JPWO2008038600A1 - 1,4-Benzodiazepine derivatives, pharmaceutical compositions containing them and their pharmaceutical use - Google Patents

Abstract

[(R) -1- (2-chloro-4-alkoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amine skeleton Certain 1,4-benzodiazepine derivatives such as methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate or methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3- Methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate and the like have a V2 receptor stimulating action, such as central diabetes insipidus, nocturia, Prevention of nocturnal enuresis Are useful as therapeutic agents. [Selection figure] None

Description

  The present invention relates to a 1,4-benzodiazepine derivative useful as a pharmaceutical or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.

  More specifically, the present invention relates to a novel 1,4-benzodiazepine derivative having a type 2 arginine vasopressin receptor (hereinafter referred to as V2 receptor) stimulating action, or a pharmacologically acceptable salt thereof, or a prodrug thereof. The present invention relates to a drug, a pharmaceutical composition containing it, and a pharmaceutical use thereof.

  Arginine vasopressin is one of the neurohormones biosynthesized in the hypothalamus and secreted from the posterior pituitary gland. Arginine vasopressin receptors are classified into subtypes V1a, V1b, and V2. There is a V2 receptor in the renal collecting duct, and arginine vasopressin binds to the V2 receptor existing in the renal collecting duct and exerts a V2 receptor acting action, thereby reabsorbing water in the renal collecting duct. Is called antidiuretic hormone (see Non-Patent Document 1). For this reason, polyuria is caused by the lack of arginine vasopressin, and specific diseases include central diabetes insipidus, childhood nocturnal enuresis, nocturia due to aging, etc. (Non-patent Document 2 and 3).

  Conventionally, desmopressin ((1-desamino, D-Arg8) vasopressin, DDAVP), which is a peptide-type compound as a V2 receptor agonist, has been used for the treatment of central diabetes insipidus / nighturia (Non-patent Document 3). See). However, since desmopressin, which is a peptide-type compound, has individual differences in terms of oral absorption rate, variations in blood concentration have been reported (see Non-Patent Document 4). Therefore, V2 receptor agonists with different skeletons are desired for patients who cannot obtain sufficient effects.

  Until now, a compound represented by the following general formula (D-1) has been reported in Patent Document 1, but the compound described in the Patent Document is a compound having no urea structure unlike the present invention. . Moreover, since the following general formula (D-1) is not a vasopressin receptor agonist but an antagonist, it has an action different from that of the compound of the present invention.

（式中の記号は特許文献１を参照）

(See Patent Document 1 for symbols in the formula)

  Moreover, the following compound (D-2) and the compound (D-2-1) are reported to patent document 2 as a compound which has the effect | action which stimulates a vasopressin receptor. However, the compound is a tricyclic derivative in which an aromatic ring is condensed to benzodiazepine, and has a chemical structural formula different from that of the compound of the present invention.

（式中の記号は特許文献２を参照）

(See Patent Document 2 for symbols in the formula)

  As described above, none of the patent documents discloses any benzodiazepine derivative having a urea structure. The 1,4-benzodiazepine derivative of the present invention is a completely new benzodiazepine derivative having a urea structure in the structural formula, and the compound has a V2 receptor stimulating action, causing central diabetes insipidus and nocturnal enuresis in children. It has not been reported so far as being useful as a drug for treating or preventing nocturia due to aging.

Japanese Patent Laid-Open No. 06-016643 International Publication No. 2001/022696 Pamphlet Goodman & Gilman's, “The Pharmacologic Basis of Therapeutics (Tenth Edition), McGraw-Hill Tsutomu Aikawa, et al., “Scan. J. Urol. Nephrol. Suppl”, 1999, vol. 202, p. 47-49 Jeffrey P.M. Weiss, et al., “J. Urol.”, 163, 2000, p. 5-12 Mogens Hammer, et al., “J. Pharmacol. Exp. Ther.”, 234, 1985, p. 754-760

  The present invention provides a novel compound having a V2 receptor stimulating action.

  As a result of intensive studies to find a compound that expresses a V2 receptor stimulating action, the present inventors have surprisingly found that certain 1,4-benzodiazepine derivatives shown below have a V2 receptor stimulating action. As described later, the present inventors have obtained the knowledge that the drug is an excellent drug having a urine volume reducing action, and have achieved the present invention.

〔式中、Ｒ^１はエチル基またはｎ−プロピル基であり；Ｒ^Ａはメチル基、ヒドロキシメチル基、イソプロピル基またはイソブチル基であり；Ｒ^Ｂは水酸基、メトキシ基、エトキシ基、アジリジノ基、アゼチジノ基、ピロリジノ基、モルホリノ基、１乃至２個の低級アルキル基を有しても良いピペリジノ基または式：

（式中、Ｒ^Ｃは水素原子、イソプロピル基、シクロプロピル基、シクロブチル基、シクロペンチル基またはシクロヘキシル基である）で示す基であるか、或いはＲ^ＡおよびＲ^Ｃが結合してトリメチレン基を形成する〕で表される、１，４−ベンゾジアゼピン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ；That is, the present invention
(1) General formula (A):

[Wherein, R ¹ represents an ethyl group or an n-propyl group; R ^A represents a methyl group, a hydroxymethyl group, an isopropyl group, or an isobutyl group; R ^B represents a hydroxyl group, a methoxy group, an ethoxy group, an aziridino group, an azetidino group; Group, pyrrolidino group, morpholino group, piperidino group optionally having 1 to 2 lower alkyl groups or formula:

(Wherein R ^C is a hydrogen atom, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group), or R ^A and R ^C combine to form a trimethylene group. 1,4-benzodiazepine derivative represented by the above or a pharmacologically acceptable salt thereof, or a prodrug thereof;

〔式中、Ｒ^１はエチル基またはｎ−プロピル基であり；Ｒ^Ａはメチル基、ヒドロキシメチル基、イソプロピル基またはイソブチル基であり；Ｒ^Ｂは水酸基、メトキシ基、エトキシ基、アジリジノ基、アゼチジノ基、ピロリジノ基、モルホリノ基、１乃至２個の低級アルキル基を有しても良いピペリジノ基または式：

（式中、Ｒ^Ｃは水素原子、イソプロピル基、シクロプロピル基、シクロブチル基、シクロペンチル基またはシクロヘキシル基である）で示す基であるか、或いはＲ^ＡおよびＲ^Ｃが結合してトリメチレン基を形成する〕で表される、上記（１）記載の１，４−ベンゾジアゼピン誘導体またはその薬理学的に許容される塩、或いはそれらのプロドラッグ；(2) General formula (B):

[Wherein, R ¹ represents an ethyl group or an n-propyl group; R ^A represents a methyl group, a hydroxymethyl group, an isopropyl group, or an isobutyl group; R ^B represents a hydroxyl group, a methoxy group, an ethoxy group, an aziridino group, an azetidino group; Group, pyrrolidino group, morpholino group, piperidino group which may have 1 to 2 lower alkyl groups or formula:

(Wherein R ^C is a hydrogen atom, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group), or R ^A and R ^C combine to form a trimethylene group. 1,4-benzodiazepine derivative of the above (1) or a pharmacologically acceptable salt thereof, or a prodrug thereof;

(3) R ^A is a methyl group, isopropyl group, or isobutyl group; R ^C is a hydrogen atom, isopropyl group, cyclopropyl group, or R ^A and R ^C combine to form a trimethylene group; A 1,4-benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to (2) above, or a prodrug thereof;

