JP4765545B2 - Pharmaceutical composition comprising a benzazepine derivative as an active ingredient - Google Patents

Description

  The present invention relates to a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzoazepine derivative or a salt thereof useful as a medicine, particularly a therapeutic agent for central diabetes insipidus and nocturia. The present invention relates to a pharmaceutical composition as an active ingredient.

Arginine vasopressin (AVP) is a peptide consisting of nine amino acids that is biosynthesized and secreted by the hypothalamus-pituitary system. AVP receptors are classified into three subtypes: V _1a , V _1b and V _2. The main pharmacological actions of AVP in the periphery include vasoconstriction via V _1a receptors and V ₂ receptors. An antidiuretic effect is known. As a V ₂ receptor selective agonist, desmopressin, which is a peptide (the amino group of cysteine at position 1 of AVP is deleted and arginine at position 8 is converted to d-type) has been synthesized. (Non-patent Document 1). However, oral desmopressin has a very low bioavailability and requires a high dose to be effective. For this reason, desmopressin preparations are expensive, and side effects are often observed due to variations in absorption among individuals. Therefore, development of a non-peptide antidiuretic with high bioavailability that selectively stimulates the V ₂ receptor is expected.

On the other hand, with the diversification and aging of medical care, it is rare that drugs are used alone, and in many cases, a plurality of drugs are administered simultaneously or at different times. The same applies to the field of AVP receptor agonists. Drugs are inactivated by the action of drug metabolizing enzymes in the liver and converted into metabolites. Among these drug metabolizing enzymes, cytochrome P450 (CYP) is the most important. Although many molecular species exist in CYP, when multiple drugs metabolized by CYP of the same molecular species compete on the metabolic enzyme, they are subject to some kind of metabolic inhibition, depending on the affinity of the drug for CYP. It is possible. As a result, drug interactions such as blood concentration increase and blood half-life extension are developed.
Such drug interaction is an undesirable effect except when it is used for the purpose of additive action and synergistic action, and may exhibit unexpected side effects. Therefore, it is desired to create a medicine with low affinity for CYP and less concern about drug interaction.

（式中の記号は、該公報参照）
また、V₂受容体選択的作動薬として、一般式（Ｄ）で示される縮合アゼピン誘導体が知られている（特許文献４）。

（式中の記号は、該公報参照）
また、一般式（Ｅ）で示されるベンゾアゼピン誘導体（特許文献５、特許文献６）、及び一般式（Ｆ）又は一般式（Ｇ）で示されるベンゾへテロ環化合物（特許文献７、特許文献８、特許文献９）がV₂受容体選択的作動薬として知られている。

（式中の記号は、該公報参照）
しかし、いずれの公報にも本発明の医薬組成物の有効成分に係る4,4-ジフルオロ-1,2,3,4-テトラヒドロ-5H-1-ベンゾアゼピン誘導体に関する開示は一切ない。
また、AVP受容体又はオキシトシン受容体に対する拮抗作用を有する、4,4-ジフルオロ-1,2,3,4-テトラヒドロ-5H-1-ベンゾアゼピン誘導体が知られているが、V₂受容体作動作用並びに中枢性尿崩症及び夜間頻尿との関連については一切知られていない（特許文献１０、特許文献１１、特許文献１２）。なお、特許文献１０及び特許文献１２には、本発明に係るベンゾアゼピン1位に置換するベンゾイル2位にCF₃、若しくはハロゲンが置換した4,4-ジフルオロ-1,2,3,4-テトラヒドロ-5H-1-ベンゾアゼピン誘導体についての開示はない。また、特許文献１１には、ベンゾアゼピン1位に置換するカルボニルに結合したヘテロアリール基に、直接芳香環が結合した化合物のみが開示されており、本発明に係るベンゾアゼピン1位に置換するカルボニルに結合した環に-O-、-S-、-NH-、若しくは-N(低級アルキル)-を含む置換基を有する4,4-ジフルオロ-1,2,3,4-テトラヒドロ-5H-1-ベンゾアゼピン誘導体については開示がない。
日本内分泌学会雑誌, 54, 676-691, 1978. 国際公開第99/06409号パンフレット 国際公開第99/06403号パンフレット 国際公開第00/46224号パンフレット 国際公開第01/49682号パンフレット 国際公開第97/22591号パンフレット 日本国特許第2926335号公報 日本国特許第3215910号公報 日本国特許出願公開特開平11-349570号公報 日本国特許出願公開特開2000-351768号公報 国際公開第95/06035号パンフレット 国際公開第98/39325号パンフレット 日本国特許出願公開特開平9-221475号公報 Conventionally, as a non-peptidic compound that is a V ₂ receptor selective agonist and exhibits an antidiuretic action, a tricyclic compound represented by general formula (A), general formula (B), or general formula (C) is available. Known (Patent Document 1, Patent Document 2, Patent Document 3).

(Refer to this publication for symbols in the formula)
Further, a condensed azepine derivative represented by the general formula (D) is known as a V ₂ receptor selective agonist (Patent Document 4).

(Refer to this publication for symbols in the formula)
In addition, benzoazepine derivatives represented by general formula (E) (Patent Document 5, Patent Document 6), and benzoheterocyclic compounds represented by General Formula (F) or General Formula (G) (Patent Document 7, Patent Document) 8, Patent Document 9) is known as a V ₂ receptor selective agonist.

(Refer to this publication for symbols in the formula)
However, none of the publications disclose any 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives related to the active ingredient of the pharmaceutical composition of the present invention.
In addition, 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives having antagonistic action against AVP receptor or oxytocin receptor are known, but V ₂ receptor action There is no known activity or relation to central diabetes insipidus and nocturia (Patent Document 10, Patent Document 11, Patent Document 12). In Patent Document 10 and Patent Document 12, 4,4-difluoro-1,2,3,4-tetrahydrohydrocarbon having CF ₃ or halogen substituted at the 2-position of benzoyl substituted at the 1-position of benzoazepine according to the present invention is disclosed. There is no disclosure of -5H-1-benzazepine derivatives. Further, Patent Document 11 discloses only a compound in which an aromatic ring is directly bonded to a heteroaryl group bonded to a carbonyl substituted at the 1-position of the benzoazepine, and the carbonyl substituted at the 1-position of the benzoazepine according to the present invention. 4,4-difluoro-1,2,3,4-tetrahydro-5H-1 having a substituent containing -O-, -S-, -NH-, or -N (lower alkyl)-in the ring bonded to -There is no disclosure of benzazepine derivatives.
Journal of the Japan Endocrine Society, 54, 676-691, 1978. WO99 / 06409 pamphlet WO99 / 06403 pamphlet International Publication No. 00/46224 Pamphlet WO 01/49682 pamphlet International Publication No. 97/22591 Pamphlet Japanese Patent No. 2926335 Japanese Patent No. 3215910 Japanese Patent Application Publication No. 11-349570 Japanese Patent Application Publication No. 2000-351768 International Publication No. 95/06035 Pamphlet International Publication No. 98/39325 Pamphlet Japanese Patent Application Publication No. 9-221475

  Under such circumstances, the development of non-peptide antidiuretics with high bioavailability for the treatment of central diabetes insipidus and / or nocturia is eagerly desired.

The present inventors conducted extensive research on compounds having a V ₂ receptor agonistic action that can be expected to be effective against central diabetes insipidus and / or nocturia. As a result, novel 4,4-difluoro-1,2, The present inventors have found that a 3,4-tetrahydro-5H-1-benzazepine derivative has an excellent effect and completed the present invention. In addition, it has been found that the compound relating to the active ingredient of the pharmaceutical composition of the present invention has an extremely low inhibitory effect on the drug-metabolizing enzymes CYP3A4 and CYP2C9, compared with the conventionally known benzoazepine derivatives having V ₂ receptor agonistic action. It was.

［式中の記号は以下の意味を示す。
R¹：置換されていてもよいアミノ、-OH、若しくは-O-低級アルキル。
R²：CF₃、若しくはハロゲン。
R³：H、若しくはハロゲン。
a、b：それぞれ単結合又は二重結合を示し、一方が単結合、他方が二重結合。
-X-：
（１）aが単結合、bが二重結合である場合、-CH=CH-、-CH=N-、-N=CH-、-N=N-、若しくは-S-。
（２）aが二重結合、bが単結合である場合、-N-。
Y：
（１）aが単結合、bが二重結合である場合、CH、若しくはN。
（２）aが二重結合、bが単結合である場合、S。
-A-：-O-、-S-、-NH-、若しくは-N(低級アルキル)-。
B：それぞれ置換されていてもよい低級アルキル、低級アルケニル、低級アルキニル、シクロアルキル、若しくはアリール。］ That is, according to the present invention, a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: Composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier; in particular, the above pharmaceutical composition which is an arginine vasopressin V ₂ receptor agonist; a therapeutic agent for nocturia or central diabetes insipidus The above-mentioned pharmaceutical composition which is an agent is provided.

