-1,2,3,4,5,6-ヘキサヒドロベンゾ[b][1 ,4] Synthesis of アザシロシン-1-カルボニル)フェニル)ベンズアミド (Compound (I-4))

[0211]

[0212] In Example 1 (5), compound (6b) obtained in Reference Example 5 was used instead of compound (6a). Otherwise, compound (I-4) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, CDCl3) δ 7.81-7.79 (m, 2H), 7.76 (s, 1H), 7.56-7.41 (m, 6H), 7.31 (dd, J = 6.9, 1.9 Hz, 2H), 7.24-7.20 (m, 2H), 6.94-6.91 (m, 1H), 4.91-4.84 (m, 1H), 3.13-3.07 (m, 1H), 2.06-1.99 (m, 1H), 1.88-1.80 (m, 2H), 1.68-1.61 (m, 1H), 1.44-1.35 (m, 1H), 0.89-0.83 (m, 1H), 0.32 (s, 3H), 0.09 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.7, 165.5, 147.7, 140.7, 138.9, 135.3, 134.6, 132.1, 132.0, 130.2, 130.1, 129.4, 128.8, 126.9, 118.3, 76.4, 50.8, 25.3, 22.2, 13.7, -0.5, -2.0 (one carbon was overlapped ); HRMS (ESI) calcd for C 26 H 28 N2O2Si: 451.1812 ([M+Na] + ), found 451.1804 ([M+Na] + ); mp: 226-230 ℃.

[0213] Example 5: Synthesis of N-(4-(6,6-dimethyl-1,2,3,4,5,6-hexahydrobenzo[b][1,4]azasilosin-1-carbonyl)phenyl)-2-methylbenzamide (compound (I-5))

[0214]

[0215] In Example 1 (5), compound (6b) obtained in Reference Example 5 was used instead of compound (6a), and in Example 1 (6), 2-methylbenzoyl chloride (8b) was used instead of benzoyl chloride (8a). Otherwise, compound (I-5) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.55 (dd, J = 7.3, 1.4 Hz, 1H), 7.40-7.17 (m, 10H), 7.10 (ddd, J =7.6, 7.6, 1.2 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 4.88 (d, J = 13.7 Hz, 1H), 2.81 (t, J = 11.7 Hz, 1H), 2.44 (s, 3H), 2.24-2.15 (m, 1H), 2.01-1.98 (m, 1H), 0.98 (td, J = 9.5, 4.7Hz, 1H), 0.83--0.76 (m, 1H), 0.40 (s, 3H), 0.33 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 168.3, 168.0, 150.9, 139.2, 137.0, 136.4, 136.0, 135.1, 131.2, 131.1, 130.5, 130.4, 130.2, 128.0, 126.6, 126.6, 125.8, 118.1, 52.6, 24.4, 19.8, 14.1, -2.5, -2.9; HRMS (ESI) calcd for C 27 H 30 N2O2Si: 443.2155 ([M+H] + ), found 429.2142 ([M+H] + ); mp: 210-214 ℃.

[0216] Example 6: Synthesis of 2-chloro-N-(4-(6,6-dimethyl-1,2,3,4,5,6-hexahydrobenzo[b][1,4]azasilocin-1-carbonyl)phenyl)benzamide (compound (I-6))

[0217]

[0218] In Example 1 (5), compound (6b) obtained in Reference Example 5 was used instead of compound (6a), and in Example 1 (6), 2-chlorobenzoyl chloride (8c) was used instead of benzoyl chloride (8a). Otherwise, compound (I-6) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (301 MHz, CDCl3, 55 ℃) δ 7.51 (dd, J = 7.2, 1.4 Hz, 1H), 7.38 (d, J = 7.2 Hz, 2H), 7.23-7.08 (m, 9H), 6.98 (t, J = 7.4 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H), 4.86 (d, J = 13.8 Hz, 1H), 2.83 (s, 1H), 2.25 (s, 1H), 2.00 (s, 1H), 0.94 (s, 1H), 0.83 (s, 1H), 0.37 (s, 3H), 0.30 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.2, 146.8, 140.8, 138.8, 136.5, 135.3, 135.1, 131.3, 130.7, 130.0, 129.8, 129.8, 129.4, 129.2, 127.6, 127.4, 127.1, 126.7, 50.5, 25.0, 22.2, 13.5, -0.6, -2.0; HRMS (APCI) calcd for C 26 H 27 ClN2O2Si: 463.1609 ([M+H] + ), found 463.1607 ([M+H] + ); mp: 218-222 ℃.