(4) The 1,4-benzodiazepine derivative according to (1) or a pharmacologically acceptable salt thereof or a prodrug thereof selected from the following compound group;
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} propionate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} propionate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -3-methylbutyrate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -3-methylbutyrate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -4-methylpentanate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -4-methylpentanate,
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} propionic acid,
(S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} propionic acid,
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -3-methylbutyric acid,
(S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -3-methylbutyric acid,
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -4-methylpentanoic acid,
(S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -4-methylpentanoic acid,
2-{[(R) -1- (2-Chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino } -3-hydroxypropionic acid,
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclobutylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopentylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclohexyl) carbamoylethyl]-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclobutylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopentylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclohexylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-2-methyl) propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclobutylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopentylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclohexylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (azetidine-1-carbonyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -2-methyl-1- (pyrrolidine-1-carbonyl)] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -2-methyl-1- (piperidine-1-carbonyl)] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -2-methyl-1- (morpholine-4-carbonyl)] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
Methyl = 2 {[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl Amino} -3-hydroxypropionate,
N- (1-carbamoyl-2-hydroxy) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- [2-hydroxy-1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopropylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclobutylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopentylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclohexylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
Methyl = 2 {[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl Amino} -3-hydroxypropionate,
2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino } -3-hydroxypropionic acid,
N- (1-carbamoyl-2-hydroxy) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- [2-hydroxy-1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopropylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclobutylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopentylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclohexylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(1-hydroxymethyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2, 3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide and N- [1-hydroxymethyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1 -(2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide;

(5) The following 1,4-benzodiazepine derivatives described in (4) above;
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-2-methyl) propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide and N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl -1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide;

(6) N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5 as described in (5) above -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide;

(7) N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 as described in (5) above -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide;

(8) A pharmaceutical composition comprising the 1,4-benzodiazepine derivative or the pharmacologically acceptable salt thereof described in (1) above or a prodrug thereof as an active ingredient;

(9) A human type 2 arginine vasopressin receptor agonist containing the 1,4-benzodiazepine derivative or the pharmacologically acceptable salt thereof according to (1) above or a prodrug thereof as an active ingredient;

(10) Prevention of central diabetes insipidus, nocturia or nocturnal enuresis containing the 1,4-benzodiazepine derivative or pharmacologically acceptable salt thereof described in (1) above or a prodrug thereof as an active ingredient Or therapeutic agent;

(11) Central diabetes insipidus, nocturia or nocturia, comprising administering an effective amount of the 1,4-benzodiazepine derivative or the pharmacologically acceptable salt thereof or the prodrug thereof according to (1) above A method for preventing or treating nocturnal enuresis;

(12) The 1,4-benzodiazepine derivative according to (1) or a pharmacologically acceptable product thereof for producing a pharmaceutical composition for preventing or treating central diabetes insipidus, nocturia or nocturnal enuresis Use of salts, or prodrugs thereof;

(13) Further, an adrenergic α1 receptor blocker, an anticholinergic agent, a cholinergic agent, an antispasmodic agent, an antiandrogen agent, an antidepressant, a calcium antagonist, a K-channel opener, a sensory nerve inhibitor, an adrenergic β receptor agonist A pharmaceutical composition according to (8) above, which is a combination of at least one drug selected from the group consisting of an acetylcholinesterase inhibitor and an antiallergic drug;

(14) Further, an adrenergic α1 receptor blocker, an anticholinergic agent, a cholinergic agent, an antispasmodic agent, an antiandrogen agent, an antidepressant, a calcium antagonist, a K-channel opener, a sensory nerve inhibitor, an adrenergic β receptor agonist Central insipidus, nocturia or nocturia described in (11) above, comprising administering an effective amount of at least one drug selected from the group consisting of an acetylcholinesterase inhibitor and an antiallergic agent Prevention or treatment method of

(15) Further, an adrenergic α1 receptor blocker, an anticholinergic agent, a cholinergic agent, an antispasmodic agent, an antiandrogen agent, an antidepressant, a calcium antagonist, a K-channel opener, a sensory nerve inhibitor, an adrenergic β receptor agonist, Use according to (12) above, wherein a combination of at least one drug selected from the group consisting of an acetylcholinesterase inhibitor and an antiallergic drug is used;

(16) A method for preventing or treating a disease which is improved by stimulating a V2 receptor, the 1,4-benzodiazepine derivative or a pharmacologically acceptable salt thereof according to (1) above, or a method thereof Administering a prodrug in an effective amount;

(17) The method described in (16) above, wherein the disease improved by stimulating the V2 receptor is selected from the group of central diabetes insipidus, nocturia and nocturia.

Among the 1,4-benzodiazepine derivatives represented by the general formula (A) of the present invention, the 1,4-benzodiazepine derivative represented by the general formula (B) is preferable. In (B), R ^A is a methyl group, isopropyl group, or isobutyl group, and R ^C is a hydrogen atom, isopropyl group, or cyclopropyl group, or R ^A and R ^C combine to form a trimethylene group. 1,4-benzodiazepine derivatives such as N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5- Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide, N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoy (L) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide is a compound showing excellent AUC in the method for measuring AUC in Test Example 4. It has been confirmed that it is more preferable.

  The V2-receptor stimulating action of the 1,4-benzodiazepine derivative represented by the general formula (A) of the present invention can be confirmed by using cells expressing human V2 receptor, and the compound of the present invention Was confirmed to have a strong V2 receptor stimulating action. Moreover, it was confirmed that the compound shown by said (1) of this invention exhibits a strong antidiuretic action by the arousal antidiuretic action confirmation test with respect to a water load diuretic rat.

  In the 1,4-benzodiazepine derivative represented by the general formula (A) of the present invention, when one or more asymmetric carbon atoms are present, the present invention is each asymmetric carbon unless otherwise specified. It includes any compound having an R configuration, an S configuration, and any combination thereof. Where one or more geometric isomerism is present, the present invention encompasses any of its cis isomers, trans isomers, and mixtures thereof.

The compounds of the present invention also include solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
In the present invention, the pharmacologically acceptable salt is not particularly limited, and includes salts with pharmacologically acceptable bases including organic bases and inorganic bases. For example, pharmacologically acceptable salts include salts with organic amines such as 2-aminoethanol, piperidine, morpholine and pyrrolidine, salts with amino acids, sodium salts, potassium salts, calcium salts, magnesium salts and the like. Etc.

In the present invention, the “lower alkyl group” means methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl. It means a linear or branched alkyl group having 1 to 6 carbon atoms such as a group, and is preferably a methyl group. In R ^B , the piperidino group optionally having 1 to 2 lower alkyl groups is preferably a 2-methylpiperidino group, a 2,2-dimethylpiperidino group or a 2,6-dimethylpiperidino group. .

  In the present invention, a prodrug refers to a compound obtained by modifying a parent compound with a group that is commonly used in pharmacologically acceptable prodrugs. For example, a prodrug is imparted with characteristics such as improved stability and durability, It can be expected to be converted into the parent compound in the body and exert its effect. The prodrug of the 1,4-benzodiazepine derivative represented by the general formula (A) of the present invention is prepared by a conventional method using a prodrug reagent such as a corresponding halide. In the 1,4-benzodiazepine derivative represented by), a group constituting a prodrug is appropriately introduced according to a conventional method, followed by isolation and purification according to a conventional method as needed. Can do. ("Monthly Pharmaceutical Affairs Clinical Pharmacokinetics for Proper Use of Drugs", March 2000 Special Issue, Vol. 42, No. 4, p. 669-707, "New Drug Delivery System", CMC Corporation Issue, January 31, 2000, p. 67-173).