[The symbols in the formula have the following meanings.
R ¹ : optionally substituted amino, —OH, or —O-lower alkyl.
R ² : CF ₃ or halogen.
R ³ : H or halogen.
a, b: each represents a single bond or a double bond, one being a single bond and the other being a double bond.
-X-:
(1) When a is a single bond and b is a double bond, -CH = CH-, -CH = N-, -N = CH-, -N = N-, or -S-.
(2) When a is a double bond and b is a single bond, -N-.
Y:
(1) CH or N when a is a single bond and b is a double bond.
(2) S when a is a double bond and b is a single bond.
-A-: -O-, -S-, -NH-, or -N (lower alkyl)-.
B: Lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, or aryl each optionally substituted. ]

The compound according to the active ingredient of the pharmaceutical composition of the present invention has a chemical structural feature in that it has a difluoro group at the ring carbon atom adjacent to the benzazepine ring carbon atom substituted by the substituted methylidene group. The structure is completely different from the previously known V ₂ receptor selective agonist. In addition, since the compound which concerns on the active ingredient of the pharmaceutical of this invention has a difluoro group, it has sufficient stability in vivo, without the double bond conjugated to the carbonyl group being isomerized.

［式中の記号は以下の意味を示す。
Z¹：単結合、低級アルキレン、若しくは-低級アルキレン-C(=O)-。
R¹¹：-OH、-O-低級アルキル、-CO₂H、-CO₂-低級アルキル、及び１つ若しくは２つの低級アルキルで置換されていてもよいカルバモイルからなる群より選択される基で置換されていてもよい低級アルキル、又は-H。
R¹²：
（１）Z¹が単結合、又は低級アルキレンを示す場合、
-H、-OH、-O-低級アルキル、-CO₂H、-CO₂-低級アルキル、１つ若しくは２つの低級アルキルで置換されていてもよいカルバモイル、置換されていてもよいアリール、置換されていてもよいシクロアルキル、置換されていてもよい芳香族ヘテロ環、又は置換されていてもよい非芳香族ヘテロ環。
（２）Z¹が-低級アルキレン-C(=O)-を示す場合、
式（ＩＩＩ）、若しくは式（ＩＶ）で示される基。

［式中の記号は以下の意味を示す。
Z²：単結合、若しくは低級アルキレン。
R¹⁵：-H、-OH、-O-低級アルキル、-CO₂H、-CO₂-低級アルキル、１つ若しくは２つの低級アルキルで置換されていてもよいカルバモイル、置換されていてもよいアリール、置換されていてもよいシクロアルキル、置換されていてもよい芳香族ヘテロ環、又は置換されていてもよい非芳香族ヘテロ環。］
R¹³、R¹⁴：隣接する窒素原子と一体となって、置換されていてもよい非芳香族環状アミノ基。］ Of these compounds, preferably, R ¹ is a group represented by the above general formula (I), which is a group represented by formula (II), formula (III), —OH, or —O-lower alkyl, 4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative or a pharmaceutically acceptable salt thereof, among which R ¹ is represented by formula (II) or formula (III) Novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the above general formula (I), or a pharmaceutically acceptable salt thereof Is preferred.

[The symbols in the formula have the following meanings.
Z ¹ : a single bond, lower alkylene, or -lower alkylene-C (═O) —.
R ¹¹ : substituted with a group selected from the group consisting of —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, and carbamoyl optionally substituted with one or two lower alkyls Optionally lower alkyl, or -H.
R ¹² :
(1) When Z ¹ represents a single bond or lower alkylene,
-H, -OH, -O- lower alkyl, -CO ₂ H, -CO ₂ - lower alkyl, one or two lower alkyl optionally substituted carbamoyl, optionally substituted aryl, optionally substituted Optionally substituted cycloalkyl, optionally substituted aromatic heterocycle, or optionally substituted non-aromatic heterocycle.
(2) When Z ¹ represents -lower alkylene-C (= O)-,
A group represented by formula (III) or formula (IV);

[The symbols in the formula have the following meanings.
Z ² : single bond or lower alkylene.
R ¹⁵ : —H, —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, carbamoyl optionally substituted with one or two lower alkyls, optionally substituted aryl , An optionally substituted cycloalkyl, an optionally substituted aromatic heterocycle, or an optionally substituted non-aromatic heterocycle. ]
R ¹³ and R ¹⁴ : a non-aromatic cyclic amino group which may be substituted together with an adjacent nitrogen atom. ]

More preferably, R ¹ is a group represented by formula (II) or formula (III); a is a single bond; b is a double bond; —X— is —CH═CH—. A novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the above general formula (I), wherein -Y- is -CH-, or a pharmaceutic product thereof Acceptable salt.
More preferably, R ¹ is a group represented by formula (II); a is a single bond; b is a double bond; -X- is -CH = CH-; -Y- is- A novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, which is CH- It is.
Particularly preferably, R ¹ is a group represented by formula (II); a is a single bond; b is a double bond; -X- is -CH = CH-; -Y- is- A novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by the above general formula (I), wherein —A— is —O—; Or a pharmaceutically acceptable salt thereof.
Most preferably, R ¹ is a group represented by formula (II); a is a single bond; b is a double bond; -X- is -CH = CH-; -Y- is- A novel 4,4-difluoro-1,2 represented by the above general formula (I), wherein -A- is -O-; -B is optionally substituted lower alkyl 3,4-tetrahydro-5H-1-benzazepine derivative or a pharmaceutically acceptable salt thereof.
Among them, particularly, a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative in which R ² is trifluoromethyl; R ³ is —H or —F or a derivative thereof Pharmaceutically acceptable salts are preferred.

Among these compounds, a particularly preferred compound is a compound selected from the group consisting of compound group P and compound group Q or a pharmaceutically acceptable salt thereof, and among them, a compound selected from compound group P or The pharmaceutically acceptable salt is preferred.
Here, “compound group P” means
(2Z) -N- (2-Amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- ( Trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -N- (2-hydroxyethyl) -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl ) Benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -N- (2-hydroxyethyl) -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl ) Benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N-[(2S) -2,3-dihydroxypropyl] acetamide,
3-[((2Z) -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1 , 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetyl) amino] propanamide, and
(2Z) -N-[(2R) -2,3-Dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy}- 2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
Is a group consisting of: "Compound group Q"
(2Z) -N- (2-amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- ( Trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1 -Benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2,3,4-tetrahydro- 5H-1-Benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -N-[(2R) -2,3-dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1, 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N-[(2S) -2,3-dihydroxypropyl] acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N-[(2R) -2,3-dihydroxypropyl] acetamide,
3-[((2Z) -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1 , 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetyl) amino] propanamide,
(2Z) -N-[(2R) -2,3-Dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy}- 2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
3-[((2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2,3, 4-tetrahydro-5H-1-benzazepine-5-ylidene} acetyl) amino] propanamide,
(2Z) -2- {4,4-Difluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene } -N-[(2R) -2,3-dihydroxypropyl] acetamide, and
(2Z) -2- {4,4-Difluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene } -N-[(2S) -2,3-dihydroxypropyl] acetamide,
A group consisting of
As the R ^1, groups of formula (II) or the formula (III) are preferred; more preferably a group represented by the formula (II); Z ¹ is a single bond, R ¹² is - More preferred is a group represented by the above formula (II), which is H and R ¹¹ is optionally substituted lower alkyl; Z ¹ is a single bond, R ¹² is —H, and R ¹¹ is A group represented by the above formula (II), which is lower alkyl optionally substituted with one or more substituents selected from the group consisting of —OH and carbamoyl, is particularly preferable.

R ² is preferably trifluoromethyl or chloro; trifluoromethyl is particularly preferred.
R ³ is preferably —H or fluoro; —H or 7-fluoro is particularly preferable.
Further, as a, b, -X- and -Y-, a is preferably a single bond, b is a double bond, -X- is -CH = CH-, and -Y- is -CH-.
As -A-, -O- is preferable.
In addition, as -B, lower alkyl which may be substituted is preferable; lower alkyl which may be substituted with F is particularly preferable.