[0219] Comparative Example 1: Synthesis of N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)phenyl)benzamide (compound (II-1))

[0220]

[0221] In Example 1 (5), compound (12a) obtained in Reference Example 7 was used instead of compound (6a). Otherwise, compound (II-1) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.52 (dd, J = 7.3, 7.3 Hz, 1H), 7.46-7.42 (m, 5H), 7.24 (d, J = 8.7 Hz, 1H), 7.15 (td, J = 7.7, 1.4 Hz, 1H), 6.89 (td, J = 7.6, 1.4 Hz, 1H), 6.59 (dd, J = 8.0, 1.1 Hz, 1H), 5.06 (d, J = 13.3 Hz, 1H), 2.77 (t, J = 11.7 Hz, 1H), 2.30-2.19 (m, 1H), 1.90-1.86 (m, 1H), 1.82-1.74 (m, 1H), 1.65-1.58 (m, 1H), 1.50 (s, 3H), 1.49 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 167.7, 165.7, 143.8, 143.2, 139.2, 134.7, 131.9, 131.1, 130.4, 129.7, 128.7, 127.5, 127.2, 127.0, 126.8, 118.5, 47.8, 39.9, 38.5, 32.0, 24.8; HRMS (ESI): calcd for C 26 H 26 N2O2: 399.2067 ([M+H] + ), found 399.2066 ([M+H] + ); mp: 227-231 ℃.

[0222] Comparative Example 2: Synthesis of N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)phenyl)-2-methylbenzamide (compound (II-2))

[0223]

[0224] In Example 1 (5), compound (12a) obtained in Reference Example 7 was used instead of compound (6a), and in Example 1 (6), 2-methylbenzoyl chloride (8b) was used instead of benzoyl chloride (8a). Otherwise, compound (II-2) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H-NMR(400 MHz, CDCl3) δ 7.89 (s, 1H), 7.46 (dd, J = 7.8, 1.4 Hz, 1H), 7.40 (dd, J = 6.4, 6.4 Hz, 3H), 7.32 (ddd, J =7.6, 7.6, 1.2 Hz, 1H), 7.23-7.15 (m, 5H), 6.92 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.59 (dd, J = 7.8, 1.4 Hz, 1H), 5.03 (d, J = 13.3 Hz, 1H), 2.75 (t, J = 11.7 Hz, 1H), 2.43 (s, 3H), 2.29-2.18 (m, 1H), 1.90-1.86 (m, 1H), 1.80-1.75 (m, 1H), 1.65-1.58 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H); 13 C-NMR(101 MHz, CDCl3) δ 168.1, 167.5, 143.8, 143.2, 139.3, 136.4, 136.1, 131.2, 130.9, 130.5, 130.3, 129.6, 127.5, 127.3, 126.8, 126.6, 125.8, 118.2, 47.8, 39.8, 38.5, 32.0, 24.8, 19.8; HRMS (ESI): calcd for C 27 H 28 N2O2: 413.2224 ([M+H] + ), found 413.2220 ([M+H] + ); mp: 149-153 ℃.

[0225] Comparative Example 3: Synthesis of 2-chloro-N-(4-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)phenyl)benzamide (compound (II-3))

[0226]

[0227] In Example 1 (5), compound (12a) obtained in Reference Example 7 was used instead of compound (6a), and in Example 1 (6), 2-chlorobenzoyl chloride (8c) was used instead of benzoyl chloride (8a). Otherwise, compound (II-3) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.47-7.26 (m, 8H), 7.17 (dd, J =7.8, 7.8 Hz, 1H), 6.92 (dd, J = 7.6, 7.6 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 5.05 (d, J = 9.6 Hz, 1H), 2.76 (t, J = 12.4 Hz, 1H), 2.30-2.21 (m, 1H), 1.91-1.87 (m, 1H), 1.81-1.77 (m, 1H), 1.66-1.59 (m, 1H), 1.50 (s, 3H), 1.49 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 167.4, 164.4, 143.8, 143.3, 138.9, 138.7, 134.9, 134.8, 131.8, 131.4, 130.5, 130.4, 129.7, 127.6, 127.3, 126.8, 118.4, 47.8, 39.9, 38.5, 32.1, 24.8 (one carbon was overlapped); HRMS (ESI): calcd for C 26 H 25 N2O2Cl: 433.1677 ([M+H] + ), found 433.1674 ([M+H] +); mp: 213-217 ℃.

