WO1998035941A1

WO1998035941A1 - New benzolactam derivatives and medicinal compositions containing the same

Info

Publication number: WO1998035941A1
Application number: PCT/JP1998/000597
Authority: WO
Inventors: Sanji Hagishita; Tetsuo Okada; Masafumi Fujimoto
Original assignee: Shionogi & Co., Ltd.
Priority date: 1997-02-18
Filing date: 1998-02-13
Publication date: 1998-08-20
Also published as: AU5880498A; JP2002241368A

Abstract

Compounds represented by general formula (I) or pharmacologically acceptable salts thereof, or hydrates of both, (wherein R?1 and R2¿ are each independently a hydrogen atom, a halogen atom, etc.; R3 is a lower alkyl group which may be substituted, an arylated lower alkyl group which may be substituted, etc.; R4 is NHCOR5, NHCONR9R10, etc.; R5 is a lower alkyl group which may be substituted; R?9 and R10¿ are each independently a hydrogen atom, a lower alkyl group which may be substituted, etc.; X is CH¿2?, etc.; n is 1 or 2), and medicinal compositions containing the same.

Description

TECHNICAL FIELD The present invention relates to a novel benzolactam derivative and a pharmaceutical composition containing the same.

The present invention relates to compounds useful as medicaments and uses thereof. Specifically, a novel benzolactam derivative having an anti-feeding action, an anti-myocardial infarction action, an anti-angina pectoris action, and a hypotensive action, and an anti-feeding agent containing the same, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, Regarding antihypertensive agent. Background art

Neuropeptide Y (hereinafter abbreviated as NPY) is a peptide consisting of 36 amino acids and is located in the central nervous system such as the hypothalamus, hippocampus, medulla oblongata, and spinal cord, and in peripheral tissues the heart, embryo, spleen, and gastrointestinal tract Etc. are distributed in nerve fibers of the blood vessel wall.

One of the central actions of N P Y is the feeding promoting action. It has been known that administration of NPY into the rat intraventricular and paraventricular nuclei stimulates eating behavior and increases the amount of carbohydrate ingested. It also plays an important role in regulating the release of neurotransmitters, especially in the hypothalamus.

In peripheral tissues, NPY is secreted from nerve fibers together with noradrenaline, causing smooth muscle contraction of blood vessels and the like and myocardial contraction. Noradrenaline causes transient contraction, whereas NPY has a persistent contractile action, so vasomotion is governed by NPY when noradrenaline withers due to strong or repeated stimulation It has been implicated in circulatory disorders.

In addition, depression, Alzheimer's dementia, and Parkinson's disease are known to decrease the amount of NPY in the cerebral spinal cord and increase the amount of NPY during head trauma. May be involved. Compounds having a structure similar to that of the compound of the present invention are disclosed in JP-A-H12-250354, JP-A-6-1720316, JP-A-59-172,475, JP-A-59 — 2 0 5 3 7 2, Japanese Patent Application Laid-Open No. 60-23031, Japanese Patent Application Laid-Open No. 8-2772 711, Japanese Patent Application Laid-Open No. 7-167272, and the like. These documents disclose that each compound has an antiamnesia effect, a growth hormone release promoting effect, an angiotensin I converting enzyme inhibitory effect or an atrial sodium diuretic peptide degrading enzyme inhibitory effect. Is not mentioned at all.

Examples of NPY antagonists include benzothiophene derivatives, sulfonylquinoline derivatives described in USP 5,504,941, USP 5,555,241, WO96 / 144,073, Various compounds have been reported, including benzylamine derivatives, but all have completely different structures from the compound of the present invention. Disclosure of the invention

The present application provides a novel compound having excellent NPY antagonism. Specifically, the present invention is based on formula (I):

(Wherein, R ¹ and R ² are each independently hydrogen, halogen, hydroxy, nitro, lower alkyl optionally having substituents, lower alkoxy optionally having substituents, carboxy An optionally substituted carbamoyl, an optionally substituted lower alkoxycarbonyl or an optionally substituted lower alkoxycarbonylamino,

R ³

I) lower alkyl optionally having substituent (s) (However, excluding unsubstituted methyl. The substituent herein means (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl,

(7) lower alkoxycarbonyl which may have a (S) substituent Ashiru, (9) amino, (1 0) nitro, (1 1) Shiano, (1 2) - NHC ( = NR 1 8 ) NR ¹⁹ R ²⁰ (where R ¹⁸ , R ¹⁹ and R ^{2 Q} are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) lower alkyl It is a good force Lubamoyl. ),

Aryl lower alkyl optionally having substituent (s)

(Here, the substituents are (1) halogen, (2) hydroxy, (3) benzyloxy, (4) substituent (where the substituent is lower alkoxycarbonyl, acyl, aryl, substituted amino or imino) (5) lower alkoxy optionally having a substituent, (6) carboxy, (7) lower alkoxycarbonyl,

(8) Shiano, (9) Nitro, (10) Asil,

(11) optionally substituted amino (substituent means lower alkyl, optionally substituted lower arylalkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, Acetyl is excluded), lower alkoxyl rubonyl, arylalkoxycarbonyl, lower alkylsulfonyl, optionally substituted rubamoyl),

(12) - NHC (= R 1 6) R 1 7

(Where R ¹⁶ is an imino or a substituent which may have a substituent (where the substituent is a lower alkoxycarbonyl or cyano) (where the substituent is a cyano or nitro) Is a lower alkylene which may have

R ¹⁷ is amino, lower alkylthio or aryloxy which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl),

(13) Heterocyclyl lower alkyl Or

(14) aryl which may have a substituent) or

III) heterocyclyl lower alkyl optionally having substituent (s),

R ⁴

I) N H C〇 R 5

[Where R ⁵ is

Lower alkyl optionally having substituent (s)

(Here, the substituents are (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8 ) Cycloalkenyl, (9) nitro, (10) cyano, (11) —NH C (—NR ⁶ ) NR ⁷ R 8 (where R ⁶ is hydrogen, cyano or nitro, and R ⁷ and R ⁸ are each Independently hydrogen or lower alkyl) or

(12) i) benzyloxycarbonyl, ii) acyl (but not formyl), i ii) lower alkylsulfonyl, or iv) amino having any carbamoyl which may have a substituent. ,

Aryl lower alkyl optionally having substituent (s)

(Where the substituent is halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, acysiloxy, acylthio, mercapto, cyano or nitro),