Compounds according to the active ingredient of the pharmaceutical composition of the present invention has the agonism excellent against arginine vasopressin V ₂ receptor. Therefore, the pharmaceutical composition of the present invention has an antidiuretic action with a profile based on this action, and is useful for dysuria and large urine, frequent urination, incontinence, enuresis, central diabetes insipidus, nocturia It is effective for prevention and / or treatment of urine and nocturnal enuresis. In addition to these, it has a blood coagulation factor VIII and von Willebrand factor releasing action based on the action of V ₂ receptor, and is useful for various bleeding states, spontaneous bleeding, hemophilia, von It is effective for diagnosis, prevention and treatment of Willebrand disease, uremia, congenital or acquired platelet dysfunction, traumatic and surgical bleeding, and cirrhosis.
In addition, since the compound relating to the active ingredient of the pharmaceutical composition of the present invention has very little inhibitory action on the drug-metabolizing enzymes CYP3A4 and CYP2C9, there has been a concern of drug interaction with other drugs metabolized via CYP3A4 or CYP2C9. less than that of the benzazepine derivatives having arginine vasopressin V ₂ receptor agonistic action known, it is superior in that it can be safely used in combination therapy with other drugs.
Drugs metabolized by CYP3A4 include simvastatin, lovastatin, fluvastatin, midazolam, nifedipine, amlodipine, nicardipine, etc., and drugs metabolized by CYP2C9 include diclofenac, ibuprofen, indomethacin, tolbutamide, glibenclamide, losartan, etc. (General clinical, 48 (6), 1427-1431, 1999.).

The compound according to the active ingredient of the pharmaceutical composition of the present invention will be further described as follows.
In the present specification, “lower alkyl” means a monovalent group of a C _1-6 linear or branched carbon chain, specifically, for example, methyl, ethyl, propyl, butyl, pentyl or These structural isomers such as hexyl, isopropyl, tert-butyl and the like, preferably C _1-4 alkyl methyl, ethyl, propyl, butyl, isobutyl.
“Lower alkylene” means a C _1-6 straight or branched carbon chain divalent group, specifically, for example, methylene, ethylene, trimethylene, methylmethylene, methylethylene, dimethylmethylene, etc. Is mentioned.
“Lower alkenyl” means a C _2-6 linear or branched carbon chain monovalent group having at least one double bond, and specifically includes, for example, vinyl, allyl, 1-butenyl. , 2-butenyl, 1-hexenyl or 3-hexenyl, or structural isomers thereof such as 2-methylallyl, preferably allyl and 2-methyl-1-propen-3-yl.
“Lower alkynyl” means a C _2-6 linear or branched carbon chain monovalent group having at least one triple bond, specifically, for example, ethynyl, propargyl, 1-butynyl, These structural isomers such as 3-butynyl, 1-hexynyl or 3-hexynyl, or 3-methyl-1-butynyl, preferably propargyl and 1-butyn-4-yl.

“Cycloalkyl” means a monovalent group of a C _3-8 non-aromatic hydrocarbon ring which may have a partially unsaturated bond, specifically, for example, cyclopropyl, cyclopentyl , Cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctanedienyl and the like.
“Aryl” means a monovalent group of a monocyclic to tricyclic C _6-14 aromatic hydrocarbon ring, and specific examples include phenyl, naphthyl, etc., preferably phenyl. .

“Aromatic heterocycle” means a monovalent group of an aromatic ring having a heteroatom such as monocyclic to tricyclic nitrogen, oxygen, sulfur and the like, specifically, for example, pyridyl, thienyl, furyl, pyrazinyl, Examples include pyridazinyl, thiazolyl, pyrimidinyl, pyrazolyl, pyrrolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl and the like, preferably pyridyl.
The term “non-aromatic heterocycle” means that it may have a partially unsaturated bond, and may have a heteroatom such as nitrogen, oxygen or sulfur which may be condensed with an aryl or aromatic heterocycle. This means a monovalent group of 7-membered ring, and specific examples include pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydrothienyl and the like, preferably pyrrolidinyl, piperazinyl, morpholinyl. .
The “non-aromatic cyclic amino group” is a 3- to 10-membered non-aromatic cyclic amine which may partially have an unsaturated bond and may contain nitrogen, oxygen and sulfur, preferably Means a monovalent group of a 5- to 7-membered non-aromatic cyclic amine, and specific examples include pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, dihydropyrrolyl, etc. Is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.
“Halogen” means a monovalent group of a halogen atom, and specific examples include fluoro, chloro, bromo, iodo and the like.

  In the present specification, the permissible substituent of the word “optionally substituted” may be any substituent that is usually used as a substituent of each group, and one or more in each group You may have the substituent of.

Specific examples of the “optionally substituted amino” in R ¹ include groups represented by the general formulas (II) and (III).
"Optionally substituted cycloalkyl", "optionally substituted aryl" in B; "optionally substituted aryl", "optionally substituted cycloalkyl" in R ¹² and R ¹⁵ ; In “an optionally substituted aromatic heterocycle”, “an optionally substituted non-aromatic heterocycle”; and “an optionally substituted non-aromatic cyclic amino group” in R ¹³ and R ¹⁴ ; Examples of the permissible substituent include the groups shown in the following (a) to (h). R ^Z is —OH, —O-lower alkyl, amino optionally substituted with one or two lower alkyls, carbamoyl optionally substituted with one or two lower alkyls, aryl, aromatic Lower alkyl optionally substituted with one or more groups selected from the group consisting of group heterocycles and halogens.
(A) halogen;
^{(B) -OH, -OR Z,} -O- aryl, -OCO-R ^Z, oxo (= O);
(C) —SH, —SR ^Z , —S-aryl, —SO—R ^Z , —SO-aryl, —SO ₂ —R ^Z , —SO ₂ -aryl, substituted with one or two R ^Z Optionally sulfamoyl;
(D) amino, —NHCO—R ^Z , —NHCO-aryl, —NHSO ₂ —R ^Z , —NHSO ₂ -aryl, nitro, optionally substituted by one or two R ^Z ;
(E) -CHO, -CO-R Z, -CO 2 H, -CO 2 -R Z, 1 or 2 R ^Z in substituted optionally carbamoyl, cyano;
(F) -OH, -O-lower alkyl, amino optionally substituted with one or two lower alkyls, carbamoyl optionally substituted with one or two lower alkyls, aryl, aromatic heterocycle Aryl or cycloalkyl each optionally substituted with one or more groups selected from the group consisting of halogen and R ^Z ;
(G) -OH, -O-lower alkyl, amino optionally substituted with one or two lower alkyls, carbamoyl optionally substituted with one or two lower alkyls, aryl, aromatic heterocycle An aromatic heterocycle or a non-aromatic heterocycle, each optionally substituted with one or more groups selected from the group consisting of halogen and R ^Z ;
(H) Lower alkyl or lower alkenyl each optionally substituted by one or more groups selected from the substituents shown in the above (a) to (g).
In addition, the substituents allowed in “lower alkyl which may be substituted”, “lower alkenyl which may be substituted” and “lower alkynyl which may be substituted” in B include the above (a) to ( The group shown by g) is mentioned.

  The compound relating to the active ingredient of the pharmaceutical composition of the present invention represented by the general formula (I) may contain an asymmetric carbon atom depending on the type of substituent, and optical isomers based on this may exist. . The present invention includes all of these optical isomers and isolated ones. In addition, there may be a case where a tautomer exists in the compound related to the active ingredient of the pharmaceutical composition of the present invention. In the present invention, a pharmaceutical composition comprising a separated or mixture of these isomers as the active ingredient. Is contained.

  In addition, the compound according to the active ingredient of the pharmaceutical composition of the present invention may form a salt, and as long as such a salt is a pharmaceutically acceptable salt, it relates to the active ingredient of the pharmaceutical composition of the present invention. Included in the compound. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, metals such as sodium, potassium, calcium, magnesium Examples thereof include inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like. Furthermore, the present invention provides a pharmaceutical composition comprising as an active ingredient a compound relating to the active ingredient of the pharmaceutical composition of the present invention and various hydrates and solvates of the pharmaceutically acceptable salts thereof, and substances having crystal polymorphism. Also includes things. In addition, the compounds related to the active ingredients of the pharmaceutical composition of the present invention include all compounds which are metabolized in vivo and converted to the compounds having the above general formula (I) or salts thereof, so-called prodrugs. Examples of the group that forms a prodrug of the compound relating to the active ingredient of the pharmaceutical composition of the present invention include those described in Prog. Med., 5; 2157-2161, 1985. Examples include groups described in “Development”, Vol. 7, Molecular Design, pages 163-198.