[0228] Comparative Example 4: Synthesis of N-(4-(2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)phenyl)benzamide (compound (II-4))

[0229]

[0230] In Example 1 (5), compound (12b) obtained in Reference Example 8 was used instead of compound (6a). Otherwise, compound (II-4) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.88 (d, J = 7.3, 7.3 Hz, 2H), 7.59-7.55 (m, 3H), 7.50 (dd, J = 7.3, 7.3 Hz, 2H), 7.29 (dd, J = 7.6, 1.1 Hz, 1H), 7.11-7.06 (m, 3H), 6.94 (dd, J = 7.3, 7.3 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 4.85 (d, J = 12.8 Hz, 1H), 2.98 (t, J = 12.8 Hz, 1H), 2.88 (s, 1H), 2.64 (t, J = 11.9 Hz, 1H), 2.02-1.98 (m, 1H), 1.85-1.78 (m, 2H), 1.42-1.34 (m, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 167.6, 165.7, 144.0, 140.0, 139.2, 134.8, 131.7, 131.4, 130.0, 128.4, 128.2, 127.7, 127.0, 126.9, 118.9, 46.9, 34.3, 29.5, 26.0 (one carbon was overlapped); HRMS (ESI): calcd for C 24 H 22 N2O2: 393.1573 ([M+Na] + ), found 393.1566 ([M+Na] +); mp: 239-240℃.

[0231] Comparative Example 5: Synthesis of 2-methyl-N-(4-(2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)phenyl)benzamide (compound (II-5))

[0232]

[0233] In Example 1 (5), compound (12b) obtained in Reference Example 8 was used instead of compound (6a), and in Example 1 (6), 2-methylbenzoyl chloride (8b) was used instead of benzoyl chloride (8a). Otherwise, compound (II-5) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, DMSO-d6)δ 10.31 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38-7.21 (m, 5H), 7.06 (d, J = 6.6 Hz, 3H), 6.93 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 4.82 (d, J = 13.2 Hz, 1H), 2.95 (t, J = 13.0 Hz 1H), 2.86-2.82 (m, 1H), 2.61 (t, J = 12.4 Hz, 1H), 2.30 (s, 3H), 1.98 (d, J = 9.4 Hz, 1H), 1.82-1.72 (m, 2H), 1.40-1.30 (m, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 168.0, 167.6, 144.0, 140.1, 139.2, 136.9, 135.2, 131.2, 130.5, 130.0, 129.7, 128.5, 128.2, 127.2, 127.0, 126.9, 125.6, 118.3, 47.0, 34.2, 29.5, 25.9, 19.3; HRMS (ESI): calcd for C 25 H 24 N2O2: 407.1730 ([M+Na] + ), found 407.1723 ([M+Na]+ ); m.p.: 230-234 °C.

[0234] Comparative Example 6: Synthesis of 2-chloro-N-(4-(2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)phenyl)benzamide (Compound (II-6))

[0235]

[0236] In (5) of Example 1, the compound (12b) obtained in Reference Example 8 was used instead of the compound (6a), and in (6) of Example 1, 2-chlorobenzoyl chloride (8c) was used instead of benzoyl chloride (8a). Except for the above operations, the same procedures as in (5) and (6) of Example 1 were performed to obtain the compound (II-6) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.55-7.40 (m, 6H), 7.29 (d, J = 7.8 Hz, 1H), 7.11-7.07 (m, 3H), 6.96 (dd, J = 7.3, 7.3 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 4.85 (d, J = 12.8 Hz, 1H), 2.98 (t, J = 12.6 Hz, 1H), 2.87-2.84 (m, 1H), 2.64 (t, J = 11.9 Hz, 1H), 2.02-1.98 (m, 1H), 1.84-1.78 (m, 2H), 1.42-1.37 (m, 1H); 13 C NMR (101 MHz, DMSO-d6) δ 167.5, 165.0, 143.9, 139.7, 139.2, 136.7, 131.6, 131.2, 130.0, 129.8, 129.6, 128.9, 128.6, 128.2, 127.3, 127.1, 126.9, 118.2, 47.0, 34.3, 29.5, 26.0; HRMS (ESI): calcd for C 25 H 21 ClN2O2: 427.1184 ([M+Na] + ), found 427.1178 ([M+Na] +); mp: 216-220 ℃.