Lower alkoxy optionally having a substituent,

Aryl which may have a substituent,

Aryloxy optionally having a substituent or

Aryl lower alkoxy optionally having substituents],

II) NH C 0 NR ⁹ R ¹⁰

(Where R ⁹ and R ¹ ° are each independently hydrogen, hydroxy, halogen, acyl, lower alkyl optionally having substituent (s), lower alkyl which may have substituent (s) Lower alkyl, aryl which may have a substituent, heterocyclyl which may have a substituent, lower alkyl which may have a substituent, cyclo which may have a substituent Alkyl, arylsulfonyl which may have a substituent or amino which may have a substituent)

III) NHC (= NR n) NR ^{1 2} R ^{1 3}

(Where R ¹¹ is hydrogen, hydroxy, lower alkyl which may have a substituent, lower alkoxy which may have a substituent, amino which may have a substituent, Aryl which may have, aryl lower alkyl which may have a substituent or heterocyclyl which may have a substituent,

R ¹² and R ¹³ are each independently hydrogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), may have substituent (s) Diamino, aryl which may have a substituent, lower alkyl which may have a substituent, aryloxy which may have a substituent, heterocyclyl which may have a substituent or R ¹² is a lower alkyl which may have a substituent, or R ¹² and R ¹³ are taken together to form an optionally substituted heterocyclyl),

IV) NHCSNR ¹⁴ R ¹⁵

(Where R ¹⁴ and R ¹⁵ are each independently hydrogen, lower alkyl which may have a substituent, aryl which may have a substituent or May also be aryl lower alkyl),

V) lower alkyl optionally having substituent (s),

VI) an optionally substituted acyl,

VII) optionally substituted heterocyclylamino or

VIII) heterocyclylthio optionally having a substituent,

X is CH ₂ , S or 、,

n is 1 or 2. However, when R ³ is lower alkyl which may have a substituent, R ⁴ is NHCONR ⁹ R ^{1 G} , and R ⁹ and R ¹ . Is not an aryl group which may have a substituent,

When R 3 is unsubstituted aryl lower alkyl, and R 4 is NHCOR ⁵ , R ⁵ is not lower alkyl which may have a substituent,

When R ³ is optionally substituted heterocyclyl lower alkyl, R ⁵ is NHC 0 NR ⁹ R ¹⁰ . )

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

The present invention also provides a drug containing Compound (I) as an active ingredient, more specifically, an NP antagonist, and more specifically, an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and a hypotensive agent. Further, the present invention provides a method for suppressing eating and a method for treating myocardial infarction, angina pectoris and hypertension, characterized by administering the compound (I). In yet another aspect, the present invention provides the use of the compound (I) for producing a medicament for controlling anorexia and treating myocardial infarction, angina and hypertension. As used herein, “halogen” includes fluorine, chlorine, bromine and iodine.

"Lower alkyl" means straight-chain or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isoptyl. , Sec —butyl, tert —butyl, n —pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n —heptyl, isoheptyl, n —octyl, isooctyl, n —nonyl and n —decyl, etc. Is included.

“Lower alkyl optionally having substituent (s)” means lower alkyl optionally substituted at one or more substituents.

The "lower alkyl optionally having substituent (s)" for R ³ means that the unsubstituted methyl is Not included, examples of the substituent include: (i) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl, (7) lower alkoxycarbonyl, ( 8) may have a substituent group Ashiru, (9) Amino, (10) nitro, (11) Xia Bruno, (12) - NHC (- NR 1 8) NR 1 9 R 20 ( wherein R ^{1 8} , R ¹⁹ and R ²⁰ are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) Rubamoyl which may be substituted by lower alkyl.

When R ⁴ is “V) lower alkyl optionally having substituent (s)”, examples of the lower alkyl substituent include halogen, hydroxy, lower alkoxy, acyl, carboxyl, lower alkoxycarbonyl, and cycloalkyl. , Nitro, cyano, optionally substituted amino

(Here, the substituent is a lower alkyl, an aryl-lower alkyl which may have a substituent, and a carbamoyl which may have a substituent (where the substituent is a lower alkyl, aryl, Lower alkyl, etc.),

Carboxy, lower alkoxycarbonyl, aryl lower alkoxycarbonyl, etc.).

Examples of the substituent for the “lower alkyl optionally having substituent (s)” for R ⁵ include (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, and (5) lower alkoxy. Carbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro,

(10) Siano,

(11) -NH C (= NR ⁶ ) NR ⁷ R ⁸ (where R ⁶ is hydrogen, cyano or nitro, and R ⁷ and R ⁸ are each independently hydrogen or lower alkyl) or

(12) i) benzyloxycarbonyl, ii) acyl (but not formyl), iii) lower alkylsulfonyl or iv) amino having any of the optionally substituted rubamoyl)

And the like.

Other substituents of "lower alkyl optionally having substituent (s)" are not particularly limited. In the case where there is no bond, examples thereof include halogen, hydroxy, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, amino, nitro, cyano and the like.

The alkyl moiety of “lower alkoxy”, “lower alkoxycarbonyl” and “lower alkoxyl ryponylamino” is the same as the above “lower alkyl”. As a substituent of "lower alkoxy optionally having substituent (s)", "lower alkoxycarbonyl optionally having substituent (s)" and "lower alkoxycarbonylamino optionally having substituent (s)" Include hydroxy, halogen, lower alkoxy, acyl, carboxyl, lower alkoxycarbonyl, cycloalkyl, amino, nitro and cyano.

“Aryl” includes phenyl, naphthyl, anthracenyl, indenyl, phenanthryl and the like.

“Aryl optionally having a substituent” means a group optionally having one or more substituents at any position of the above aryl.

Examples of the substituent of the “aryl which may have a substituent” of R ⁹ and R ¹⁰ include, for example, halogen, hydroxy, lower alkyl which may have a substituent, and a substituent. Lower alkoxy, acyl, carboxy, optionally substituted lower alkoxycarbonyl, sulfate residue (〇SO ₃ H or its metal salt), tetrahydroviranyloxy, sulfamoyl, nitro, cyano An optionally substituted amino, an optionally substituted aryl (lower alkyl, halogen or hydroxy), an optionally substituted aryl (lower alkyl, halogen or hydroxy) Aryl lower alkyl, aryl lower alkoxy which may have a substituent (lower alkyl, halogen or hydroxy) and Substituent (lower alkyl, halogen or human Dorokishi) heterocyclyl may have a hetero Scicli Ruo alkoxy, and the like to which may have a substituent. It also includes aryl which is condensed with a saturated carbocycle, such as indanyl. Unless otherwise specified, other substituents of "aryl which may have a substituent (s)" include, for example, halogen, hydroxy, lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, cycloalkyl, cycloalkyl Alkenyl, acyl, amino, nitro, cyano, aryl and the like can be mentioned.

The lower alkyl portion and the aryl portion of "aryl lower alkyl" are the same as the above "lower alkyl" and "aryl", respectively.