For example, when the 1,4-benzodiazepine derivative of the present invention has a carboxy group, as a prodrug, the hydrogen atom of the carboxy group and the following group: C _1-7 alkyl group (for example, methyl group, ethyl group) Propyl group, isopropyl group, butyl group, tert-butyl group, etc.); C _2-7 acyloxymethyl group (eg, pivaloyloxymethyl group); 1- (C _2-7 acyloxy) ethyl group (eg, 1- (pivaloyloxy) ethyl group, etc.); C _3-7 cycloalkoxycarbonyloxy (C _1-7 alkyl) group (eg, 1-cyclohexyloxycarbonylethyl group); C _1-6 alkoxycarbonyloxymethyl group (eg, and tert- butoxycarbonyl oxymethyl group); 1- _{(C 1-6} alkoxycarbonyl Aryloxy) ethyl group (e.g., 1-(tert-butoxycarbonyl-oxy) ethyl group and the like); or 3-phthalidyl group, an ester formed by the replacement with the like.

When the 1,4-benzodiazepine derivative of the present invention has a hydroxyl group, as a prodrug, a hydrogen atom of the hydroxyl group and the following group: C _2-7 acyl group (for example, acetyl group, propionyl group, butyryl group) , isobutyryl group, pivaloyl _{group); C 1-6} alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, such as tert- butoxycarbonyl group); succinoyl _{groups; C 2- 7} acyloxymethyl group (eg, pivaloyloxymethyl group); 1- (C _2-7 acyloxy) ethyl group (eg, 1- (pivaloyloxy) ethyl group); or C _1-6 alkoxycarbonyloxymethyl group (For example, tert-butoxycarbonyloxy A methyl group); and C _3-7 cycloalkoxy group (e.g. cyclohexyl oxycarbonyl group), compounds formed by substitution of the the like.

  The 1,4-benzodiazepine derivative of the present invention can be produced, for example, according to the method shown in the following schemes 1 and 2 or a method analogous thereto. In addition, when a protective group is required depending on the type of functional group, it can be carried out by appropriately combining the introduction and desorption operations according to a conventional method. For example, the type, introduction and elimination of the protecting group can be carried out according to the method described in “Protective Groups in Organic Synthesis (third edition)” (edited by WILEY-INTERSCIENCE, edited by Green & Wuts).

  The typical manufacturing method of the 1, 4- benzodiazepine derivative represented by the said general formula (A) of this invention is shown below. Each step in each of the following schemes may be carried out by combining multistage reactions, and a plurality of steps that can be usually selected by those skilled in the art may be combined.

  The 1,4-benzodiazepine derivative represented by the general formula (A) of the present invention can be produced, for example, by the method shown in the following scheme 1. In addition, since the manufacturing method shown in Scheme 1 can be carried out by steric retention, when an optically active starting material or reagent is used, an optically active compound (1-7) or compound (1-8) is obtained. Can do. Further, when optical isomers and diastereoisomers are produced during the production process, they can be separated by using a general technique such as chromatography or recrystallization.

(In the formula, R ¹ is an ethyl group or an n-propyl group, R ² is a methyl group, an isopropyl group, an isobutyl group or a hydroxymethyl group in which a hydroxyl group may be protected, and R ³ is a methyl group or an ethyl group. R ⁴ is a hydrogen atom, isopropyl group, 2-hydroxyethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, R ⁵ is a hydrogen atom, or NR ⁴ R ⁵ is aziridino A pyridine group, an azetidino group, a pyrrolidino group, a morpholino group or a piperidino group which may have one or two lower alkyl groups, or R ² and R ⁴ are combined to form a trimethylene chain, and PG ¹ is (This is a protecting group for nitrogen atom.)

Step 1-1
Introduction of a protecting group onto the nitrogen atom of the compound represented by formula (1-1) is, for example, “Protective Groups in Organic Synthesis (third).
edition) ”(edited by Green & Wuts, WILEY-INTERSCIENCE), and a compound represented by the corresponding general formula (1-2) can be obtained.

Step 1-2
By condensing the compound represented by the general formula (1-2) and the acid halide represented by the general formula (II) in a solvent in the presence of a base such as triethylamine, pyridine, or potassium carbonate. The compound represented by general formula (1-3) can be obtained. Examples of the solvent used in the reaction include dichloromethane, tetrahydrofuran, a mixed solvent thereof and the like. It is preferable to use 1 to 5 equivalents of the acid halide and base represented by the general formula (II) relative to the compound represented by the general formula (1-2). The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-3
The removal of the protecting group of the compound represented by the general formula (1-3) can be carried out, for example, according to the method described in “Protective Groups in Organic Synthesis (third edition)” (edited by WILEY-INTERSCIENCE, Green & Wuts). And an amine derivative represented by the corresponding general formula (1-4) can be obtained.

Step 1-4
A compound represented by the general formula (1-5) can be obtained by applying the methods (a) to (c) shown below or the method.
(A) After reacting the compound represented by the general formula (I-II) or a salt thereof with triphosgene in a solvent in the presence or absence of a base such as triethylamine or N, N-diisopropylethylamine, The compound represented by the general formula (1-5) can be obtained by reacting with an amine derivative represented by the general formula (1-4) or a salt thereof. Examples of the solvent used in the reaction include dichloromethane, ethyl acetate, tetrahydrofuran, a mixed solvent thereof and the like. Triphosgene is preferably used in an amount of 0.3 to 1 equivalent to the compound represented by the general formula (I-II), and the base is used in an amount of 1 to 5 based on the compound represented by the general formula (I-II). It is desirable to use an equivalent amount. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. This step can also be carried out using an activating reagent such as 1,1′-carbonylbis-1H-imidazole instead of triphosgene.
(B) An active ester compound represented by general formula (I-III) and an amine derivative represented by general formula (1-4) or a salt thereof in a solvent in the presence of a base such as triethylamine or pyridine. Alternatively, the compound represented by the general formula (1-5) can be obtained by condensation in the absence. Examples of the solvent used in the reaction include dichloromethane, tetrahydrofuran, ethyl acetate, a mixed solvent thereof and the like. The base and the active ester compound represented by the general formula (I-III) are desirably used in an amount of 1 to 5 equivalents with respect to the amine derivative represented by the general formula (1-4) or a salt thereof. The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
(C) the amine derivative represented by the general formula (1-4) or a salt thereof and the isocyanate compound represented by the general formula (I-IV) in a solvent in the presence of a base such as triethylamine or pyridine; By reacting in the absence, the compound represented by the general formula (1-5) can be obtained. Examples of the solvent used in the reaction include dichloromethane, tetrahydrofuran, ethyl acetate, a mixed solvent thereof and the like. The isocyanate compound represented by the general formula (I-IV) and the base are desirably used in an amount of 1 to 5 equivalents with respect to the amine derivative represented by the general formula (1-4) or a salt thereof. The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-5
Carboxylic acid represented by general formula (1-6) by hydrolyzing the compound represented by general formula (1-5) using a base such as lithium hydroxide or sodium hydroxide in a solvent. Derivatives can be obtained. Examples of the solvent used in the reaction include water, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof and the like. It is desirable to use 1 to 5 equivalents of the base with respect to the compound represented by the general formula (1-5). The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-6
A carboxylic acid derivative represented by the general formula (1-6) and an amine derivative represented by the general formula (IV) or a salt thereof are converted into 1-ethyl-3- (N, N-dimethylaminopropyl). ) In the presence of a condensing agent such as carbodiimide hydrochloride or dicyclohexylcarbodiimide, a base such as 4-dimethylaminopyridine or triethylamine and an activating reagent such as 1-hydroxybenzotriazole or N-hydroxysuccinimide are added as necessary. By condensing in a solvent, the compound represented by the general formula (1-7) can be obtained. Examples of the solvent used in the reaction include dichloromethane, N, N-dimethylformamide, a mixed solvent thereof and the like. The amine derivative represented by the general formula (IV) or a salt thereof, a condensing agent and a base are used in an amount of 0.5 to 5 equivalents relative to the carboxylic acid derivative represented by the general formula (1-6). desirable. The reaction temperature is usually from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-7
An acid generated in the reaction system by treating the carboxylic acid derivative represented by the general formula (1-6) with a base such as isobutyl chloroformate and N-methylmorpholine or N, N-diisopropylethylamine in a solvent. The compound represented by the general formula (1-8) can be obtained by reducing the anhydride using a reducing agent such as sodium tetrahydroborate. Examples of the solvent used in the reaction include tetrahydrofuran, dichloromethane, ethanol and a mixed solvent thereof. As for isobutyl chloroformate, a base, and a reducing agent, it is desirable to use 1-5 equivalent with respect to the carboxylic acid derivative represented with the said general formula (1-6). The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-8
Compound (1-7) can be obtained by a method analogous to the method described in Step 1-4.