(Production method)
The compound relating to the active ingredient of the pharmaceutical composition of the present invention and a pharmaceutically acceptable salt thereof are produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. can do. The typical production method is illustrated below. Depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with an appropriate protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. is there. Thereafter, the protecting group is removed as necessary to obtain the desired compound. Examples of such a functional group include a hydroxyl group, a carboxyl group, and an amino group. Examples of the protective group include those described in “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts. Can be used as appropriate according to the reaction conditions.

（式中、R²、a、b、X、Y、Aは前記の意味を示し；Lvは脱離基を示し；B¹は前記のB又は水酸基、アミノ基若しくはスルファニル基の保護基を示し；R^aはカルボキシル基、低級アルキルオキシカルボニル基又はシアノ基を示す。以下同様。）
本製法は、化合物(a)の脱離基Lvを化合物(b)で置換し、化合物(c)を製造し、必要に応じて加水分解することにより化合物(d)を製造する方法である。 <Production method of intermediate>

(Wherein R ² , a, b, X, Y and A represent the above meanings; Lv represents a leaving group; B ¹ represents the above-described protecting group for B or a hydroxyl group, an amino group or a sulfanyl group. R ^a represents a carboxyl group, a lower alkyloxycarbonyl group or a cyano group, and so on.
This production method is a method for producing the compound (d) by substituting the leaving group Lv of the compound (a) with the compound (b) to produce the compound (c) and hydrolyzing as necessary.

(First step)
Examples of the leaving group Lv in the compound (a) include fluoro, chloro, methanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy, and preferably fluoro, chloro and methanesulfonyloxy.
The reaction is carried out in the absence of a solvent, or aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform N, N-dimethylformamide (DMF); dimethylacetamide (DMA); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); esters such as ethyl acetate (EtOAc); acetonitrile and other solvents inert to the reaction, or methanol (MeOH), ethanol (EtOH), alcohols such as 2-propanol (iPrOH), etc., compound (a) and compound (b) are used in equimolar amounts or in excess and carried out at room temperature or under reflux with heating. it can. Depending on the compound, an organic base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine or a metal salt base (preferably potassium carbonate, cesium carbonate, sodium hydroxide) In the presence of sodium hydride).
In addition, although the compound (a) which is a raw material compound of this process contains a novel compound, for example, a method described in Reference Examples or a method according thereto, a method obvious to those skilled in the art, or these It can be produced by a modified method.

(Second step)
The reaction is carried out with respect to compound (c) in a solvent inert to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohol solvents, DMF, DMA, DMSO, pyridine, water, sulfuric acid, hydrochloric acid In the presence of a mineral acid such as hydrobromic acid, an organic acid such as formic acid or acetic acid, or a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia, the reaction is carried out under cooling to heating under reflux. be able to. The reaction temperature can be appropriately selected depending on the compound.

（式中、R¹及びR³は前記の意味を、R^bは低級アルキルを示す。以下同様。）
本製法は、上記中間体の製法で製造した化合物(d)を化合物(1a)と縮合して化合物(1b)を製造し、加水分解することにより化合物(1c)を製造し、化合物(1d)を縮合することにより、B¹がBである本発明の医薬組成物の有効成分に係る化合物（Ｉ）若しくはB¹が水酸基、アミノ基若しくはスルファニル基の保護基である化合物(1e)を製造する方法である。 <First manufacturing method>

(In the formula, R ¹ and R ³ have the same meanings, and R ^b represents lower alkyl. The same shall apply hereinafter.)
In this production method, the compound (d) produced by the above intermediate production method is condensed with the compound (1a) to produce a compound (1b), and then hydrolyzed to produce the compound (1c), and the compound (1d) To produce a compound (I) according to the active ingredient of the pharmaceutical composition of the present invention in which B ¹ is B or a compound (1e) in which B ¹ is a protecting group for a hydroxyl group, an amino group or a sulfanyl group Is the method.

(First step)
Compound (d) can be used in the reaction as a free acid, but a reactive derivative thereof can also be used in the reaction. Examples of reactive derivatives of the compound (d) include ordinary esters such as methyl ester, ethyl ester and tert-butyl ester; acid halides such as acid chloride and acid bromide; acid azide; N-hydroxybenzotriazole and p-nitrophenol. Active esters with N, N-hydroxysuccinimide, etc .; symmetrical acid anhydrides; halocarboxylic acid alkyl esters such as alkyl carbonate halides, mixed acid anhydrides with pivaloyl halide, p-toluenesulfonic acid chloride, etc .; diphenylphosphoryl chloride, Examples thereof include mixed acid anhydrides such as phosphoric acid mixed acid anhydrides obtained by reacting with N-methylmorpholine.
When reacting the compound (d) with a free acid or reacting without isolating the active ester, dicyclohexylcarbodiimide (DCC), 1,1′-carbonylbis-1H-imidazole (CDI), diphenylphosphoryl azide It is preferable to use a condensing agent such as (DPPA), diethyl phosphoryl cyanide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD).
In particular, in the present invention, the acid chloride method, the method of reacting in the presence of an active esterifying agent and a condensing agent, and the method of treating a normal ester with an amine simply and easily relate to the active ingredients of the pharmaceutical composition of the present invention. Since it can be a compound, it is convenient.
The reaction varies depending on the reactive derivative and condensing agent used, but is cooled in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF and DMSO. Under cooling, at room temperature, or at room temperature to under heating.
In the reaction, the compound (1a) is used in excess, or N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, In some cases, the reaction in the presence of a base such as lutidine is advantageous for allowing the reaction to proceed smoothly. Further, a salt composed of a weak base and a strong acid such as pyridine hydrochloride, pyridine p-toluenesulfonate, N, N-dimethylaniline hydrochloride may be used. Pyridine can also be used as a solvent.
In particular, the reaction is preferably carried out in a solvent such as acetonitrile or DMF in the presence of a base such as pyridine, N, N-dimethylaniline, or a salt such as pyridine hydrochloride.

(Second step)
The reaction can be carried out according to the second step of the intermediate production method.
(Third process)
The reaction can be carried out according to the first step of the first production method.
Compound (1e) can be led to Compound (I) of the present invention by removing a protecting group as necessary, or by introducing a necessary side chain according to a conventional method. Necessary side chains can be introduced according to the third step of the second production method described later.

（式中、B²は水酸基、アミノ基若しくはスルファニル基の保護基を示す。以下同様。）
本製法は、上記中間体の製法で製造した、B²がBでない化合物(dd)を化合物(1a)と縮合して化合物(2a)を製造し、保護基B²を除去して化合物(2b)を製造し、化合物(2c)若しくは(2d)と縮合して化合物(2e)を製造し、加水分解することにより化合物(2f)を製造し、化合物(1d)と縮合することにより、本発明の医薬組成物の有効成分に係る化合物（Ｉ）を製造する方法である。 <Second manufacturing method>

(In the formula, B ² represents a protective group for a hydroxyl group, an amino group or a sulfanyl group. The same applies hereinafter.)
In this production method, the compound (dd) produced by the above intermediate production method, wherein B ² is not B is condensed with compound (1a) to produce compound (2a), and protecting group B ² is removed to obtain compound (2b ), Is condensed with compound (2c) or (2d) to produce compound (2e), and is hydrolyzed to produce compound (2f), which is then condensed with compound (1d). It is the method of manufacturing the compound (I) which concerns on the active ingredient of this pharmaceutical composition.

(First step)
The reaction can be carried out according to the first step of the first production method.
(Second step)
Examples of the protecting group for the hydroxyl group, amino group or sulfanyl group include the protecting groups described in the above-mentioned “Protective Groups in Organic Synthesis (third edition)”. The reaction can be performed according to the method described in “Protective Groups in Organic Synthesis (third edition)”.
In particular, when a benzyl group is used as a hydroxyl-protecting group, a method of removing benzyl group by acting pentamethylbenzene in a strongly acidic solution such as trifluoroacetic acid can also be used.