"Aryl lower alkyl which may have a substituent (s)" means aryl lower alkyl which may be substituted with one or more substituents at any position of a lower alkyl moiety or an aryl moiety. Examples of the substituent include halogen, hydroxy, lower alkyl, lower alkoxy which may be substituted with aryl, carboxy, lower alkoxycarbonyl, acyl, cycloalkyl, cycloalkenyl, amino, nitro and cyano, unless otherwise specified. And the like.

As the substituent of the “aryl lower alkyl optionally having substituent (s)” for R ³ ,

(I) halogen, (2) hydroxy, (3) benzyloxy, (4) a substituent (where the substituent is lower alkoxycarbonyl, acyl, aryl, substituted amino or imino) Lower alkyl, (5) lower alkoxy which may have a substituent, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl,

(II) optionally substituted amino (substituent means lower alkyl, optionally substituted lower alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (However, acetyl is excluded), lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl, and optionally substituted rubamoyl),

(12)-NHC (= R ¹⁶ ) R ¹⁷

(Where R ¹⁶ is an imino or a substituent which may have a substituent (where the substituent is lower alkoxycarbonyl or cyano). Is nitro) and R ¹⁷ is a lower alkylene which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl). Or (13) heterocyclyl lower alkyl and the like.

The aryl portion of “aryloxy” is synonymous with the above “aryl”, and “aryloxy optionally having a substituent” means that aryl has one or more substituents at any position. Means good. Examples of the substituent include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, nitro, cyano and the like.

The aryl part and the lower alkyl part of "aryl lower alkoxy" are the same as the above "aryl" and "lower alkyl", respectively. “Aryl lower alkoxy which may have a substituent” means that the aryl or lower alkyl moiety may have one or more substituents at any position, and the substituent Examples thereof include halogen, hydroxy, lower alkoxy, aryl lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, nitro, cyano and the like.

“Heterocyclyl” means a heterocyclyl having at least one heteroatom in the ring arbitrarily selected from 〇, S and N. Specifically, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl , Triazinyl, pyrrolinyl, isoxazolyl, oxazolyl, oxaziazolyl, isotizazolyl, thiazolyl, thiadiazolyl, furyl, chenyl, ethyleneoxydinyl, dioxanyl, thiiranyl, oxaxiolanil, azedinidinyl, piranilinyl, piranilinyl , Morpholinyl, benzazepine, etc., monocyclic heterocyclyl and indolyl, benzimidazolyl, indazolyl, indolizinyl Quinolyl, isoquino Lil, Shin Noriniru, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridine lysinyl, chromanyl, chromenyl, benz I Soki no doubt Lil, benz O hexa benzisoxazolyl, Includes fused ring heterocyclyls such as oxadiazolyl, benzisothiazolyl, benzthiazolyl, benzthiadiazolyl, benzofuryl, benzothenyl, benzopiperazinyl, benzpiberidinyl, phthalimid and the like.

Examples of the substituent of “heterocyclyl optionally having substituent (s)” include lower alkyl, halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, aryl, substituent (halogen, hydroxy, lower alkoxycarbonyl) Optionally substituted with lower alkyl, heterocyclyl, carbamoyl, cyano, nitro, and optionally substituted (lower alkyl, halogen or hydroxy) And arylsulfonyl, oxo, and the like, and may have a substituent at one or more arbitrary positions.

The heterocyclyl part and the lower alkyl part of "heterocyclyl lower alkyl" are the same as the above "heterocyclyl" and "lower alkyl". "Heterocyclyl lower alkyl optionally having substituent (s)" means heterocyclyl lower alkyl optionally having one or more substituents at any position of heterocyclyl and lower alkyl. Examples of the substituent include the above-mentioned "heterocyclyl optionally having substituent (s)" and the substituent of "lower alkyl optionally having substituent (s)".

Heterocyclyl of "heterocyclylamino optionally having substituent (s)", "heterocyclyloxy optionally having substituent (s)" and "heterocyclylthio optionally having substituent (s)" The moieties and substituents are the same as in the above “heterocyclyl optionally having substituent (s)”. Preferred examples of the heterocyclyl moiety include imidazolyl and triazolyl, and preferred examples of the substituent include alkyl, amino and phenyl.

"Amino optionally having substituent (s)" includes substituted and unsubstituted amino,

It may have one or two substituents. Examples of the substituent include a hydroxy, a lower alkyl optionally having a substituent, and a substituent unless otherwise specified. Aryl which may be substituted, aryl lower alkyl which may have a substituent, and the like.

"Acyl" means an acyl having 1 to 10 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isoptyryl, benzoyl, 'relyl, bivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl and crotonoyl, and cyclohexyl. Xan's power Includes aliphatic acyl such as luponyl or benzoyl, aroyl and the like.

Examples of the substituent of the "optionally substituted acyl" include halogen, hydroxy, lower alkyl, lower alkoxy, ethoxylate, lower alkoxycarbonyl, acyl, and optionally substituted amino, nitro, Examples include cyano, aryl, lower aryl alkyl, and heterocyclyl.

The acyl part of “Asiloxy” and “Asilthio” is the same as the above “Asil”.

The term "optionally substituted rubamoyl" includes substituted and unsubstituted rubamoyl, and the substituents include hydroxy, lower alkyl, cycloalkyl, aryl, and substituents. And lower alkyl, amino and lower alkylamino.

"Cycloalkyl" is a carbon ring having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclopentyl, bicyclohexyl, and bicyclo Heptyl, bicyclooctyl, bicyclononyl, bicyclodecyl and the like.

The substituent of "cycloalkyl optionally having substituent (s)" includes hydroxy, halogen, lower alkyl, lower alkoxycarbonyl, lower alkoxy, aryl, heterocyclyl, etc., and one or more arbitrary Positions may be substituted with these substituents.

“Cycloalkenyl” is a carbon ring having 3 to 10 carbon atoms having one or more double bonds at any position. For example, cyclopentenyl, cyclobutenyl, cyclopentyl And phenyl, cyclohexenyl, cycloheptenyl, cycloheptenyl, cyclooctenyl, cyclohexenyl, cyclononenyl, cyclodecenyl and the like.

In the present specification, the term "compound (I)" also includes a pharmaceutically acceptable salt capable of forming each compound. Examples of “pharmaceutically acceptable salts” include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citrate, Salts of organic acids such as fumaric acid, maleic acid, and succinic acid: salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; salts of alkali metals such as sodium and potassium or calcium; Salts of alkaline earth metals such as magnesium can be mentioned.