Step 1-9
Compound (1-8) can be obtained by a method analogous to the method described in Step 1-4.

  Further, the 1,4-benzodiazepine derivative of the present invention can also be produced by the method shown in the following scheme 2. Since the production method shown in Scheme 2 can be carried out by steric retention, when an optically active starting material or reagent is used, an optically active compound (1-7) can be obtained.

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above.)

Step 2-1
Compound (2-1) can be obtained by a method according to the method described in Step 1-4.

Step 2-2
Compound (1-5) can be obtained by a method analogous to the method described in Step 1-2.

Step 2-3
Compound (1-6) can be obtained by a method analogous to the method described in Step 1-5.

Step 2-4
Compound (1-7) can be obtained by a method analogous to the method described in Step 1-6.

Step 2-5
Compound (2-2) can be obtained by a method according to the method described in Step 1-4.

Step 2-6
Compound (1-7) can be obtained by a method analogous to the method described in Step 1-2.

  The schemes shown above are some examples of methods for preparing the compounds of the present invention or intermediates thereof, and various modifications to the schemes that can be readily understood by those skilled in the art. Is possible.

  For example, by using a racemic mixture or diastereomeric mixture corresponding to the raw materials and intermediates shown in the above scheme, the product is subjected to optical resolution by column chromatography or recrystallization, or by diastereomeric resolution. Also, the compound of the present invention can be obtained.

  The 1,4-benzodiazepine derivative of the present invention and the intermediate used to produce the derivative are optionally extracted by solvent extraction, re-purification, which is well known to those skilled in the art. Isolation and purification can be performed by performing operations such as crystallization, chromatography, preparative high performance liquid chromatography, and the like.

  The pharmaceutical composition containing the 1,4-benzodiazepine derivative of the present invention or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient should be used in various dosage forms depending on the usage. Can do. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, and the like. Or it is administered parenterally.

  These pharmaceutical compositions are prepared according to pharmacologically known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives. And can be produced by appropriately mixing or diluting / dissolving with a pharmaceutical additive such as a wetting agent, an emulsifier, a dispersant, a stabilizer, a solubilizing agent.

  In the present invention, the V2 receptor agonist has an action of stimulating the V2 receptor and means acting on the V2 receptor as an agonist or a V2 receptor partial agonist. The 1,4-benzodiazepine derivative of the present invention can act as an agonist or partial agonist for the V2 receptor.

  The 1,4-benzodiazepine derivative of the present invention exhibits a strong human V2 receptor stimulating action in, for example, human V2 receptor binding experiments and V2 receptor stimulating action measurement tests. Therefore, the 1,4-benzodiazepine derivative of the present invention can significantly reduce urine output. Therefore, the 1,4-benzodiazepine derivative of the present invention can be applied to all symptoms caused by an increase in urine output. Moreover, since it has the blood factor VIII and von Willebrand factor releasing action, it can treat bleeding disorders. Therefore, the pharmaceutical composition containing the 1,4-benzodiazepine derivative of the present invention, a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient is, for example, various urination disorders, large urine or bleeding Useful for trends, frequent urination, incontinence, enuresis, central diabetes insipidus, nocturia, overactive bladder, spontaneous bleeding, hemophilia, von Willebrand disease, congenital or acquired platelet function Suitable as a therapeutic, preventive or ameliorating agent for disorders and the like.

  In addition, by administering an effective amount of the 1,4-benzodiazepine derivative of the present invention, a pharmacologically acceptable salt thereof, or a prodrug thereof, for example, it is useful for various urination disorders, large urine or bleeding tendency. Yes, treatment for urinary frequency, urinary incontinence, enuresis, central diabetes insipidus, nocturia, overactive bladder, spontaneous bleeding, hemophilia, von Willebrand disease, congenital or acquired platelet dysfunction It is possible to prevent or improve.

  In addition, according to the present invention, diseases improved by stimulating the V2 receptor include, for example, frequent urination, urinary incontinence, overactive bladder, enuresis, central diabetes insipidus, nocturia, spontaneous occurrence Diseases such as sexual bleeding, hemophilia, von Willebrand disease, congenital or acquired platelet dysfunction.

    The 1,4-benzodiazepine derivative of the present invention or a pharmacologically acceptable salt thereof, or a prodrug thereof can be used in appropriate combination with at least one of the following drugs. Drugs that can be used in combination in the present invention include adrenergic α1 receptor blockers, anticholinergics, cholinergic drugs, antispasmodics, antiandrogens, antidepressants, calcium antagonists, K-channel openers, sensory nerve inhibitors, Examples thereof include drugs suitable for central diabetes insipidus, nocturia and nocturnal enuresis, including an adrenergic β receptor agonist, an acetylcholinesterase inhibitor, an antiallergic agent and the like.

  When a compound of the present invention and one or more of the above agents are used in combination, the present invention includes simultaneous administration as a single formulation, simultaneous administration by the same or different routes of administration as separate formulations, and separate A pharmaceutical composition comprising a combination of the compound of the present invention and the above-mentioned drug, including any dosage form in which the same or different administration routes are used as a dosage form, and the dosage form is combined as described above. And dosage forms that combine separate formulations.

  When the compound of the present invention is used in combination with one or more kinds of the above-mentioned drugs, it is possible to obtain advantageous effects more than additive in terms of prevention or treatment of the above diseases. Or similarly, compared with the case where it uses independently, the usage-amount can be decreased, or the side effect of the chemical | medical agent used together can be avoided or reduced.

  Specific compounds of the drugs used in combination are exemplified as follows, but the contents of the present invention are not limited to these, and in the specific compounds, the free form and the pharmacologically Contains acceptable salts.

  Adrenaline α1 receptor blockers include terazosin, bunazosin, urapidil, tamsulosin, bunitrolol, doxazosin, prazosin, carvedilol, bevantolol, WY-21901, naphthopidyl, alfuzosin, levobunolol, silodosin, IDR-16804, fiduxosin, PM-96. S) -doxazin, KRG-3332 and the like.

  Examples of anticholinergic agents include propiverine, oxybutynin, tolterodine, solifenacin and the like.

  Examples of cholinergic agents include besacholine.

  Examples of antispasmodic agents include flavoxate.

  Antiandrogen drugs include chlormadinone acetate, allylestrenol and the like.

  Examples of antidepressants include imipramine.

  Calcium antagonists include fasudil, nifedipine, nimodipine, nilvadipine, bepridil, manidipine, varnidipine, nitrendipine, benidipine, isradipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, galopamil, diltiazepine, cilnidipine diazenidipine, Examples include pranidipine, ranolazine, IQB-875D, and iganidipine.

  Examples of the K-channel opener include NS-8, nicorandil, tirisolol, pinacidil, lebucromacarim, GKE-841, PNU-83757, NN-414, KCO-912, AZD-0947, ABT-598, and the like.