(Third process)
Examples of the leaving group Lv in the compound (2c) include chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, preferably bromo, methanesulfonyloxy, p-toluenesulfonyloxy. It is.
The reaction using the compound (2c) can be a normal alkylation reaction, and preferably the compounds (2b) and (2c) in a solvent inert to the reaction such as acetonitrile, DMF, DMSO, ethers, etc. The reaction can be carried out in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide under cooling, cooling to room temperature, or room temperature to heating, using an excess amount of one mole or one. .
The reaction using compound (2d) was conducted in an inert solvent for aprotic reaction such as ethers, DMF, N-methylpyrrolidone, organic phosphine such as triphenylphosphine, diethyl azodicarboxylate, diisopropyl azodicarboxylate. Can be carried out under Mitsunobu reaction conditions in the presence of dialkyl azodicarboxylates (Synthesis, 1981, pp. 1).
(Fourth process)
The reaction can be performed according to the second step of the first production method.

(Fifth process)
The reaction can be carried out according to the first step of the first production method.
Furthermore, the compound which concerns on the active ingredient of some pharmaceutical composition of this invention shown by Formula (I) is well-known alkylation, acylation from this invention compound obtained by the 1st manufacturing method or the 2nd manufacturing method, It can be produced by arbitrarily combining processes that can be usually employed by those skilled in the art, such as substitution reaction, oxidation, reduction, and hydrolysis. Specifically, for example, oxidation of a sulfur atom by an oxidizing agent such as metachloroperbenzoic acid can be mentioned, and such a reaction is described in “Experimental Chemistry Course 4th Edition” (Maruzen Co., Ltd., 1990-1992). The described method can be applied or carried out accordingly. In addition, the steps that can be usually employed by those skilled in the art are not limited to the application to the compound of the present invention, and can also be applied to the production intermediate. Specifically, for example, it can be applied to the compound obtained in the third step of the second production method, and then it can proceed to the next step.

The compound relating to the active ingredient of the pharmaceutical composition of the present invention produced as described above is isolated or purified as it is free or subjected to salt formation treatment by a conventional method. Isolation / purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by conventional methods utilizing differences in physicochemical properties between isomers. For example, a racemic mixture can be led to an optically pure isomer by a common racemic resolution method, such as a method for optical resolution by diastereomeric salts with common optically active acids such as tartaric acid. . The diastereo mixture can be separated by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

  The pharmaceutical composition of the present invention comprises one or more compounds relating to the active ingredient of the pharmaceutical composition of the present invention represented by the general formula (I), a simple substance for pharmaceuticals, an excipient, etc. It can be prepared by commonly used methods using additives. Administration is any of oral administration by tablets, pills, capsules, granules, powders, liquids, injections such as intravenous injection, intramuscular injection, or parenteral administration by suppositories, nasal, transmucosal, transdermal, etc. It may be a form.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. Mixed with magnesium acid etc. The composition is prepared according to conventional methods with additives other than inert diluents such as lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers such as lactose, glutamic acid or asparagine It may contain a solubilizing agent such as an acid. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or a gastric or enteric film.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. Contains ethanol. In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.

  Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, polysorbate 80, and the like. Such compositions may further contain preservatives, wetting agents, emulsifiers, dispersants, eg stabilizers such as lactose, eg adjuvants such as solubilizing agents such as glutamic acid and aspartic acid. . These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

  Usually, in the case of oral administration, the daily dose is about 0.0001 to 50 mg / kg per body weight, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg, This is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dose is about 0.0001 to 1 mg / kg, preferably about 0.0001 to 0.1 mg / kg per body weight, and is administered once a day or divided into multiple times. The dosage is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like. However, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples.

Example 1 V ₂ Receptor Binding Test A human V ₂ expressing CHO cell membrane specimen was prepared according to the method of Tahara et al. (British Journal of Pharmacology, Vol 125, p.1463-1470, 1998). 2 μg of the membrane preparation was mixed with [ ³ H] -arginine-vasopressin (hereinafter simply referred to as “[ ³ H] -vasopressin”) (0.5 nM, Specific activity = 75 Ci / mmol) and the test compound (10 ⁻¹⁰ to 10 ⁻ with _{^{5 M), 10 mM MgCl 2}} , 0.1% bovine serum albumin (BSA) 50 mM tris containing - HCl buffer (pH = 7.4) the total amount 250 60 minutes in μl of incubation at 25 ° C.. Thereafter, free using a cell harvester ^[3 H] - vasopressin the receptor bound ^[3 H] - vasopressin was separated, receptor bound to Unifilter plate GF / B glass filters ^[3 H] - vasopressin Was adsorbed. After sufficiently drying, it was mixed with a microplate scintillation cocktail, the amount of receptor-bound [ ³ H] -vasopressin was measured using a top count, and the inhibition rate was calculated from the following formula.
Inhibition rate (%) = 100− (C ₁ −B ₁ ) / (C ₀ −B ₁ ) × 100
C ₁ : The amount of [ ³ H] -vasopressin bound to the membrane specimen when it is treated with the receptor membrane specimen in the presence of a known concentration of the test compound and [ ³ H] -vasopressin.
C _0: test compound in the absence, ^[3 H] - when processing the vasopressin and the receptor membrane sample, ^[3 H] - amount of vasopressin binding to membrane specimen
B ₁ : When an excess amount of vasopressin (10 ^-6 M) and [ ³ H] -vasopressin coexist with a receptor membrane specimen, the amount of [ ³ H] -vasopressin binds to the membrane specimen The concentration (IC ₅₀ value) of the test compound at which the inhibition rate was 50% was calculated, and the affinity of the test compound for the receptor, that is, the dissociation constant (Ki) was calculated from the following equation.
Dissociation constant (Ki) = IC ₅₀ / (1+ [L] / Kd)
[L]: [ ³ H] -Vasopressin concentration
Kd: Dissociation constant for the receptor of [ ³ H] -vasopressin determined from saturation binding experiments

なお、比較化合物とは、国際公開第WO 97/22591号記載の実施例３２の化合物（化合物名：2-[(5R)-1-(2-クロロ-4-ピロリジン-1-イルベンゾイル)-2,3,4,5-テトラヒドロベンゾアゼピン-5-イル]-N-イソプロピルアセトアミド）を示す。
表１に示すように、本発明の医薬組成物はV₂受容体に対する高い親和性を有することが明らかとなった。

The comparative compound is the compound of Example 32 described in International Publication No. WO 97/22591 (compound name: 2-[(5R) -1- (2-chloro-4-pyrrolidin-1-ylbenzoyl)- 2,3,4,5-tetrahydrobenzazepine-5-yl] -N-isopropylacetamide).
As shown in Table 1, it was revealed that the pharmaceutical composition of the present invention has a high affinity for the V ₂ receptor.

Example 2 Antidiuretic test (intravenous administration)
In the experiment, 5 male Wistar rats (10-12 weeks old) were used in each group. In Groups A to E, 0.3 mg / kg of the test compound dissolved in a solvent (saline containing DMSO), and in Groups F to J, 0.1 mg / kg of the test compound as a solvent (saline containing DMSO). For comparison, group Z was intravenously administered with only the solvent at 1 ml / kg, and 15 minutes later, 30 ml / kg of distilled water was forcibly orally administered (water load). The urine up to 2 hours after water load was collected in a metabolic cage, and the urine volume when the water load was 100% was calculated as the urinary excretion rate. For the evaluation, the average value in each group of the urinary excretion rate up to 1 hour and the urinary excretion rate up to 2 hours was used. The results are shown in Table 2.

表２に示すように、本発明の医薬組成物は優れた抗利尿作用を有することが明らかとなった。

As shown in Table 2, it was revealed that the pharmaceutical composition of the present invention has an excellent antidiuretic action.

Example 3 Antidiuretic test (oral administration)
For the experiment, male Wistar rats (10-12 weeks old) were used. The test compound was orally administered, and 15 minutes later, 30 ml / kg of distilled water was forcibly orally administered (water load). The urine up to 4 hours after water load was collected in a metabolic cage, and the urine volume when the water load was 100% was calculated as the urinary excretion rate. In the evaluation, the dose of the test compound (ED ₅₀ ) necessary for reducing the urinary excretion rate by 50% was used. The results are shown in Table 3.

表３に示すように、本発明の医薬組成物は静脈内投与のみならず、経口投与によっても優れた抗利尿作用を有することが明らかとなった。

As shown in Table 3, it was revealed that the pharmaceutical composition of the present invention has an excellent antidiuretic effect not only by intravenous administration but also by oral administration.