[0237] Comparative Example 7: Synthesis of N-(4-(1,2,3,4,5,6-hexahydrobenzo[b]azosin-1-carbonyl)phenyl)benzamide (compound (II-7))

[0238]

[0239] In Example 1 (5), compound (12c) obtained in Reference Example 9 was used instead of compound (6a). Otherwise, compound (II-7) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.58-7.47 (m, 5H), 7.34-7.11 (m, 6H), 4.72-4.66 (m, 1H), 2.97-2.91 (m, 1H), 2.55 (d, J = 3.4 Hz, 1H), 1.85-1.81 (m, 1H), 1.77-1.70 (m, 1H), 1.54-1.50 (m, 1H), 1.39-1.22 (m, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 169.0, 165.7, 141.7, 140.8, 139.8, 134.8, 131.7, 131.6, 129.9, 129.0, 128.5, 128.4 (one carbon was overlapped), 127.6, 127.4, 118.8, 50.8, 31.1, 30.4, 25.8, 25.7; HRMS (ESI): calcd for C 25 H 24 N2O2: 407.1730 ([M+Na] + ), found 407.1723 ([M+Na] + ); mp: 224-228 ℃.

[0240] Comparative Example 8: Synthesis of N-(4-(1,2,3,4,5,6-hexahydrobenzo[b]azosin-1-carbonyl)phenyl)-2-methylbenzamide (compound (II-8))

[0241]

[0242] In Example 1 (5), compound (12c) obtained in Reference Example 9 was used instead of compound (6a), and in Example 1 (6), 2-methylbenzoyl chloride (8b) was used instead of benzoyl chloride (8a). Otherwise, compound (II-8) was obtained as a white solid by the same method as in Example 1 (5) and (6). 1 H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.39-6.94 (m, 12H), 4.79 (t, J = 9.2 Hz, 1H), 2.97-2.93 (m, 1H), 2.66 (td, J = 12.6, 3.4 Hz, 1H), 2.51-2.48 (m, 1H), 2.40 (s, 3H), 1.91-1.78 (m, 2H), 1.60-1.25 (m, 4H); 13 C NMR (101 MHz, CDCl3) δ 169.9, 168.1, 141.8, 141.2, 139.2, 136.4, 136.1, 131.8, 131.1, 130.2, 130.1, 129.3, 128.6, 128.5, 127.4, 126.7, 125.7, 118.3, 51.7, 31.3, 31.1, 26.3, 26.1, 19.8; HRMS (ESI): calcd for C 26 H 26 N2O2: 421.1886 ([M+Na] + ), found 421.1879 ([M+Na] + ); mp: 205-208 ℃.

[0243] Comparative Example 9: Synthesis of 2-chloro-N-(4-(1,2,3,4,5,6-hexahydrobenzo[b]azosin-1-carbonyl)phenyl)benzamide (compound (II-9))

[0244]

[0245] In Example 1 (5), compound (12c) obtained in Reference Example 9 was used instead of compound (6a), and in Example 1 (6), 2-chlorobenzoyl chloride (8c) was used instead of benzoyl chloride (8a). Otherwise, compound (II-9) was obtained as a white solid by the same method as in Examples 1 (5) and (6). 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.65-7.63 (m, 1H), 7.42-7.28 (m, 7H), 7.18-7.08 (m, 4H), 4.86-4.80 (m, 1H), 2.98 (ddd, J = 13.3, 7.4, 3.0 Hz, 1H), 2.68 (td, J = 12.9, 3.7 Hz, 1H), 2.54-2.49 (m, 1H), 1.92-1.76 (m, 2H), 1.63-1.58 (m, 1H), 1.52-1.33 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 169.8, 164.4, 141.8, 141.3, 138.5, 134.9, 132.4, 131.7, 130.6, 130.3, 130.2, 130.1, 129.4, 128.6, 128.5, 127.4, 127.2, 118.5, 51.7, 31.3, 31.1, 26.3, 26.1; HRMS (ESI): calcd for C 25 H 23 ClN2O2: 441.1340 ([M+Na] + ), found 441.1333 ([M+Na] + ); mp: 247-250 ℃.