The compound (I) of the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be bound to an arbitrary number of water molecules. In addition, the compound of the present invention can exist as an optical isomer, and the present invention includes each optically active isomer and a racemic mixture thereof. BEST MODE FOR CARRYING OUT THE INVENTION

All of the compounds (I) have an antifeedant effect, a therapeutic effect on myocardial infarction, a therapeutic effect on angina pectoris, and an antihypertensive effect. Among them, the following compounds are particularly preferred.

In equation (I),

1) R ¹ and R ² are each independently hydrogen, hydroxy, or an optionally substituted lower alkoxy (hereinafter abbreviated as R 12-1) compound, more preferably each independently A hydrogen or lower alkoxy (hereinafter abbreviated as R 12 -2)

Compounds which are particularly preferably both hydrogen (hereinafter abbreviated as R 12-3),

2) R ³ lower alkyl optionally substituted with R ³

(Here, the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) A lower alkyl optionally having a substituent (wherein the substituent is a lower alkyloxy group such as luponyl, acyl, aryl, substituted amino or imino),

(5) lower alkoxy which may have a substituent, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl,

(11) amino optionally having substituent (s)

(Here, the substituent means lower alkyl, arylalkyl which may have a substituent, lower alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl) , Lower alkylsulfonyl or optionally substituted rubamoyl),

(12)-NHC (= R ¹⁶ ) R ¹⁷

(Where R ¹⁶ is an imino or a substituent which may have a substituent (where the substituent is lower alkoxycarbonyl or cyano) (where the substituent is cyano or nitro) R ¹⁷ is a lower alkylene which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl), which is an amino, a lower alkylthio or an aryloxy which may have a substituent. Or

(13) Heterocyclyl lower alkyl)

(Hereinafter, R ³ is abbreviated as R 3-1)

Preferably, R ³ is aryl lower alkyl which may have a substituent, and the substituent is (2) hydroxy, (3) benzyloxy,

(11) amino optionally having a substituent

(Here, the substituent means lower alkyl, aryl lower alkyl which may have a substituent, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl) , A lower alkylsulfonyl or an optionally substituted rubamoyl Yes) or

(12) '— NHC (= R ^{1 6} ') R ^{1 7} '

(Where R ¹⁶ ′ is imino optionally substituted with tert-butoxycarbonyl and R ¹⁷ ′ is amino optionally substituted with tert-butoxycarbonyl)

(Hereinafter, R ³ is abbreviated as R 3-2),

More preferably, R ³ is an aryl lower alkyl which may have a substituent [wherein the substituent means a substituent (l-rubamoyl, lower-alkyl lumbamoyl, lower-alkylaminocarbamoyl or tert-butoxycarbonyl)] (Hereinafter, R ³ is abbreviated as R 3-3);

More preferably, R ³ is an aryl lower alkyl which may have a substituent [wherein the substituent is an amino which may have a substituent (lower alkyl group rubamoyl or tert-butoxycarbonyl)]. A compound (hereinafter, R ³ is abbreviated as R 3-4),

Particularly preferably, R ³ is an aryl lower alkyl which may have a substituent [wherein the substituent is an unsubstituted amino, NH C ONH—iso-Pr, NH C ONH—tert_Bu or NH B oc] (hereinafter, R ³ is abbreviated as R 3-5), 3) R ⁴ force

I) NHCOR ⁵ '

[Where R ⁵ 'is

Lower alkyl optionally having substituent (s)

(Here, the substituents are (1) nodogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8 ) Cycloalkenyl, (9) nitro, (10) cyano,

(11)-NHC (= NR ⁶ ) NR ⁷ R ⁸ (where R ⁶ is hydrogen, cyano or nitro, and R ⁷ and R ⁸ are each independently hydrogen or lower alkyl) or (12) i) benzyloxycarbonyl, ii) acyl (but not formyl), iii) lower alkylsulfonyl or iv) amino having any of carbamoyl which may have a substituent.

Lower alkoxy, aryloxy or aryl lower alkoxy],

II) NHCONR ⁹ 'R ¹ °'

(Where R ⁹ ′ and R ¹⁰ ′ each independently represent hydrogen, acyl, lower alkyl optionally having substituents, aryl lower alkyl optionally having substituents, and substituents Optionally substituted, heterocyclyl optionally substituted, heterocyclyl lower alkyl, cycloalkyl, arylsulfonyl or optionally substituted amino),

III) NH C (= NR ^{1 1} ') NR ^{1 2} ' R ^{1 3} '

(Where R ¹¹ ′ is hydrogen, lower alkyl which may have a substituent or aryl which may have a substituent, and R ¹² ′ and R ¹³ ′ each independently represent hydrogen. , Hydroxy, aryl, optionally substituted, amino or heterocyclyl) or

IV) NH CS NR ¹⁴ 'R ¹⁵ '

(Where R ¹⁴ ′ and R ¹⁵ ′ are each independently hydrogen, aryl which may have a substituent or aryl which may have a substituent) R ⁴ is abbreviation R 4 — 1)

Preferably

I) NHC 0 R ⁵ ''

(Where R 5 ″ is — NHC (= NR ⁶ ) NR ⁷ lower alkyl optionally substituted with R ⁸ (where R ⁶ is hydrogen, cyano or nitro, and R ⁷ and R ⁸ are each Independently hydrogen or lower alkyl), aryloxy or aryl lower alkoxy),

II) NHC ONR ⁹ '' R ^{1 0} '' (Where R ⁹ ″ and R ¹ o ″ are each independently (1) hydrogen, (2) lower alkyl optionally substituted with hydroxy,

(3) an aryl group which may have a substituent

(The wherein the substituent, halogen, carboxy, tetrazolyl, sulfuric ester residue (0 S_〇 ₃ H or a metal salt thereof), pyridyl, human Dorokishi, Tetorahi Dorobira two Ruokishi, Benjiruokishi, optionally substituted by halogen Lower alkoxy, sulfamoyl, nitro or lower alkylamino),

(4) cycloalkyl,

(5) optionally substituted heterocyclyl

(Where the substituent is lower alkyl, lower alkoxy, hydroxy, toluenesulfonyl; t er t-butoxycarbonylamino or aryl lower alkyl which may be substituted by amino); or carbamoyl

(6) Amino which may be replaced by aryl)

III) NHC (= NR ^{1 1} '') NR ^{1 2} '' R ^{1 3} ''

(Wherein R ^{1 1} '' is Ri a lower alkyl der have a hydrogen or human Dorokishi, R ^{1 2} '' and R ^{1 3} '' are each independently hydrogen, substituted May be reel or heterocyclyl) or

IV) NHC S NR ^{1 4} '' R ^{1 5} ''

(Where R ¹⁴ ″ and R ¹⁵ ″ are each independently hydrogen, aryl or aryl lower alkyl)