  Examples of the sensory nerve inhibitor include KW-7158, capsaicin, resiniferatoxin and the like.

  Adrenergic β receptor agonists include mabuterol, ritodrine, fenoterol, denopamine, docarpamine, clenbuterol, formoterol, procaterol, pyrbuterol, KWD-2183, xamoterol, terbutaline, tulobuterol, salmeterol, dopexamine, levalbutol -58611, armormotorol, CHF-4226, KUR-1246, KUC-7283, KTO-7924, YM-178, QAB-149, TD-3327, LY-362884, GW-427353, N-5984, KUL-7221, etc. Can be mentioned.

Examples of acetylcholinesterase inhibitors include donepezil, itopride, rivastigmine, metriphonate, galantamine, phenserine, KA-672, CHF-2819, T-82, EN-101, ZT-1, TAK-802, ladostigil and the like. .
Antiallergic agents include suplatast tosylate and the like.

  The dose of the compound of the present invention is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. In the case of oral administration, it is in the range of about 0.01 mg to about 1000 mg per day for an adult. Also in the case of administration, it can be appropriately administered in one or several divided doses in the range of about 0.01 mg to about 1000 mg per day for an adult.

  In a pharmaceutical composition comprising a combination of the compound of the present invention and at least one selected from a therapeutic agent for central diabetes insipidus other than a V2 receptor agonist, a therapeutic agent for nocturia, a therapeutic agent for nocturia and overactive bladder The dosage of the drug can be appropriately selected depending on the patient's age, sex, weight, symptoms, administration time, dosage form, administration method, drug combination, and the like.

  The 1,4-benzodiazepine derivative of the present invention showed a strong human V2 receptor stimulating action in, for example, human V2 receptor binding experiments and V2 receptor stimulating action measurement tests. Therefore, the 1,4-benzodiazepine derivative of the present invention can significantly reduce urine output. Therefore, the compound represented by the above general formula (A) of the present invention has an antidiuretic action, blood factor VIII and von Willebrand factor releasing action based on this action, and has various urination disorders and large-scale urine Also useful for bleeding tendency, frequent urination, urinary incontinence, enuresis, central diabetes insipidus, nocturia, overactive bladder, spontaneous bleeding, hemophilia, von Willebrand disease, congenital or acquired It is useful as an agent for treating or preventing platelet dysfunction.

  The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to the contents. Of the symbols used in each reference example, each example, and each table, Ref. No. Are reference example numbers, Ex. No. Represents an example number, Strc represents a chemical structural formula, Physical data represents a physical property value, and 1H-NMR represents a hydrogen nuclear magnetic resonance spectrum. CDCl3 means chloroform-d. MS means mass spectrometry. ESI means measured by electrospray ionization method.

(Reference Example 1)
tert-Butyl = (R) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate (R) -3-methyl-2,3 at room temperature , 4,5-Tetrahydro-1H-benzo [e] -1,4-diazepine (1.81 g) in tetrahydrofuran (11 mL) was added di-tert-butyl dicarbonate (2.56 g) and the solution was stirred at room temperature. Stir down for 1 hour. The reaction solution was concentrated under reduced pressure. Diethyl ether was added to the residue, the precipitate was collected by filtration, and tert-butyl = (R) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate. (2.17 g) was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Example 2)
tert-butyl = (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate ice Under cold stirring, tert-butyl = (R) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate (0.500 g) and N, N- A solution of 2-chloro-4-propoxybenzoyl chloride (0.578 g) in dichloromethane (1.0 mL) was added to a solution of diisopropylethylamine (0.997 mL) in dichloromethane (4.8 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by aminopropylsilylated silica gel column chromatography (elution solvent: ethyl acetate-hexane), and tert-butyl = (R) -1- (2-chloro-4- Propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate (0.845 g) was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Example 3)
tert-butyl = (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate 2 Tert-Butyl = (R) -1- (2-chloro-4-ethoxybenzoyl) in the same manner as in Reference Example 2 using the corresponding acid chloride instead of -chloro-4-propoxybenzoyl chloride -3-Methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Example 4)
(2-Chloro-4-propoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone under ice-cooling and stirring, tert-butyl = (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate ( To a solution of 0.840 g) in dichloromethane (1.4 mL) was added trifluoroacetic acid (1.4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate. A saturated aqueous sodium hydrogen carbonate solution was added to this solution with stirring under ice cooling, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and (2-chloro-4-propoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepine-1 -Yl) methanone (0.608 g) was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Example 5)
(2-Chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone tert-butyl = ( R) -1- (2-Chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxylate instead of the corresponding carboxy (2-chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1, 4-Diazepin-1-yl) methanone was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Example 6)
2- (4-Nitrophenoxycarbonylamino) ethyl 4-nitrophenyl carbonate Under cooling with ice, pyridine (0.0900 mL) was added to a solution of 4-nitrophenyl chloroformate (0.139 g) in dichloromethane (3.0 mL). And 2-aminoethanol (0.0350 g) were added sequentially. The mixture was stirred at room temperature for 30 minutes. 2 mol / L hydrochloric acid was added to the reaction mixture, and the organic layer was separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- (4-nitrophenoxycarbonylamino) ethyl = 4-nitrophenyl carbonate (0. 0771 g) was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Example 7)
2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino } Ethyl 4-nitrophenyl carbonate 2- (4-nitrophenoxycarbonylamino) ethyl 4-nitrophenyl carbonate (0.0771 g) in dichloromethane (2.0 mL) suspension in (2-chloro-4- Propoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone (0.0919 g) and N, N-diisopropylethylamine (0.0331 g) was added and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3- Methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} ethyl = 4-nitrophenyl carbonate (0.102 g) was obtained. The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Examples 8-1 to 8-2)
(2-Chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone and 2- (4 Using the raw materials corresponding to -nitrophenoxycarbonylamino) ethyl = 4-nitrophenyl carbonate, the compounds of Reference Examples 8-1 to 8-2 were obtained in the same manner as in Reference Example 7. These structural formulas and physical property values are shown in Table 1.

(Reference Example 9)
3-tert-butoxy-2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} propionic acid Methyl = 3-tert-butoxy-2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2 under ice-cooling and stirring , 3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate (0.778 g) in methanol (4.2 mL) in a 5 mol / L aqueous sodium hydroxide solution (0.833 mL) And the mixture was stirred at room temperature for 6 hours. Under ice-cooling and stirring, ethyl acetate and 1 mol / L hydrochloric acid were sequentially added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and 3-tert-butoxy-2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carbonyl] amino} propionic acid (0.780 g) was obtained.

(Reference Example 10)
3-tert-butoxy-2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine Methyl-4-carbonyl] amino} propionate = 3-tert-butoxy-2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5- Using a raw material corresponding to tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate, in the same manner as in Reference Example 9, 3-tert-butoxy-2-{[(R)- 1- (2-Chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionic acid was obtained. The structural formula and physical property values are shown in Table 1.

(Reference Example 11)
N- [1-tert-butoxymethyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2 , 3,5-Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide Under ice-cooling and stirring, 3-tert-butoxy-2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) ) -3-Methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionic acid (0.0700 g) and 1-ethyl-3- (3-dimethyl) To a suspension of aminopropyl) carbodiimide hydrochloride (0.0505 g) in dichloromethane (0.39 mL) was added morpholine (0.0230 mL) and the mixture was stirred at room temperature overnight. Dichloromethane and water were added to the reaction mixture, and the organic layer was separated. This organic layer was directly purified by aminopropylsilylated silica gel column chromatography (elution solvent: ethyl acetate-hexane), and N- [1-tert-butoxymethyl-2- (morpholin-4-yl) -2-oxo] Ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide (0.0671 g ) The structural formula and physical property values of the obtained compound are shown in Table 1.