Example 4 Cytochrome P450 (3A4) enzyme inhibition test
Experiments were performed according to the method of Crespi et al. (Analytical Biochemistry, 248, 188-190, 1997).
Using a 96-well plate, 7-benzyloxy-4- (trifluoromethyl) coumarin (5 × 10 ⁻⁵ M), test compound (4.9 × 10 ^{−8 to} 5 × 10 ⁻⁵ M) and enzyme ( 5 × 10 ⁻⁹ M) in 200 mM phosphate buffer (pH = 7.4) containing 8.2 μM NADP +, 0.41 mM glucose-6-phosphate, 0.41 mM MgCl ₂ and 0.4 Units / ml glucose-6-phosphate dehydrogenase Incubated at 37 ° C. for 30 minutes in a total volume of 200 μl. Then, the reaction was stopped by adding an aqueous solution of 0.5 M 2-amino-2-hydroxymethyl-1,3-propanediol containing 80% acetonitrile, and the fluorescence intensity (excitation wavelength: 409 nm, fluorescence wavelength: 530 nm) was measured with a fluorescence plate reader. It was measured. The inhibition rate was calculated from the following formula, and the test compound concentration (IC ₅₀ ) at which the inhibition rate was 50% was determined. The results are shown in Table 4.
Inhibition rate (%) = 100- (C ₁ -B ₁ ) / (C ₀ -B ₁ ) × 100
C ₁ : Fluorescence intensity in the presence of known concentration of test compound, enzyme and substrate
C ₀ : fluorescence intensity in the absence of test compound and in the presence of enzyme and substrate
B ₁ : Fluorescence intensity of blank well

Example 5 Cytochrome P450 (2C9) enzyme inhibitory action
Experiments were performed according to the method of Crespi et al. (Analytical Biochemistry, 248, 188-190, 1997).
Using 96-well plate, 7-methoxy-4- (trifluoromethyl) coumarin (7.5 × 10 ⁻⁵ M), test compound (4.9 × 10 ^{−8 to} 5 × 10 ⁻⁵ M) and enzyme (10 ^-8 M) in a total volume of 200 μl of 200 mM phosphate buffer (pH = 7.4) containing 8.2 μM NADP +, 0.41 mM glucose-6-phosphate, 0.41 mM MgCl ₂ and 0.4 Units / ml glucose-6-phosphate dehydrogenase Incubated at 37 ° C for 45 minutes. Thereafter, an aqueous solution of 0.5 M 2-amino-2-hydroxymethyl-1,3-propanediol containing 80% acetonitrile was added to stop the reaction, and fluorescence intensity (excitation wavelength: 409 nm, fluorescence wavelength: 530 nm) with a fluorescence plate reader ) Was measured. The inhibition rate was calculated by the same formula as (4) above, and the test compound concentration (IC ₅₀ ) at which the inhibition rate was 50% was determined. The results are shown in Table 4.

表３に示すように、本発明の医薬組成物は薬物代謝酵素CYP3A4及びCYP2C9に対して極めて低い阻害作用を示した。なお、比較化合物とは、表１に示す比較化合物と同一である。

As shown in Table 3, the pharmaceutical composition of the present invention showed a very low inhibitory action on the drug metabolizing enzymes CYP3A4 and CYP2C9. The comparative compound is the same as the comparative compound shown in Table 1.

Example 6 Production of a pharmaceutical composition for oral administration
20 g of the compound according to the active ingredient of the pharmaceutical composition of the invention is taken and mixed with 51 g of lactose and 21.8 g of corn starch. This mixture is granulated and dried with 20 g of an aqueous solution of 10% hydroxypropylcellulose (for example, trade name HPC-SL, manufactured by Shin-Etsu Chemical) using a fluidized bed granulator. 2 g of low-substituted hydroxypropylcellulose (for example, trade name L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) is mixed with the dried product, and further mixed with 0.2 g of magnesium stearate to obtain a mixed powder for tableting. This mixed powder is tableted using a rotary tableting machine (for example, manufactured by Kikusui Co., Ltd.), a tableting punch and a mortar having a diameter of 7 mm to obtain 100 mg tablets.

Example 7 Production of a pharmaceutical composition for parenteral administration
1 g of the compound according to the active ingredient of the pharmaceutical composition of the present invention is weighed and dissolved in 700 mL of water for injection. An additional 9 g of sodium chloride is dissolved in this solution. Adjust the pH to a predetermined value with a solution of hydrochloric acid / sodium hydroxide, and adjust the total volume to 1000 mL. Then, after aseptic filtration with a 0.2 μm filter, it is filled and sealed in an ampoule made of deborogenated borosilicate glass. Sterilization is performed in a high-pressure steam sterilizer under predetermined conditions to obtain an injection.

(Production example)
Hereinafter, the manufacture example of the compound which concerns on the active ingredient of the pharmaceutical composition of this invention is shown. In addition, the raw material compound used in a manufacture example also contains a novel substance, The manufacturing method from the well-known thing of such a raw material compound is demonstrated as a reference manufacture example.

Reference production example 1
A 60% sodium hydride oil dispersion (5.2 g) was suspended in DMF (50 ml), and benzyl alcohol (6.73 ml) was added under ice cooling. After raising the temperature to room temperature, 12.3 g of 4-fluoro-2-trifluoromethylbenzoic acid was added, and the mixture was stirred at room temperature for 6 hours. A 1M aqueous hydrochloric acid solution was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 16.39 g of 4- (benzyloxy) -2- (trifluoromethyl) benzoic acid.
MS (+): 297
Similar to Reference Production Example 1, Reference Production Examples 2 to 4 shown in Table 5 were produced using the corresponding raw materials.
The symbols in the table have the following meanings (the same applies hereinafter).
Rf: Reference production example number
Data: Physicochemical data (NMR: (CH ₃ ) ₄ Si is used as an internal standard, and unless otherwise specified, shows peak δ (ppm) in ¹ H-NMR using DMSO-d ₆ as a measurement solvent. MS (+): FAB-MS [M + H] ⁺ , MS (-): FAB-MS [MH] ⁺ , EMS (+): ESI-MS [M + H] ⁺ , EMS (-): ESI- MS [MH] ⁺ ),
R ^A , R ^B : a substituent in the general formula,
nPr: normal propyl, cPr: cyclopropyl.
Regarding NMR data, complicated data due to the presence of two or more kinds of conformers may be given depending on the compound, but only the peaks corresponding to the conformers considered to be mainly present are described. Moreover, these peaks converged to a peak indicating one kind of compound by measuring under heating.

Reference production example 5
Methyl 4-fluoro-2-trifluorobenzoate (4.44 g) was dissolved in DMF (40 ml), potassium carbonate (3.32 g) and N-methyl-N-propylamine (4.10 ml) were added, and the mixture was stirred at 80 ° C. for 14 hours. After cooling the reaction solution, water and EtOAc were added to carry out a liquid separation operation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the resulting crude product was subjected to silica gel column chromatography, eluting with hexane-EtOAc (4: 1). After concentration under reduced pressure, 4.79 g of methyl 4- [methyl (propyl) amino] -2- (trifluoromethyl) benzoate was obtained.
MS (+): 276

Reference production example 6
4.78 g of the compound of Reference Production Example 5 was dissolved in 20 ml of MeOH, 6.94 ml of 5M aqueous sodium hydroxide solution was added, and the mixture was stirred at 70 ° C. for 5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The obtained residue was neutralized with 1M aqueous hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 4.36 g of 4- [methyl (propyl) amino] -2- (trifluoromethyl) benzoic acid.
MS (+): 262

Reference production example 7
8.0 g of the compound of Reference Production Example 1 was dissolved in 80 ml of THF, 8 ml of thionyl chloride and 3 drops of DMF were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was distilled off and dried to obtain an acid chloride. To this was added (Z) -methyl (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene) acetate 6.84 g, and 50 ml of pyridine was added under ice cooling. For 12 hours. After completion of the reaction, the solvent was distilled off, and 1M aqueous hydrochloric acid and EtOAc were added to carry out a liquid separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was recrystallized from EtOH, and 9.12 g of methyl (2Z)-{1- [4- (benzyloxy) -2- (trifluoromethyl) benzoyl] -4,4 -Difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine 5-ylidene} acetate was obtained.
EMS (+): 532
Similarly to Reference Production Example 7, Reference Production Examples 8 to 11 shown in Table 6 were produced using the corresponding raw materials.
The symbols in the table have the following meanings (the same applies hereinafter).
Me: methyl.