[0246] Test Example 1: Measurement of solubility and LogD (lipid solubility evaluation) of compound (I) of the present invention

[0247] (Test Method) Each test compound was dissolved in PBS and diluted to a final concentration of 100 μM with 1% DMSO. After shaking for 20 minutes, each solution was filtered using a MultiScreen HTS MSSLBPC10 (Millipore), and the filtrate was analyzed using UPLC (ACQUITY UPLC, Waters) with a BEH C18 column (1.7 μm, 2.1 × 50 mm, Waters) and a photodiode array detector (wavelength 280 nm). The solubility (%) of each test compound was calculated by comparing it with the peak area of ​​each solution (100 μM in 5% DMSO). Mobile phase A = 10 mM ammonium acetate / 5% acetonitrile / water, Mobile phase B = 10 mM ammonium acetate / 5% water / acetonitrile, Gradient: 0 min-0% B, 1.0 min-100% B, Flow rate: 0.8 mL / min. Furthermore, the LogD (pH 7.4) value was calculated by comparing it with the retention time of a standard compound for which the LogD value is known.

[0248] LC-MS / MS data were acquired using a BEH C18 column (1.7 μm, 2.1 × 50 mm, Waters) connected to a UPLC (ACQUITY UPLC, Waters) and a mass spectrometer (Xevo TQ-S, Waters). Mobile phase A = 0.1% formic acid / water, mobile phase B = 0.1% formic acid / acetonitrile, gradient: 0 min - 2% B, 1.8 min - 98% B, flow rate: 0.5 mL / min.

[0249] (Test Results) The solubility and LogD measurements for each test compound, as well as the calculated clogP values, are shown in Table 1 below.

[0250]

[0251] According to Table 1, compound (I) of the present invention, which is a silicon analog of tolvaptan, showed improved lipophilicity compared to the corresponding tolvaptan analog (carbon analog).

[0252] Test Example 2: Metabolic Stability Test of Compound (I) of the Invention in Liver Microsomes

[0253] (Test Method) In the metabolic stability assay, each compound was reacted at 500 μM in liver microsomes (Sekisui XenoTech, LLC, Kansas City, KS, USA, final concentration 0.2 mg protein / mL), coenzyme groups (1.3 mM NADPH, 3.3 mM G-6-P: Sigma, Marlborough, MA, USA, 3.3 mM MgCl2: Wako, Osaka, Japan), and 0.45 U / mL G6PDH (Oriental Yeast, Tokyo, Japan) at 37°C for 0 minutes and 60 minutes. Acetonitrile was added to each mixture, mixed with a vortex mixer, and then centrifuged at 3500 rpm for 20 minutes. The supernatant was analyzed by LC-MS / MS, and the percentage of unchanged compound at 10 minutes and 60 minutes (remaining percentage) was calculated, with the unchanged compound at 0 minutes set as 100%.

[0254] (Test Results) The results are shown in Table 2 below.

[0255]

[0256] According to Table 2, compound (I) of the present invention, which is a silicon analog of tolvaptan, was confirmed to exhibit stability comparable to that of the corresponding tolvaptan analog (carbon analog). Generally, linear silicon compounds are known to be chemically and biologically unstable to acids and bases, but in compound (I) of the present invention, it was found that the incorporation of silicon into the nitrogen-containing medium-sized ring results in metabolic stability equivalent to that of the corresponding tolvaptan analog (carbon analog).

[0257] Test Example 3: Evaluation of the inhibitory activity of compound (I) of the present invention and comparative compound (compound (II)) on vasopressin V1a and V2 receptors.

[0258] (Test Method) The inhibitory activity of compound (I) of the present invention and comparative compound (compound (II)) against vasopressin V1a and V2 receptors was measured and evaluated according to the method described in the literature (PNAS, 2005, 102, 3307-3311).

[0259] (Test Results) Figure 1 shows the results for inhibitory activity against the vasopressin V1a receptor, and Figure 2 shows the results for inhibitory activity against the vasopressin V2 receptor. According to Figures 1 and 2, it was confirmed that compound (I) of the present invention exhibits inhibitory activity against both the vasopressin V1a and V2 receptors.