(Hereinafter, R ⁴ is abbreviated as R 4-2),

More preferably

II) NHC ONR ⁹ '''R ^{1 0} '''

(Where one of R ⁹ ′ ″ and R ¹ ° ′ ′ ′ is hydrogen, and the other is (1) phenyl or optionally substituted with lower alkyl, (2) halogen, hydroxy, nitro or lower alkylamino. (3) heterocyclyl), III) NH C (= NR ^{1 1} ''') NR ^{1 2} ''' R ^{1 3}

(Wherein R ¹ '' is Ri a lower alkyl der have a hydrogen or hydroxy, R ^{1 2} '''and R ^{1 3'} '' is one of hydrogen, the other is hydrogen, heat Dorokishi Or phenyl or benzothiazolyl which may have

IV) NHC S NR ^{1 4} '''R ^{1 5} '''

(Where R ¹⁴ '''and R ¹⁵ ''' are hydrogen and the other is phenyl or benzyl)

(Hereinafter, R ⁴ is abbreviated as R 4-3),

More preferably

II) NH C ONR ⁹ '''R ^{1 0} '

(Where one of R ⁹ ′ ″ and R ¹⁰ ′ ′ ′ is hydrogen and the other is (1) lower alkyl,

(2) phenyl optionally substituted by halogen, hydroxy, nitro or lower alkylamino or (3) heterocyclyl),

(Hereinafter, R ⁴ is abbreviated as R 4-4),

Particularly preferably

(Hereinafter, R ⁴ is abbreviated as R 4-5),

4) Compound X is CH _2,

5) a compound wherein n is 1;

6) A compound wherein R ¹ and R ² are R 12-1, and R ³ is R 3-1. More preferably R ¹ and R ² R 1 2-1, R ³ is R 3 - compound is 2, more preferably R ¹ and R ² R 1 2-2, R ³ is R 3 — A compound that is 3,

More preferably, a compound wherein R ¹ and R ² are R 12-2, and R ³ is R 3-4.

Most preferably, a compound wherein R ¹ and R ² are R 12-3 and R ³ is R 3-5,

7) a compound wherein R ¹ and R ² are R 12 -1 and R ⁴ is R 4-1

More preferably R ¹ and R ² R 1 2-1, R ⁴ is R 4 - compound is 2, more preferably R ¹ and R ² R 1 2-2, R ⁴ is R 4 — A compound that is 3,

More preferably still more preferably a compound wherein R ¹ and R ² are R 12-2 and R ⁴ is R 4-14;

Most preferably, compounds wherein R ¹ and R ² are R 12-3 and R ⁴ is R 4-5,

8) compounds wherein R ¹ and R ² are R 12 -1 and X is CH ₂

More preferably a compound wherein R ¹ and R ² are R 12-2, and X is CH ₂ ,

9) a compound wherein R ³ is R 3-1 and R ⁴ is R 4-1

Preferably a compound wherein R ³ is R 3-1 and R ⁴ is R 4-2

A compound wherein R ³ is R 31 and R ⁴ is R 4-2,

And R ³ is R 3 2 R ⁴ is R 4-2,

A compound wherein R 3 is R 3 2 and R ⁴ is R 4-3,

And R ³ is R 3 2 R ⁴ is R 4-4,

And R ³ is R 3 2 R ⁴ is R 4-5,

And R ³ is R 3 3 R ⁴ is R 4-2,

A compound wherein R 3 is R 3 3 and R ⁴ is R 4-3,

And R ³ is R 3 3 R ⁴ is R 4-4,

And R ³ is R 3 3 R ⁴ is R 4-5, A compound wherein R ³ is R 3-4 and R ⁴ is R 4-2,

A compound wherein R ³ is R 3-4 and R ⁴ is R 4-3,

More preferably R ³ is R 3- 4, compounds wherein R ⁴ is R 4-4, and most preferably R ³ is R 3- 5, compounds wherein R ⁴ is R 4-5,

10) a compound wherein R ³ is R 3-1 and X is CH ₂ ;

Preferably a compound wherein R ³ is R 3-2 and X is CH ₂ ;

A compound wherein R ³ is R 3 _ 3 and X is CH ₂ ;

More preferably, a compound wherein R ³ is R 3-4 and X is CH ₂ ,

Most preferably a compound wherein R ³ is R 3-5 and X is CH ₂ ;

1 1) a compound wherein R ⁴ is R 4-1 and X is CH ₂

Preferably, a compound wherein R ⁴ is R 4-2 and X is CH ₂ ;

More preferably, a compound wherein R ⁴ is R 4-3 and X is CH ₂ .

Most preferably a compound wherein R ⁴ is R 4-4 and X is CH ₂ ;

1 2) a compound wherein R ¹ and R ² are R 12-1, R ³ is R 3-1, and R ⁴ is R 4-1,

Preferably, a compound wherein R ¹ and R ² are R 12-1, R ³ is R 3-1 and R 4 is R 4-12,

A compound wherein R ¹ and R ² are R 12-1, R ³ is R 3-1 and R ⁴ is R 4-3,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-1 and R ⁴ is R 4-4,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-1 and R ⁴ is R 4-5,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-2, and R ⁴ is R 4-1,

R ¹ and R ² are R 12—1, R ³ is R 3—2, and R ⁴ is R 4—2 Compound,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-2, and R ⁴ is R 4-3,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-2, and R ⁴ is R 4-4;

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-2 and R ⁴ is R 4-5;

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-3, and R ⁴ is R 4-1,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3 -3 and R ⁴ is R 4-2,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3, and R ⁴ is R 4-3,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3 and R ⁴ is R 4-4,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3 and R ⁴ is R 4-5,

A compound wherein R ¹ and R ² are R 12 _ 1, R ³ is R 3-4, and R ⁴ is R 4-1,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3 -4 and R ⁴ is R 4-2

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, and R ⁴ is R 4-3,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, and R ⁴ is R 4-4,

R ¹ and R ² is R 1 2-2, R ³ is R 3- ^4, R 4 is a R 4-5 Compound,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-1,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-2,

More preferably, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-3,

Most preferably, compounds wherein R ¹ and R ² are R 12-3, R ³ is R 3-5, and R ⁴ is R 4-4,

Most preferably, compounds wherein R ¹ and R ² are R 12-3, R ³ is R 3-5, and R ⁴ is R 4-5,

1 3) R ¹ and R ² is R 1 2- 1, R ³ is R 3- 1, X is CH ₂ der Ru compound, R ¹ and R ² is R 1 2-1, A compound wherein R ³ is R 3-2 and X is CH ₂ ;

Preferably, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3 and X is CH ₂ ,

More preferably, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, and X is CH ₂ ,