(Reference Examples 12-1 to 12-16)
3-tert-butoxy-2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine In the same manner as in Reference Example 11, the compounds of Reference Examples 12-1 to 12-16 were obtained using raw materials corresponding to [-4-carbonyl] amino} propionic acid and morpholine. These structural formulas and physical property values are shown in Table 1.

Example 1
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} propionate under cooling with ice, (2-chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4 -Methyl (S) -2-isocyanatopropionate (0.180 g) was added to a solution of diazepin-1-yl) methanone (0.400 g) in dichloromethane (6.0 mL) and the reaction mixture was stirred at room temperature for 4 hours. Stir. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane), and methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl- 1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate (0.442 g) was obtained. Table 2 shows the structural formula and physical property values of the obtained compound.

(Examples 2-1 to 2-5)
(2-Chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone and methyl = (S ) The compounds of Examples 2-1 to 2-5 were obtained in the same manner as in Example 1 using the raw materials corresponding to 2-isocyanatopropionate. These structural formulas and physical property values are shown in Table 2.

(Example 3)
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} propionic acid Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5 under ice-cooling stirring -Tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate (0.389 g) in methanol (4.0 mL) was added 2 mol / L aqueous sodium hydroxide (0.616 mL) and the mixture Was stirred at room temperature for 5 hours. After adding 2 mol / L hydrochloric acid to the reaction mixture under ice cooling, the mixture was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carbonyl] amino} propionic acid (0.408 g) was obtained. Table 2 shows the structural formula and physical property values of the obtained compound.

(Examples 4-1 to 4-7)
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine In the same manner as in Example 3, the compounds of Examples 4-1 to 4-7 were obtained using the raw material corresponding to [-4-carbonyl] amino} propionate. These structural formulas and physical property values are shown in Table 2.

(Example 5)
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide N, N-Diisopropylethylamine (0.0421 g) was added to a suspension of ammonium chloride (0.0140 g) in N, N-dimethylformamide (2.5 mL) with stirring at room temperature, and the mixture was stirred. Stir vigorously for 20 minutes at room temperature (suspension A). Under stirring at room temperature, (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carbonyl] amino} propionic acid (0.100 g), hydroxybenzotriazole monohydrate (0.0499 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (0.625 g) was added and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide (0.0759 g) was obtained. Table 2 shows the structural formula and physical property values of the obtained compound.

(Examples 6-1 to 6-31)
Ammonium chloride and (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4- Diazepine-4-carbonyl] amino} In the same manner as in Example 5, using the corresponding starting material instead of propionic acid, the compounds of Examples 6-1 to 6-31 were obtained. These structural formulas and physical property values are shown in Table 2.

(Example 7)
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-Diazepine-4-carboxamide To a solution of triphosgene (0.0156 g) in chloroform (0.5 mL) under ice-cooling, N, N-diisopropylethylamine (0.0484 g) and (2-chloro-4-ethoxyphenyl)- ((R) -3-Methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone (0.0517 g) was sequentially added, and the mixture was cooled with ice. And stirred for 30 minutes. Under ice-cooling and stirring, a solution of 3-aminopiperidin-2-one (0.0273 g) in chloroform (0.50 mL) was added to this mixture. The mixture was stirred at room temperature for 14 hours. The reaction solution was purified by silica gel column chromatography (elution solvent: ethanol-ethyl acetate) and octadodecylated silica gel column chromatography (elution solvent: acetonitrile-0.1% formic acid aqueous solution), and N- (2-oxopiperidine-3 -Yl)-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide (0 0135 g). Table 2 shows the structural formula and physical property values of the obtained compound.

(Examples 8-1 to 8-2)
Corresponding instead of (2-chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone The compounds of Examples 8-1 to 8-2 were obtained in the same manner as in Example 7 using amine. These structural formulas and physical property values are shown in Table 2.

Example 9
Methyl = 2 {[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl Amino} -3-hydroxypropionate Methyl = 3-tert-butoxy-2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, under ice-cooling and stirring] To a solution of 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} propionate (0.0400 mg) in dichloromethane (0.056 mL) was added trifluoroacetic acid (0.056 mL), The solution was stirred overnight at room temperature. The reaction mixture was directly applied to silica gel and purified by aminopropylsilylated silica gel column chromatography (elution solvent: ethyl acetate-hexane), methyl-2-{[(R) -1- (2-chloro-4-ethoxy). Benzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino} -3-hydroxypropionate (0.0346 g) was obtained. Table 2 shows the structural formula and physical property values of the obtained compound.

(Examples 10-1 to 10-18)
Methyl = 3-tert-butoxy-2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4 -Diazepine-4-carbonyl] amino} propionate In place of the corresponding ether derivative, the compounds of Examples 10-1 to 10-18 were obtained in the same manner as in Example 9. These structural formulas and physical property values are shown in Table 2.

(Example 11)
Corresponding instead of (2-chloro-4-ethoxyphenyl)-((R) -3-methyl-2,3,4,5-tetrahydrobenzo [e] -1,4-diazepin-1-yl) methanone The compound of Example 11 was obtained in the same manner as in Example 7 using amine.

(Continued from Table 1)

(Continued from Table 1)

(Continued from Table 1)

(Continued from Table 1)

(Continued from Table 1)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Continued from Table 2)

(Comparative example)
The compound of the following Table 3 of the international publication 2006/104008 pamphlet was used for the comparative example compound.

(Test Example 1)
Human V2 Receptor Stimulating Action Confirmation Test Cells for human V2 receptor stimulating action confirmation test prepared by the following method were used to test the response of human V2 receptor to each test compound.
Dissolve the test compound to 10 mM with dimethyl sulfoxide, and further dilute it 10-fold using Assay buffer (0.1% BSA, 20 mM HEPES / Hank's Balanced Salt Solution, pH 7.4). Were prepared to be 0.1 nM to 10 μM, and these were used for the test.
The human V2 receptor is coupled to the Gs protein, which is one of the G proteins, to produce cyclic adenosine 3 ′, 5′-monophosphate (cAMP) via adenylate cyclase, but the Gqs chimeric protein and the human V2 receptor are produced. By co-expressing, cAMP production can be replaced by an increase in intracellular Ca ²⁺ (Mol. Pharmacol., 50, p.885-890 (1996)). With the measurement of intracellular Ca ²⁺ , the reactivity of the human V2 receptor to each test compound was quantified. Using FLIPR CALCIUM ASSAY KIT (manufactured by Molecular Devices), changes in intracellular Ca ²⁺ concentration after addition of the test compound at each concentration (0.1 nM to 10 μM) of the test compound were detected by FlexStation (manufactured by Molecular Devices). .
Intrinsic activity (IA) of the test compound was calculated assuming that the maximum response by AVP was 1.00. In addition, the EC ₅₀ value of each test compound was calculated with a full response of 100% as the maximum response due to AVP, and with a partial agonist as the maximum response of the test compound as 100%. A value showing 50% response from the concentration-response curve of the test compound was defined as an EC ₅₀ value. The obtained EC ₅₀ values are shown in Table 4 below as values of the action of stimulating the human V2 receptor.