[0260] Test Example 4: Ca of Compound (I) of the present invention 2+ Imaging

[0261] (Test method) When excited at 340 nm, the fluorescence intensity is measured by Ca 2+ It increases with increasing concentration and decreases when excited at 380 nm. Intracellular Ca 2+ The concentration was measured using Fura-2, which exhibits fluorescence properties. Intracellular Ca 2+ The concentration was estimated by calculating the fluorescence intensity ratio (Ratio = Fex340 nm / Fex380 nm). For compounds (I-2) and (II-5) that showed strong inhibitory activity against the vasopressin V1a receptor in Test Example 3, and compounds (I-3) and (II-6) that showed strong inhibitory activity against the vasopressin V2 receptor, the inhibitory activity against the vasopressin V1a and V2 receptors was evaluated by measuring intracellular Ca2+ activity. 2+ The concentration was measured. For the vasopressin V1a receptor, HEK293T cells co-expressing TRPC3, which is activated downstream of DAG / IP3, were used to measure intracellular Ca 2+ Imaging was evaluated. Similarly, for the vasopressin V2 receptor, the same HEK293T cells co-expressing TRPM2, which is activated by elevated cAMP, were used. IC 50 The value was obtained using Hill's formula. In the formula below, Vmax is the maximum response in the absence of the inhibitor (i.e., the maximum intracellular Ca). 2+ This parameter indicates the signal, and in this study, it is defined as a relative value to the control. Therefore, the data is normalized, and Vmax is treated as 1 (100%).

[0262]

[0263] (Test Results) The results are shown in Figures 3a to 3d. From Figures 3a and 3b, the IC25 reaction of compound (I-2) and compound (II-5) to the V1a receptor is shown. 50 The values ​​were calculated to be 86.5 nM and 134.6 nM, respectively. From Figures 3c and 3d, the IC20 levels of compound (I-3) and compound (II-6) against the V2 receptor were determined. 50 The calculated values ​​were 105.2 nM and 103.4 nM, respectively.

[0264] Test Example 5: Evaluation of the brain penetration of compound (I) of the present invention

[0265] (Test Method) Six-week-old male ICR mice (manufactured by SLC Japan Co., Ltd.) were used. Each test compound (compound (I-2) or compound (II-5)) was administered intravenously to the mice at a concentration of 1 mg / kg, and the concentrations (μM) of each test compound in the plasma and brain were measured 40 minutes later. Specifically, each test compound (compound (I-2) or compound (II-5)) was administered intravenously to the mice at a dose of 1 mg / kg, and 20 μL of blood was collected from the tail at 5, 10, and 20 minutes. In addition, the entire blood volume was collected under anesthesia 40 minutes after administration, and the brain was collected. Acetonitrile was added to the plasma separated from the blood and the homogenized brain homogenate, and after mixing with a vortex mixer, the mixture was centrifuged at 3500 rpm for 20 minutes. The supernatant was analyzed by LC-MS / MS, and the concentrations (μM) of each test compound in the plasma and brain were measured.

[0266] (Test Results) The results are shown in Tables 3-5 below.

[0267]

[0268]

[0269]

[0270] The results above confirm that in compound (I-2), the incorporation of silicon into the nitrogen-containing medium-sized ring results in a brain concentration approximately twice as high as that of the corresponding tolvaptan analog (compound (II-5)).

[0271] Based on the above results, in compound (I) of the present invention, the incorporation of silicon within the nitrogen-containing medium-membered ring allows it to exhibit vasopressin receptor inhibitory activity equivalent to or greater than that of the corresponding tolvaptan analog (compound (II)), while simultaneously improving lipid solubility and enhancing brain penetration without reducing metabolic stability. As a result, compound (I) of the present invention can particularly effectively inhibit vasopressin V1a receptors, which are widely distributed in the brain, such as the cerebral cortex and hippocampus, making it useful in the treatment of mental illnesses such as schizophrenia, autism, and depression.

[0272] Examples of formulations of the present invention include the following formulations. However, the present invention is not limited to these examples of formulations.

[0273] Formulation Example 1: Tablet Manufacturing 1) Compound (I-2) 10 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amounts of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and then granulated. 14 g of 4) and 1 g of 5) are mixed into this granulated powder and compressed into tablets using a tablet press. In this way, 1000 tablets containing 10 mg of compound (I-2) per tablet are obtained.

[0274] Formulation Example 2: Capsule Manufacturing 1) Compound (I-2) 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Mix 1), 2), 3), and 4) and fill into gelatin capsules.