Most preferably, compounds wherein R ¹ and R ² are R 12—3, R ³ is R 3—5, and X is CH ₂ ,

1 4) a compound wherein R ¹ and R ² are R 12 -1, R ⁴ is R 4-1 and X is CH ₂ ,

Preferably, a compound wherein R ¹ and R ² are R 12-1, R ⁴ is R 4-2, and X is CH ₂ ,

More preferably, a compound wherein R ¹ and R ² are R 12-2, R ⁴ is R 4-3 and X is CH ₂ , More preferably, a compound wherein R ¹ and R ² are R 12-3, R ⁴ is R 4-4, and X is CH ₂ ,

Most preferably, compounds wherein R ¹ and R ² are R 12—3, R ⁴ is R 4—5, and X is CH ₂ ,

1 5) a compound wherein R ³ is R 3-1, R ⁴ is R 4-1 and X is CH ₂ , preferably R ³ is R 3-2, and R ⁴ is R 4-1 Wherein X is CH ₂ , a compound wherein R ³ is R 3 — 3, R ⁴ is R 4-1, and X is CH ₂ ,

A compound wherein R ³ is R 3 — 4, R ⁴ is R 4-1 and X is CH ₂ ,

A compound wherein R ³ is R 3 — 5, R ⁴ is R 4-1 and X is CH ₂ ,

A compound wherein R ³ is R 3 —1, R ⁴ is R 4—2 and X is CH ₂ ,

A compound wherein R ³ is R 3 — 2, R ⁴ is R 4 — 2 and X is CH ₂ ,

A compound wherein R ³ is R 3-3, R ⁴ is R 4-2, and X is CH ₂ ,

A compound wherein R ³ is R 3-4, R ⁴ is R 4-2 and X is CH ₂ ,

A compound wherein R ³ is R 3 — 5, R ⁴ is R 4 — 2 and X is CH ₂ ,

A compound wherein R ³ is R 3-1, R ⁴ is R 4-3 and X is CH ₂ ;

A compound wherein R ³ is R 3 — 2, R ⁴ is R 4 — 3 and X is CH ₂ ,

A compound wherein R ³ is R 3 — 3, R ⁴ is R 4 — 3 and X is CH ₂ ,

A compound wherein R ³ is R 3-4, R ⁴ is R 4-3 and X is CH ₂ ,

A compound wherein R ³ is R 3-5, R ⁴ is R 4-3 and X is CH ₂ ,

A compound wherein R ³ is R 3-1, R ⁴ is R 4-4 and X is CH ₂ ;

A compound wherein R ³ is R 3-2, R ⁴ is R 4-4, and X is CH ₂ ,

A compound wherein R ³ is R 3-3, R ⁴ is R 4-4, and X is CH ₂ ,

A compound wherein R ³ is R 3-4, R ⁴ is R 4-4, and X is CH ₂ ,

A compound wherein R ³ is R 3-5, R ⁴ is R 4-4 and X is CH ₂ ,

A compound wherein R ³ is R 3-1 and R ⁴ is R 4-5 and X is CH ₂ ;

A compound wherein R ³ is R 3-2, R ⁴ is R 4-5, and X is CH, A compound wherein R ³ is R 3-3, R ⁴ is R 4-5 and X is CH ₂ , more preferably R ³ is R 3-4 and R ⁴ is R 4-5 A compound wherein X is CH ₂ ,

Most preferably, a compound wherein R ³ is R 3-5, R ⁴ is R 4-5, and X is CH ₂ ,

16) a compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-1 and R ⁴ is R 4-1;

Preferably, compounds wherein R ¹ and R ² are R 12-1, R ³ is R 3-2, and R ⁴ is R 4-11,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, and R ⁴ is R 4-1,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-1,

A compound wherein R ¹ and R ² are R 12-1, R ³ is R 3-1, and R ⁴ is R 4-2,

A compound wherein R ¹ and R ² are R 12 — 1, R ³ is R 3 — 2, and R ⁴ is R 4 -2,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, and R ⁴ is R 4-2,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-2,

R ¹ and R ² are R 12—1, R ³ is R 3—1, and R ⁴ is R 4—3 Compound,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3, and R ⁴ is R 4-3,

A compound wherein R ¹ and R ² are R 12 — 2, R ³ is R 3 — 4, and R ⁴ is R 4 — 3,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, and R ⁴ is R 4-3,

A compound wherein R ¹ and R ² are R 12 — 1, R ³ is R 3 — 1, and R ⁴ is R 4 — 4,

A compound wherein R ¹ and R ² are R 12 — 1, R ³ is R 3 — 2, and R ⁴ is R 4 — 4,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3 and R ⁴ is R 4-4,

More preferably, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, and R ⁴ is R 4-4,

Most preferably, a compound wherein R ¹ and R ² are R 12-3, R ³ is R 3-5, and R ⁴ is R 4-4,

A compound wherein R ¹ and R ² are R 12 _1, R ³ is R 3-1 and R ⁴ is R 4-5,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-2 and R ⁴ is R 4-5,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3 and R ⁴ is R 4-5,

More preferably, R ¹ and R ² are R 12-2, R ³ is R 3-4, and R ⁴ is A compound which is R 4-5,

17) a compound wherein R ¹ and R ² are R 12-1, R ³ is R 3-1, R ⁴ is R 4-1 and X is CH ₂ ;

Preferably, a compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-2, R ⁴ is R 4 -1 and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3 -3, R ⁴ is R 4-1 and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12 — 2, R ³ is R 3 — 4, R ^-1 is R 4-1, and X is CH 2,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3 — 5, R ⁴ is R 4-1 and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-1, R ⁴ is R 4-2, and X is CH ₂ ;

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3 — 2, R ⁴ is R 4-2, and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-3, R ⁴ is R 4-2 and X is CH ₂ ;

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, R ⁴ is R 4-2 and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, R ⁴ is R 4-2, and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-1, R ⁴ is R 4-3, and X is CH ₂ ,

R ¹ and R ² are R 12 2—1, R ³ is R 3—2, R ⁴ is R 4—3, A compound wherein X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3, R ⁴ is R 4-3, and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, R ⁴ is R 4-3 and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-5, R ⁴ is R 4-3, and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3-1, R ⁴ is R 4-4, and X is CH ₂ ;

A compound wherein RL and R ² are R 12-1, R ³ is R 3 — 2, R ⁴ is R 4 — 4 and X is CH ₂ ,

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3, R ⁴ is R 4-4 and X is CH ₂ ,

More preferably, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-4, R ⁴ is R 4-4, and X is CH ₂ ,

Most preferably, compounds wherein R ¹ and R ² are R 12-3, R ³ is R 3-5, R ⁴ is R 4-4 and X is CH ₂

A compound wherein R ¹ and R ² are R 12 -1, R ³ is R 3 -1, R ⁴ is R 4 -5 and X is CH,

A compound wherein R ¹ and R ² are R 12-1, R ³ is R 3-2, R ⁴ is R 4-5 and X is CH ₂ ;

A compound wherein R ¹ and R ² are R 12-2, R ³ is R 3-3, R ⁴ is R 4-5 and X is CH ₂ ;

More preferably, a compound wherein R ¹ and R ² are R 12-2, R ³ is R 3 _4, R ⁴ is R 4-5, and X is CH ₂ ,

Most preferably, R ¹ and R ² are R 12—3, R ³ is R 3—5, and R ⁴ is A compound wherein R 4—5 and X is CH ₂

Is mentioned.