Preparation of Human V2 Receptor Stimulation Action Confirmation Cells (HEK293 Cells Expressing Human V2 Receptor and Gqs Chimeric Protein) HEK293 cells (American Type Culture Collection) were added to 1 mM sodium amino acid (nonscientific amino acids 0.1). , Streptomycin (100 μg / mL), penicillin (manufactured by Invitrogen) (100 U / ml), 10% fetal calf serum (manufactured by Sanko Junyaku Co., Ltd.) and Eagle's Minimum Essential Medium (manufactured by EMEM, Invitrogen) The cells were cultured at 37 ° C. in a 5% CO 2 incubator. For transfection, a cell suspension was prepared to 1 × 10 ⁶ cells / mL with the above-mentioned EMEM without antibiotics using cells that reached confluent, and diluted with Opti-MEM I Reduced Serum Medium (manufactured by Invitrogen). PCI-neo / hV2 and an expression vector (pLEC-Gqs5, manufactured by Molecular Devices) inserted with a gene encoding a Gqs chimeric protein and Lipofectamine 2000 (manufactured by Invitrogen) were mixed with the cell suspension. It was. Evaluation of test compounds using cells cultured in 5% CO2 incubator for 2 days after transfection (HEK293 cells expressing human V2 receptor and Gqs chimeric protein) as cells for confirming human receptor stimulation Used for. The human V2 receptor expression plasmid vector represented by pCI-neo / hV2 was prepared by the following method.

Preparation of Human V2 Receptor Expression Plasmid Vector Human kidney-derived total RNA was converted to SuperScript II RNase H ⁻
Reverse transcription was performed with Reverse Transscriptase (manufactured by Invitrogen) and oligo dT to prepare a cDNA library. Using this cDNA library as a template, pfu DNA polymerase (manufactured by Stratagene) was used by using the forward primer shown in SEQ ID NOS: 1 to 3 below and the reverse primer shown in SEQ ID NOs: 4 to 6 below. The DNA fragment encoding the human V2 receptor was amplified by the PCR reaction. The amplified DNA fragment and a cloning plasmid vector, pCR-Blunt (manufactured by Invitrogen) were ligated according to the standard method of this kit. This ligation product was introduced into E. coli TOP10 (manufactured by Invitrogen) by a conventional method, and a transformant was selected on an LB agar medium containing 50 μg / mL kanamycin. One of the transformants was grown in liquid LB medium, and the vector was extracted and purified. This vector was cleaved with the restriction enzyme EcoRI to obtain a DNA fragment. On the other hand, pCI-neo (manufactured by Promega), which is a mammalian expression plasmid vector, was cleaved with a restriction enzyme EcoRI and subjected to Calf intestinal alkalin phosphatase treatment to prevent self-ligation. The DNA fragment obtained by this pCI-neo and the above EcoRI digestion was ligated using Quick Ligation Kit (manufactured by New England BioLabs). After this ligation product was introduced into E. coli TOP10 by a conventional method, the transformed strain was selected on an LB agar medium containing 100 μg / mL of ampicillin. One of the transformed strains was grown in a liquid LB medium, and the vector was extracted and purified. When the nucleotide sequence of the DNA fragment inserted into the multicloning site of this vector was examined, Accession No. Consistent with the human V2 receptor registered as AF030626. This human V2 receptor expression plasmid vector was designated as pCI-neo / hV2.

SEQ ID NO: 1 AGTCCGCACATCACCTCAG
SEQ ID NO: 2 ATGCTCATGGCGTCACCACAC
SEQ ID NO: 3 GCCCTCAGAACACCCTGC
SEQ ID NO: 4 GCTCCTCACGATGAAGTGTC
Sequence number 5 GCAAGACACCCACAACAGCTCC
SEQ ID NO: 6 GCTGAGCTTCTCAAAGCCCTCT

(Test Example 2)
Antidiuretic test-Confirmation test of awake antidiuretic action on water-loaded diuretic rats SD male rats (7 weeks old) were used for experiments. After fasting overnight (about 16 hours), 0.3 mg / kg of the Example compound was dissolved in a solution of dimethylacetamide (Wako Pure Chemical): 0.5% methylcellulose (Wako Pure Chemical) = 2: 98, and it was dissolved into a sonde. Was orally administered. 15 minutes after compound administration, 30 mL / kg of distilled water was orally administered (water load), and the distilled water administered at this time was used as the water load. Thereafter, the urine volume is measured every hour for up to 8 hours, and the cumulative urinary excretion is calculated as a ratio to the water load (cumulative urinary excretion rate). Used for evaluation. In calculating the time when the cumulative urinary excretion rate becomes 50%, data at two time points sandwiching the cumulative urinary excretion rate 50% were used, and the time when the cumulative urinary excretion rate 50% was calculated from a straight line connecting the two time points. The results are shown in Table 5. From this result, it was shown that the compound of the present invention has an excellent antidiuretic action.

The abbreviations used above are as follows.
AVP: arginine vasopressin [< ³ > H] -AVP: tritium-labeled vasopressin HEPES: 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid HEK: human embryonic kidney
Tris: 2-amino-2-hydroxymethyl-1,3-propanediol CHO: Chinese hamster ovary cell

(Test Example 3)
Acute toxicity test Test compounds were administered to male SD rats (250-300 g) with tracheal cannula and jugular vein cannula under urethane anesthesia (1.5 g / kg, subcutaneous administration) to give a dose of 10 mg / kg. Was dissolved in a suitable solvent and prepared via an intravenous cannula. Life or death was judged by follow-up for 1 hour. The results are as shown in Table 6. No death was observed, suggesting that the compound of the present invention has low toxicity.

(Test Example 4)
Rat Plasma Concentration-Area Under Time Curve (AUC) Measurement Test Male Sprague-Dawley (Crj: CD (SD) IGS: Charles River Japan Co., Ltd.) rats were used as experimental animals at 7 weeks of age. Rats were fasted for about 16 hours from the day before oral administration. After dissolving the test compound in N, N-dimethylacetamide, 0.5% methylcellulose 400 cp (Wako Pure Chemical Industries) was added to prepare a concentration of 1 mg / 2 mL (2/98, v / v). On the other hand, the test compound was orally administered once by a sonde at a dose of 1 mg / kg. About 200 μL of blood was collected with a syringe heparinized from the jugular vein at 15, 30 minutes, 1 and 2 hours after oral administration of the test compound. The collected blood was temporarily stored under ice cooling and centrifuged to obtain plasma. The prepared plasma was stored at 4 ° C. until measurement. To 50 μL of plasma, 350 μL of acetonitrile and 100 μL of internal standard substance solution were added, and the supernatant after centrifugation and deproteinization was used as a sample, and the plasma concentration was measured by LC / MS / MS under the following measurement conditions. The peak was identified by the mass-to-charge ratio (m / z), and the quantification was performed by the internal standard method based on the peak area ratio of the test compound to the internal standard substance. The calibration curve was created by assigning a weight of 1 / X to the linear regression equation. The area under the plasma concentration-time curve (AUC) up to the final time when the plasma concentration was quantifiable was calculated by the trapezoidal method. AUC is expressed in units of ng min / mL, and the results of each test compound are shown in Table 7. From this result, in oral administration, AUC almost twice or more as compared with the comparative example was observed, and it was confirmed that a high plasma drug concentration was obtained.
<Measurement conditions>
LC / MS / MS: Applied Biosystems API-4000TM with Agilent 1100
Column: Imtakt Cadenza 4.6x50mm C18 3um
Mobile phase
Solution A: 10 mM ammonium acetate
B solution: acetonitrile Gradient elution method:
0.0 ~ 3.0min A solution 90%
3.0-4.0 minutes A solution 90-10%
4.0-7.0 minutes A solution 10%
7.0-7.1 minutes A solution 10-90%
7.1 ～ 12.0 min A solution 90%
Temperature: 40 ° C
Flow rate: 0.5mL / min
Ionization method: ESI (+)

  The 1,4-benzodiazepine derivative of the present invention showed a strong human V2 receptor stimulating action in, for example, human V2 receptor binding experiments and V2 receptor stimulating action measurement tests. Therefore, the 1,4-benzodiazepine derivative of the present invention can significantly reduce urine output. Therefore, the 1,4-benzodiazepine derivative of the present invention has an antidiuretic action based on this action, a blood factor VIII and von Willebrand factor releasing action, and is useful for various urination disorders, large urine or bleeding tendency Treatment or prevention of frequent urination, urinary incontinence, enuresis, central diabetes insipidus, nocturia, spontaneous bleeding, hemophilia, von Willebrand disease, congenital or acquired platelet dysfunction It is suitable as.