Reference production example 12
9.1 g of the compound of Reference Production Example 7 was dissolved in 100 ml of trifluoroacetic acid, 5.1 g of pentamethylbenzene was added, and the mixture was stirred at room temperature for 12 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration, and 6.22 g of methyl (2Z)-{4,4-difluoro-1- [4-hydroxy-2- (trifluoromethyl) benzoyl]- 1,2,3,4-tetrahydro-5H-1-benzazepine 5-ylidene} acetate was obtained.
EMS (+): 442

Reference production example 13
The compound of Reference Production Example 12 (3.89 g) was dissolved in DMSO (20 ml), and tert-butyl bromoacetate (2.06 g) and potassium carbonate (1.46 g) were added thereto, followed by stirring at room temperature for 2 hours. After insoluble matter was filtered, water and EtOAc were added to carry out a liquid separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, and 3.55 g of methyl (2Z)-{1- [4- (2-tert- Butoxy-2-oxoethoxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetate was obtained.
EMS (+): 556

Reference production example 14
3.75 g of the compound of Reference Production Example 13 was dissolved in 20 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 3.25 g of [4-{[(5Z) -4,4-difluoro-5- (2-methoxy-2-oxoethylidene) -2,3,4,5-tetrahydro-1H -1-Benzazepin-1-yl] carbonyl} -3- (trifluoromethyl) phenoxy] acetic acid was obtained.
MS (+): 450

Reference production example 15
1.09 g of the compound of Reference Production Example 14 was dissolved in 10 ml of DMF, HOBt 324 mg, WSCD 460 mg, dimethylamine (2.0 M THF solution) 1.20 ml and triethylamine 0.335 ml were added, and the mixture was stirred at room temperature for 6 hours. . An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting precipitate was collected by filtration, washed with water, dried under reduced pressure, and 1.14 g of methyl (2Z)-{1- [4- (2-Dimethylamino-2-oxoethoxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzoazepine-5-ylidene} acetate Got.
MS (+): 527

Reference Production Example 16
1.00 g of the compound of Reference Production Example 12 was dissolved in 15 ml of THF, 0.415 ml of 1-butanol, 1.19 g of triphenylphosphine and 2.08 ml of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 17 hours. Water and EtOAc were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent was subjected to silica gel column chromatography, eluted with chloroform-MeOH (50: 1), concentrated under reduced pressure, and 1.41 g of crude methyl (2Z)-{1 -[4-Butoxy-2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetate was obtained. A. The compound obtained above was dissolved in MeOH 5 ml-THF 10 ml, 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, 1M hydrochloric acid and chloroform-iPrOH (3: 1 mixed solvent) were added to carry out a liquid separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to give 1.01 g of (2Z)-{1- [4-butoxy-2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H- 1-Benzazepine-5-ylidene} acetic acid was obtained.
MS (+): 484
Similarly to Reference Production Example 16, Reference Production Examples 17 to 19 shown in Table 7 were produced using the corresponding raw materials.
The symbols in the table have the following meanings (the same applies hereinafter).
iBu: Isobutyl.

Reference Production Example 20
The compound of Reference Production Example 7 (1.43 g) was dissolved in a mixed solvent of MeOH 15 ml-THF 25 ml, 10 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. After distilling off the organic solvent, 1M hydrochloric acid was added to make the solution acidic, and the precipitated white solid was collected by filtration and dried under reduced pressure, and 1.39 g of (2Z)-{1- [4- (benzyloxy) -2 -(Trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetic acid was obtained.
MS (+): 518
Similarly to Reference Production Example 20, Reference Production Examples 21 to 25 shown in Table 8 were produced using the corresponding raw materials.

Reference Production Example 26
Concentrated sulfuric acid was added to the MeOH solution of the compound of Reference Production Example 1 and the mixture was heated to reflux for 3 days. The reaction solvent was poured into ice water and extracted with ether. The residue obtained after evaporation of the solvent was dissolved in EtOH, 10% palladium on carbon was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 24 hours to obtain methyl 4-hydroxy-2- (trifluoromethyl) benzoate. It was.
MS (+): 221

Reference Production Example 27
Bromoacetone and potassium carbonate were added to an acetonitrile solution of the compound of Reference Production Example 26, followed by stirring at 60 ° C. for 1 hour to obtain methyl 4- (2-oxopropoxy) -2- (trifluoromethyl) benzoate.
ESI-MS (+): 299 [M + 23] ⁺

Reference Production Example 28
(Diethylamino) sulfur trifluoride was added to a methylene chloride solution of the compound of Reference Production Example 27 at −78 ° C., and the mixture was stirred at room temperature for 24 hours. Methyl 4- (2,2-difluoropropoxy) -2- (trifluoromethyl) I got benzoart.
EI-MS: 298 [M] ⁺

Reference Production Example 29
A 5M aqueous sodium hydroxide solution was added to the MeOH solution of the compound of Reference Production Example 28 and the mixture was stirred at 90 ° C. for 2.5 hours to obtain 4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoic acid.
MS (-): 283

Reference Production Example 30
After adding triethylamine to a methylene chloride solution of (2S) -propane-1,2-diol, a methylene chloride solution of paratoluenesulfonyl chloride was added at −20 ° C. and stirred at room temperature for 18 hours. 2-Hydroxypropyl-4-methylbenzenesulfonate was obtained.
MS (+): 231

Reference Production Example 30A
To a THF solution of the compound of Reference Production Example 30, N, N-dimethylaniline and acetic anhydride were added and stirred at 0 ° C. for 1 hour. (1S) -1-methyl-2-{[(4-methylphenyl) sulfonyl] oxy } Ethyl acetate was obtained.
MS (+): 273

Reference Production Example 30B
To the DMF solution of the compound of Reference Production Example 30A, add the compound of Reference Production Example 26 and potassium carbonate, and stir at 70 ° C. for 17 hours. Methyl 4-{[(2S) -2- (acetyloxy) propyl] oxy} -2 -(Trifluoromethyl) benzoate was obtained.
MS (+): 321

Reference Production Example 31
To the MeOH solution of the compound of Reference Production Example 30B, 1M potassium hydroxide-MeOH solution was added at 0 ° C. and stirred at room temperature for 1 hour, and methyl 4-{[(2S) -2-hydroxypropyl] oxy} -2 -(Trifluoromethyl) benzoate was obtained.
MS (+): 279

Reference Production Example 32
(Diethylamino) sulfur trifluoride was added to a methylene chloride solution of the compound of Reference Production Example 31 at −78 ° C., and the mixture was stirred at room temperature for 15 hours and methyl 4-{[(2R) -2-fluoropropyl] oxy} -2- (Trifluoromethyl) benzoate was obtained.
FAB-MS (+): 280 [M] ⁺

Reference Production Example 33
5M aqueous sodium hydroxide solution was added to the MeOH solution of the compound of Reference Production Example 32, and the mixture was stirred at 70 ° C. for 6 hours. 4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoic acid The acid was obtained.
MS (+): 267

Reference Production Example 34
Sodium borohydride was added to an EtOH solution of the compound of Reference Production Example 27 at 0 ° C. and stirred at room temperature for 1 hour to obtain methyl 4- (2-hydroxypropoxy) -2- (trifluoromethyl) benzoate. .
ESI-MS (+): 301 [M + 23] ⁺

Reference Production Example 35
In the same manner as in Reference Production Example 30, (2R) -2-hydroxypropyl-4-methylbenzenesulfonate was produced using (2R) -propane-1,2-diol.
MS (+): 231

Reference Production Example 35A
In the same manner as in Reference Production Example 30A, (1R) -1-methyl-2-{[(4-methylphenyl) sulfonyl] oxy} ethyl acetate was produced using the compound of Reference Production Example 35.
MS (+): 273

Reference Production Example 35B
Similar to Reference Preparation Example 30B, methyl 4-{[(2R) -2- (acetyloxy) propyl] oxy} -2- (trifluoromethyl) benzoate was prepared using the compound of Reference Preparation Example 35A. .
MS (+): 321

Reference Production Example 36
In the same manner as in Reference Production Example 31, methyl 4-{[(2R) -2-hydroxypropyl] oxy} -2- (trifluoromethyl) benzoate was produced using the compound of Reference Production Example 35B.
MS (+): 279

Reference Production Example 37
In the same manner as in Reference Production Example 32, methyl 4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoate was produced using the compound of Reference Production Example 36.
MS (+): 281

Reference Production Example 38
In the same manner as in Reference Production Example 33, 4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoic acid was produced using the compound of Reference Production Example 37.
MS (+): 267
Similarly to Reference Production Example 7, Reference Production Examples 39 to 41 shown in Table 9 were produced using the corresponding raw materials.