Hereinafter, the method for producing the compound (I) of the present invention will be described.

R ⁴ = NH C〇 R ⁵ , NH C〇NR ⁹ R ¹⁰ , NH C (= NR ¹¹ ) NR ¹² R ¹³ , NHCSNR ¹⁴ R ¹⁵

(Wherein, R ¹ , R ² , R ³ , R ⁴ , X and n are as defined above)

[First step]

First, compound b is obtained by reducing compound a.

The reduction reaction uses, for example, palladium-carbon, triphenylphosphine-water, tin (II) chloride, lithium aluminum hydride, etc., and alcohol tetrahydrofuran such as methanol, ethanol, etc. as a solvent. The reaction may be carried out under conditions that do not impair other functional groups.

For the compound a, use the known compound described in J. Med. Chem., 28, 1511 (19985), or]. Chem. Soc. 19 Compounds synthesized by a conventional method may be used according to the method described in 69, 216.

Compound b is described in the literature (J. Org. Chem. 50, 334 (1985)), WO9404142, Chem. Pharm. , 3 1 _ (3) 1 1 2 8-1 1 4 7 (Chem.Pharm.Bull., 3_ _ (3) It can be obtained according to the method described in 1986). Therefore, if these known compounds b are used as starting materials, the first step of the reduction reaction is unnecessary, and the reaction can be started directly from the next second step.

[Second step]

Next, a substituent R ⁴ corresponding to compound b is introduced to obtain compound c. When R ⁴ is NHCOR ⁵ , compound b has an acetic acid derivative (eg, guanidinoacetic acid, (1—trityl—1H—imidazo-l- 4-yl) acetic acid, N—C bz _ i3— Alanine) to produce the target compound by a coupling reaction. Using DCC (dicyclohexylcarbodiimide), WSCD (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), DPPA (diphenylphosphoryl azide), etc. Then, the reaction may be carried out using ice-cooled to room temperature, preferably ice-cooled, for several tens of hours using tetrahydrofuran, dimethylformamide, getyl ether, dichloromethane, or the like. If necessary, triethylamine, dimethylaminopyridine or the like may be used as a catalyst, and the reaction may be carried out in the presence of 1-hydroxybenzotriazole.

The amide compound can be prepared by a conventional method using an ordinary acylating agent corresponding to the target compound (for example, acid chlorides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride, active esters, etc.). Can be manufactured.

Furthermore, an alkyl carbamate compound group can be obtained by reacting compound b with a carbonic acid carbonate (eg, alkyl chlorocarbonate, arylalkyl carbonate). In this case, the reaction may be carried out using ethyl acetate, dioxane, acetonitrile or the like as a solvent in the presence of a base such as carbon dioxide, sodium hydroxide, or triethylamine.

When the substituent R ⁴ is NHCONR ⁹ R ^{1 G} , compound b is an isocyanate compound having a substituent according to the target compound (for example, lower alkyl isocyanate, aryl isocyanate, etc.) ) To give compound c. Acetonitrile, dimethylformamide, methylene chloride, tetrahydrofuran, etc. are used as the solvent, and if necessary, triethylamine is used as the catalyst, and the reaction is carried out under ice-cooling to warming, preferably around room temperature for several tens of minutes to several days. It should be done.

Compound b and a phenyl carbonate compound having a substituent corresponding to the target compound are mixed in a solvent such as dimethylformamide or acetonitrile under ice-cooling to heating. After reacting for several hours to several tens of hours, the target compound can be obtained by reacting with an amino having a substituent corresponding to the target compound. If necessary, if triethylamine is used as a catalyst, the reaction can proceed favorably.

Further, after reacting compound b with carbonyldiimidazole, phosgene, phenyl chlorocarbonate or the like, an amino compound (for example, aniline which may have a substituent, The compound of interest can also be obtained by the reaction of aminobenzothiazole, lower alkylamine, etc. The reaction may be carried out using acetonitrile, tetrahydrofuran, or the like as a solvent, and using triethylamine as a catalyst, if necessary, under ice-cooling to heating, preferably at room temperature for several tens to several tens of hours. „

When R ⁴ is NHCSNR ¹⁴ R ¹⁵ , the compound b and an isothiocyanate compound having a substituent corresponding to the target compound can be obtained by cooling the compound b with ice-cooling using acetonitrile, dimethylformamide, tetrahydrofuran or the like as a solvent. The reaction may be carried out under heating, preferably around room temperature, for several hours to several tens of hours.

Compound b, thiocarbodilimidazole, and an amino compound having a substituent corresponding to the target compound are reacted in a solvent such as acetonitrile and tetrahydrofuran at 180 ° C. to room temperature for several minutes to several hours. To obtain the desired compound.

When R ⁴ is NHC (= NRH) NR ¹² R ¹³ , for example, the compound obtained by the above-mentioned method wherein R ⁴ is a thiolide and methyl iodide are mixed in a solvent such as acetonitrile under ice-cooling to room temperature. The reaction is preferably performed at around room temperature for several minutes to several hours. The thus obtained thiomethyl compound and the amine compound corresponding to the target compound can be obtained by using methanol, ethanol, or the like as a solvent at room temperature to under heating, preferably at about 50 to 80 ° C for several tens to several hours. The desired compound may be obtained by the reaction.

Further, compound b and a hydrogen iodide salt of a methylisothiourea compound (eg, 3- (thiazole-2-yl) methylisothiourea, 3-phenylmethylisothiourea, etc.) By heating to reflux for several tens of hours to several days in You can get things.

When the amino group and R ⁴ in the compound b, first introducing a group R ^'1' convertible to R ^4, oxidation at an appropriate stage, reduction, alkylation, hydrolysis, Ashiru of Ammi de reduction, halo The compound may be converted to R ⁴ by a known reaction such as genation or sulfonylation.