Claims (17)

Formula (A):

[Wherein, R ¹ represents an ethyl group or an n-propyl group; R ^A represents a methyl group, a hydroxymethyl group, an isopropyl group, or an isobutyl group; R ^B represents a hydroxyl group, a methoxy group, an ethoxy group, an aziridino group, an azetidino group; Group, pyrrolidino group, morpholino group, piperidino group optionally having 1 to 2 lower alkyl groups or formula:

(Wherein R ^C is a hydrogen atom, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group), or R ^A and R ^C combine to form a trimethylene group. 1,4-benzodiazepine derivatives represented by the above, pharmacologically acceptable salts thereof, or prodrugs thereof. Formula (B):

[Wherein, R ¹ represents an ethyl group or an n-propyl group; R ^A represents a methyl group, a hydroxymethyl group, an isopropyl group, or an isobutyl group; R ^B represents a hydroxyl group, a methoxy group, an ethoxy group, an aziridino group, an azetidino group; Group, pyrrolidino group, morpholino group, piperidino group optionally having 1 to 2 lower alkyl groups or formula:

(Wherein R ^C is a hydrogen atom, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group), or R ^A and R ^C combine to form a trimethylene group. The 1,4-benzodiazepine derivative | guide_body or its pharmacologically acceptable salt of Claim 1 represented by these, or those prodrugs. R ^A is a methyl group, an isopropyl group or an isobutyl group; R ^C is a hydrogen atom, an isopropyl group or a cyclopropyl group, or R ^A and R ^C are combined to form a trimethylene group. The 1,4-benzodiazepine derivative according to 2, or a pharmacologically acceptable salt thereof, or a prodrug thereof. The 1,4-benzodiazepine derivative or pharmacologically acceptable salt thereof according to claim 1 or a prodrug thereof selected from the following group of compounds:
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} propionate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} propionate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -3-methylbutyrate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -3-methylbutyrate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -4-methylpentanate,
Methyl = (S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine -4-carbonyl] amino} -4-methylpentanate,
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} propionic acid,
(S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} propionic acid,
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -3-methylbutyric acid,
(S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -3-methylbutyric acid,
(S) -2-{[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -4-methylpentanoic acid,
(S) -2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4 -Carbonyl] amino} -4-methylpentanoic acid,
2-{[(R) -1- (2-Chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino } -3-hydroxypropionic acid,
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclobutylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopentylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclohexyl) carbamoylethyl]-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclobutylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopentylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclohexylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1-methyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1, 2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-2-methyl) propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclobutylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopentylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclohexylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (azetidine-1-carbonyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -2-methyl-1- (pyrrolidine-1-carbonyl)] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -2-methyl-1- (piperidine-1-carbonyl)] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -2-methyl-1- (morpholine-4-carbonyl)] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2- (morpholin-4-yl) -2-oxo] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
Methyl = 2 {[(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl Amino} -3-hydroxypropionate,
N- (1-carbamoyl-2-hydroxy) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- [2-hydroxy-1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopropylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclobutylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopentylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclohexylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- [1-hydroxymethyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3 , 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
Methyl = 2 {[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl Amino} -3-hydroxypropionate,
2-{[(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carbonyl] amino } -3-hydroxypropionic acid,
N- (1-carbamoyl-2-hydroxy) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- [2-hydroxy-1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopropylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclobutylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclopentylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N- [1- (N-cyclohexylcarbamoyl) -2-hydroxy] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(1-hydroxymethyl-2-oxo-2- (pyrrolidin-1-yl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2, 3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide and N- [1-hydroxymethyl-2-oxo-2- (piperidin-1-yl)] ethyl- (R) -1 -(2-Chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide. The following 1,4-benzodiazepine derivatives according to claim 4;
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [ e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl)] ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [E] -1,4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-2-methyl) propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-isopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5 -Tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N-[(S) -1- (N-cyclopropylcarbamoyl) -2-methyl] propyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3 5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N- (2-oxopiperidin-3-yl)-(R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e] -1, 4-diazepine-4-carboxamide,
N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [e ] -1,4-diazepine-4-carboxamide and N-((S) -1-carbamoyl-3-methyl) butyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl -1,2,3,5-tetrahydrobenzo [e] -1,4-diazepine-4-carboxamide. The N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-ethoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [according to claim 5. e] -1,4-diazepine-4-carboxamide. The N-((S) -1-carbamoyl) ethyl- (R) -1- (2-chloro-4-propoxybenzoyl) -3-methyl-1,2,3,5-tetrahydrobenzo [according to claim 5. e] -1,4-diazepine-4-carboxamide. A pharmaceutical composition comprising the 1,4-benzodiazepine derivative according to claim 1 or a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient. A human type 2 arginine vasopressin receptor agonist comprising the 1,4-benzodiazepine derivative or pharmacologically acceptable salt thereof according to claim 1 or a prodrug thereof as an active ingredient. A preventive or therapeutic agent for central diabetes insipidus, nocturia or nocturnal enuresis comprising the 1,4-benzodiazepine derivative according to claim 1 or a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient. The prevention of central diabetes insipidus, nocturia or nocturnal enuresis, comprising administering an effective amount of the 1,4-benzodiazepine derivative or a pharmacologically acceptable salt thereof according to claim 1 or a prodrug thereof, or Method of treatment. The 1,4-benzodiazepine derivative or a pharmacologically acceptable salt thereof according to claim 1, or a pharmacologically acceptable salt thereof, for producing a pharmaceutical composition for preventing or treating central diabetes insipidus, nocturia or nocturia Use of prodrugs. In addition, adrenergic α1 receptor blockers, anticholinergics, cholinergic drugs, antispasmodics, antiandrogens, antidepressants, calcium antagonists, K-channel openers, sensory nerve inhibitors, adrenergic beta receptor agonists, acetylcholinesterase The pharmaceutical composition according to claim 8, comprising a combination of at least one drug selected from the group consisting of an inhibitor and an antiallergic drug. In addition, adrenergic α1 receptor blockers, anticholinergics, cholinergic drugs, antispasmodics, antiandrogens, antidepressants, calcium antagonists, K-channel openers, sensory nerve inhibitors, adrenergic beta receptor agonists, acetylcholinesterase 12. Prevention or treatment of central diabetes insipidus, nocturia or nocturnal enuresis, comprising administering an effective amount of at least one agent selected from the group consisting of an inhibitor and an antiallergic agent in combination. Method. In addition, adrenergic α1 receptor blockers, anticholinergics, cholinergic drugs, antispasmodics, antiandrogens, antidepressants, calcium antagonists, K-channel openers, sensory nerve inhibitors, adrenergic beta receptor agonists, acetylcholinesterase The use according to claim 12, wherein at least one drug selected from the group consisting of an inhibitor and an antiallergic drug is used in combination. A method for preventing or treating a disease ameliorated by stimulating a V2 receptor, wherein the 1,4-benzodiazepine derivative or a pharmacologically acceptable salt thereof according to claim 1 or a prodrug thereof is effective. A method comprising administering an amount. The method according to claim 16, wherein the disease ameliorated by stimulating the V2 receptor is selected from the group of central diabetes insipidus, nocturia and nocturnal enuresis.