[0275] According to the present invention, it is possible to provide a silicon analog obtained by replacing one of the ring member carbon atoms of the seven-membered azacycle portion of tolvaptan, which has vasopressin receptor inhibitory activity, with a silicon atom, as well as a vasopressin receptor inhibitor and a pharmaceutical product containing the silicon analog as an active ingredient. According to the present invention, by converting tolvaptan into compound (I) of the present invention, which is a silicon analog, or a salt thereof, it is possible to enhance its ability to penetrate the brain. Therefore, by acting antagonistically on vasopressin V1a receptors, which are widely distributed in the brain, such as the cerebral cortex and hippocampus, it is particularly useful for treating mental illnesses such as schizophrenia, autism, and depression. Furthermore, the present invention is also useful in that it can provide an efficient method for producing medium-membered ring silicon compounds containing nitrogen as a heteroatom, for which there has been no synthesis method until now.

[0276] This application is based on Japanese Patent Application No. 2025-068122, filed in Japan on April 17, 2025, the contents of which are fully incorporated herein.

Claims

1. Formula (I): [wherein, R represents a hydrogen atom, C １－６ alkyl, or a halogen atom; m R １ groups each independently represent a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ２ represents a hydrogen atom, a halogen atom, hydroxy, amino optionally substituted with 1 or 2 C １－６ alkyl groups, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ３ represents a hydrogen atom, a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ４ and R ５ each independently represent C １－６ alkyl; m represents an integer of 0 to 2; and n represents an integer of 1 or 2.] or a salt thereof.

2. R is a hydrogen atom, a methyl atom, or a chlorine atom, and R ２ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy, and R ３ However, hydrogen atoms, halogen atoms, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, or C １－４ It is a haloalkoxy, and R ４ and R ５ However, each is independent of C １－４ The compound or salt thereof according to claim 1, wherein it is alkyl, m is 0, and n is 1 or 2.

3. R ​​is a hydrogen atom, a methyl atom, or a chlorine atom, and R ２ However, it is a hydrogen atom or a methyl atom, R ３ However, it is a hydrogen atom, R ４ and R ５ However, each is independent of C １－４ The compound or salt thereof according to claim 1, wherein it is alkyl, m is 0, and n is 1 or 2.

4. R is methyl, and R ２ However, it is a hydrogen atom, R ３ However, it is a hydrogen atom, R ４ and R ５ The compound or salt thereof according to claim 1, wherein both are methyl, m is 0, and n is 1.

5. R is a chlorine atom, and R ２ However, it is a hydrogen atom, R ３ However, it is a hydrogen atom, R ４ and R ５ The compound or salt thereof according to claim 1, wherein both are methyl, m is 0, and n is 1.

6. A vasopressin receptor antagonist containing a compound or salt thereof as described in any one of claims 1 to 5 as an active ingredient.

7. A pharmaceutical product containing a compound or a salt thereof as described in any one of claims 1 to 5.

8. The pharmaceutical agent according to claim 7 for the prevention and / or treatment of a disease whose symptoms can be alleviated by vasopressin receptor antagonism.

9. The pharmaceutical product according to claim 8, wherein the disease whose symptoms can be alleviated by vasopressin receptor antagonism is selected from the group consisting of edema caused by heart failure or cirrhosis of the liver, schizophrenia, autism, and depression.

10. Formula (1): [wherein, P １ represents a protecting group; R ３ represents a hydrogen atom, a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ４ and R ５ each independently represent C １－６ alkyl; and p and q each independently represent 0 or 1, provided that the case where both p and q are 0 is excluded.], or a salt thereof, is subjected to a ring-closing metathesis reaction using a Grubbs catalyst, to convert the compound or the salt into a compound represented by formula (2): (wherein each symbol has the same definition as each group in the above formula (1).], or a salt thereof. A process for producing a compound represented by formula (I): [wherein, R ３ , R ４ , and R ５ have the same definitions as the respective groups in the above formula (1); R represents a hydrogen atom, C １－６ alkyl, or a halogen atom; m R １ groups each independently represent a halogen atom, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; R ２ represents a hydrogen atom, a halogen atom, hydroxy, amino optionally substituted by 1 or 2 C １－６ alkyl groups, C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, or C １－６ haloalkoxy; m represents an integer of 0 to 2; and n represents 1 or 2.], or a salt thereof.

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