  Similarly to Reference Production Example 20, Reference Production Examples 42 to 46 shown in Table 10 were produced using the corresponding raw materials.

Production Example 1
150 mg of the compound of Reference Production Example 20 was dissolved in 5 ml of DMF, and 43 mg of HOBt, 61 mg of WSCD, 35 mg of glycinamide hydrochloride and 0.045 ml of triethylamine were added, followed by stirring at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution and EtOAc were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was recrystallized from EtOH, and 139 mg of (2Z) -N- (2-amino-2-oxoethyl) -2- {1- [4- (benzyloxy)- 2- (Trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide was obtained.
Similar to Production Example 1, Production Examples 2 to 16 shown in Table 11 were produced using the corresponding raw materials.

Production Example 17
150 mg of the compound of Reference Production Example 20 was dissolved in 3.5 ml of THF, 0.3 ml of thionyl chloride and 2 to 3 drops of DMF were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and thionyl chloride was distilled off azeotropically using toluene. The obtained residue was dissolved in THF, and this solution was added dropwise to aqueous ammonia. EtOAc was added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The obtained crude product was recrystallized from a mixed solvent of iPrOH-diisopropyl ether, and 126 mg of (2Z) -2- {1- [4- (benzyloxy) -2- (trifluoromethyl) benzoyl] -4, 4-Difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide was obtained.
Similar to Production Example 17, Production Example 18 shown in Table 11 was produced using the corresponding raw materials. Similarly to Reference Production Example 12, Production Examples 19 to 20 shown in Table 11 were produced using the corresponding raw materials.

Production Example 21
325 mg of the compound of Production Example 6 was dissolved in 5 ml of 1,2-dichloroethane, 148 mg of metachloroperbenzoic acid was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% (w / v) Na ₂ S ₂ O ₃ .5H ₂ O aqueous solution, water and chloroform were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting crude product was subjected to silica gel column chromatography, eluting with chloroform-MeOH (23: 2). And concentrated under reduced pressure to give 121 mg of (2Z) -N- (2-amino-2-oxoethyl) -2- {4,4-difluoro-1- [4- (propylsulfinyl) benzoyl] -1, 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide was obtained.
Similarly to Production Example 21, Production Example 22 shown in Table 11 was produced using the corresponding raw materials. In addition, Production Examples 23 to 147 shown in Tables 12 to 19 were produced by using the corresponding raw materials by the above-described production methods and the methods described in the production examples, methods obvious to those skilled in the art, or variations thereof. did.
The symbols in the table have the following meanings (the same applies hereinafter).
Ex: Production example number,
R ^C : a substituent in the general formula,
Et: ethyl, nBu: normal butyl, Ph: phenyl, Py: pyridyl, Bn: benzyl, Gly: carbamoylmethylamino (—NHCH ₂ CONH ₂ ), Etha: 2-hydroxyethylamino (—NHCH ₂ CH ₂ OH), Car: amino (-NH _2). The number before the substituent indicates the substitution position. Specifically, for example, -NHPh (2-OH) represents 2-hydroxyphenylamino, and -NHCH ₂ (2-Py) represents pyridin-2-ylmethylamino.

以下、表２０〜表２３にいくつかの製造例化合物のNMRデータを示す。

Hereinafter, Tables 20 to 23 show NMR data of some of the production example compounds.

Tables 24 to 40 below show structures of other compounds of the present invention. These are synthesized or can be synthesized by using the above-described production methods, the methods described in the production examples, methods obvious to those skilled in the art, or variations thereof.
The symbols in the table have the following meanings.
No: Compound number.
R ^1A , -A ^A -B ^A , X, Y: a substituent in the general formula,
iPr: isopropyl, tBu: tert-butyl, cBu: cyclobutyl, nPen: normal pentyl, cPen: cyclopentyl, iAm: isoamyl, nHex: normal hexyl, pyrr: pyrrolidin-1-yl, pipe: piperidin-1-yl, pipa: Piperazin-1-yl, mor: morpholin-4-yl, Ac: acetyl, Ms: methanesulfonyl, cyano: cyano.

Claims (6)

4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier A pharmaceutical composition comprising

[The symbols in the formula have the following meanings.
R ¹ : a group represented by the formula (II).

[The symbols in the formula have the following meanings.
Z ¹ : a single bond, lower alkylene, or -lower alkylene-C (═O) —.
R ¹¹ : substituted with a group selected from the group consisting of —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, and carbamoyl optionally substituted with one or two lower alkyls Optionally lower alkyl, or -H.
R ¹² :
(1) When Z ¹ represents a single bond or lower alkylene,
-H, -OH, -O- lower alkyl, -CO ₂ H, -CO ₂ - lower alkyl, one or two lower alkyl optionally substituted carbamoyl, optionally substituted aryl, optionally substituted Optionally substituted cycloalkyl, optionally substituted aromatic heterocycle, or optionally substituted non-aromatic heterocycle.
(2) When Z ¹ represents -lower alkylene-C (= O)-,
A group represented by formula (III) or formula (IV);

[The symbols in the formula have the following meanings.
Z ² : single bond or lower alkylene.
R ¹⁵ : —H, —OH, —O-lower alkyl, —CO ₂ H, —CO ₂ -lower alkyl, carbamoyl optionally substituted with one or two lower alkyls, optionally substituted aryl , An optionally substituted cycloalkyl, an optionally substituted aromatic heterocycle, or an optionally substituted non-aromatic heterocycle.
R ¹³ and R ¹⁴ : a non-aromatic cyclic amino group which may be substituted together with an adjacent nitrogen atom. ]]
R ² : CF ₃ or halogen.
R ³ : H or halogen.
a: Single bond.
b: Double bond.
-X-: -CH = CH-.
-Y-: -CH-.
-A-: -O-.
B: Lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, or aryl each optionally substituted. ] The pharmaceutical composition according to claim 1, wherein -B is optionally substituted lower alkyl. The pharmaceutical composition according to claim 2, wherein R ² is trifluoromethyl and R ³ is -H or -F. Among the pharmaceutical compositions according to claim 1,
(2Z) -N- (2-Amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- ( Trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -N- (2-hydroxyethyl) -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl ) Benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -N- (2-hydroxyethyl) -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl ) Benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N-[(2S) -2,3-dihydroxypropyl] acetamide,
3-[((2Z) -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1 , 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetyl) amino] propanamide,
(2Z) -N-[(2R) -2,3-Dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-{[(2R) -2-fluoropropyl] oxy}- 2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -N- (2-amino-2-oxoethyl) -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- ( Trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4-difluoro-1,2,3,4-tetrahydro-5H-1 -Benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2,3,4-tetrahydro- 5H-1-Benzazepine-5-ylidene} -N- (2-hydroxyethyl) acetamide,
(2Z) -N-[(2R) -2,3-dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1, 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N-[(2S) -2,3-dihydroxypropyl] acetamide,
(2Z) -2- {4,4-Difluoro-1- [4-{[(2R) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1,2,3,4- Tetrahydro-5H-1-benzazepine-5-ylidene} -N-[(2R) -2,3-dihydroxypropyl] acetamide,
3-[((2Z) -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy} -2- (trifluoromethyl) benzoyl] -1 , 2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetyl) amino] propanamide,
(2Z) -N-[(2R) -2,3-Dihydroxypropyl] -2- {4,4,7-trifluoro-1- [4-{[(2S) -2-fluoropropyl] oxy}- 2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene} acetamide,
3-[((2Z) -2- {1- [4- (2,2-difluoropropoxy) -2- (trifluoromethyl) benzoyl] -4,4,7-trifluoro-1,2,3, 4-tetrahydro-5H-1-benzazepine-5-ylidene} acetyl) amino] propanamide,
(2Z) -2- {4,4-Difluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene } -N-[(2R) -2,3-dihydroxypropyl] acetamide, or
(2Z) -2- {4,4-Difluoro-1- [4-propoxy-2- (trifluoromethyl) benzoyl] -1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene } -N-[(2S) -2,3-dihydroxypropyl] acetamide,
Or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to any one of claims 1 to 4, which is an arginine vasopressin receptor agonist. The pharmaceutical composition according to any one of claims 1 to 4, which is a therapeutic agent for nocturia, a therapeutic agent for nocturia, a therapeutic agent for urinary incontinence, or a therapeutic agent for central diabetes insipidus.