For example, when R ⁴ ′ has hydroxy as a substituent and the substituent of R ⁴ is a sulfate residue, the compound having R ⁴ ′ is converted to a sulfur trioxide pyridine complex in a solvent such as pyridine. In addition, the mixture is stirred under heating at 0 ° C for several tens of hours to several days. Further sodium reduction hydroxide if necessary, R ⁴ is dissolved in a solution such as potassium hydroxide to obtain a compound which is a sulfuric acid ester residue (OS 0 ₃ H or a metal salt).

When R ⁴ ′ has hydroxy as a substituent and the desired substituent of R is alkoxyalkyl which may be substituted, potassium carbonate and an alkyl corresponding to the target compound are dissolved in a solvent such as acetone. Add 8 lights and heat for several hours to several days to obtain the target compound.

When R ⁴ ′ has ditrogandino as a substituent and the intended substituent of R ⁴ is guanidino, the compound having R ⁴ ′ is prepared by a conventional method in a solvent such as acetic acid Z-methanol. Reduction using a reducing agent such as palladium-carbon gives the target compound in which R ⁴ is guanidino.

When R ⁴ ′ has acetylthio as a substituent and the target substituent of R ⁴ is mercapto, a compound having R ⁴ ′ is degassed with ethanol and degassed aqueous sodium hydroxide solution, etc. When the reaction is carried out at 0 ° C. under heating for several tens of minutes to several tens of hours, the desired compound having R ⁴ can be obtained.

R ⁴ 'is has a terminal amino, when end of R ⁴ of interest is amino-de, R ^4' in the compound having the compound and force Ppuri ing reagent having a carboxylic acid corresponding to the desired compound Is reacted under ice-cooling to room temperature for several hours to several tens of hours using dry tetrahydrofuran or the like as a solvent to obtain the desired compound having R ⁴ . If necessary, a catalyst such as triethylamine or dimethylaminopyridine may be used. The reaction may be performed in the presence of 1-hydroxybenzotriazole.

Further, the compound having R ⁴ ′ and the substituted isocyanate corresponding to the target compound may be reacted in a solvent such as dimethylformamide or tetrahydrofuran at 0 ° C. to room temperature for several tens minutes to several hours, and acetyl chloride may be used. The acylation may be carried out using a commonly used acylating agent such as

When the terminal of R ⁴ ′ is amino and the terminal of R ⁴ is lower alkylsulfonyl, the lower alkylsulfonyl chloride corresponding to the target compound is added to a solution of the compound having R ⁴ ′ in tetrahydrofuran, dimethylformamide, or the like. Then, a solution of the compound R ⁴ in tetrahydrofuran, dimethylformamide, or the like is added, and the mixture is reacted under ice-cooling to room temperature for several minutes to several hours to obtain a compound having the desired R ⁴ .

R ⁴ 'end of a Amino, when end of R ⁴ is Ru may Guanijino der substituted, R ^4' compounds which may have a substituent phenylene Ruisourea compound having (e.g. The desired compound can be obtained by reacting N-cyano-N-methyl _ {1-phenylisodiarea) in an alcohol such as ethanol or propanol at room temperature to 130 ° C for several tens of hours to several days. . The reaction can proceed favorably if triethylamine is used as necessary.

[Third step]

Finally, compound c is subjected to a substitution reaction of R ³ to obtain compound (I).

Compound c and a halogen derivative having a substituent corresponding to the target compound (for example, lower alkyl halide, aryl halide, aryl lower alkyl halide, heterocyclyl lower alkyl halide, etc.) are subjected to an N-alkylation reaction, Produce compound (I). N—Alkylation is carried out by potassium carbonate, potassium hydride, sodium hydride, potassium hydroxide, n-tetrabutylammonium halide, and tert—potassium butyl alcohol. Using tetrahydrofuran, dioxane, getyl ether, dimethylformamide, etc. under ice-cooling to room temperature, preferably around room temperature for several tens minutes to several tens of hours. When introducing a substituent R ^3, first introducing a group R ³ 'convertible to R ^3, oxidation at an appropriate stage, reduction, alkylation, hydrolysis, Ashiru of Ammi de, halogenation, sulfonyl The compound may be converted to R ³ by a known reaction such as hydrolysis.

For example, when the terminal of R ³ ′ is amino and the target R ³ has a sulfonamide bond, the compound having R ³ ′ and the sulfonyl chloride derivative having the target substituent can be obtained by using tetrahydrofuran, benzene, etc. The reaction can be carried out at −80 ° C. in the presence of a catalyst such as triethylamine, dimethylaminopyridine or the like at −80 ° C. (： 0 ° C. for several tens of minutes to several hours) to obtain a substituted or disubstituted sulfonamide. it can.

Further, 'a terminal Amino for, when end of R ³ of interest is Guanijino, in a solvent such as dimethyl formamidine de, under ice-cooling and room temperature under, R ³ preferably at about room temperature' R ³ a The guanidine compound can be produced by reacting the compound having the compound with the amidine compound for several hours to several days. Examples of the amidine compound include pyrazolylamidines (eg, N, N′-bis-amidinopyrazole, N, N′-bis-Cbz methylthioamidine) and nitroguanidines (eg, methylthionitroamidine).

When the terminal of R ³ ′ is cyano and the terminal of the intended substituent R ³ is amidino, first, an alcohol is added under an acid catalyst such as hydrochloric acid to obtain an imidate compound. Next, the desired compound is obtained by reacting with an amino compound such as ammonium chloride for several hours at room temperature to 100 ° C using ethanol or the like as a solvent.

An isocyanate or isothiocyanate can be reacted with a compound in which the terminal of R ³ ′ is amino to obtain a peridode compound or a thioperido compound. When the terminal of R ³ 'is amino and the desired substituent R ³ is cyanoguanidino or nitroamidino, diphenylcyanocarboimidate, 1,1-dimercapto-12-nitroethane, etc. are reacted. To synthesize a phenoxy compound and a thiomethyl compound. Thereafter, the desired compound is obtained by reacting with an amino compound having a desired substituent in a solvent such as methanol at room temperature to heating. R ⁴ == lower alkyl optionally having substituent (s)

(Wherein, RR ² , R ³ , R ⁴ , X and n are as defined above, and Ha 1 represents halogen)

First, a known compound d described in J. Med. Chem., 28, 1511 (1895) is reacted with a cyano compound to obtain a compound e. Examples of the cyano compound include sodium cyanide, potassium cyanide, and copper cyanide. Next, the compound e is subjected to a reaction such as hydrolysis and reduction by a conventional method, and is subjected to a conversion reaction to R ^{4 in} the same manner as described above to obtain a compound c. Finally, the compound (I) is obtained by subjecting R ^{3 to} a substitution reaction in the same manner as described above.

Compound (I) can be produced by the above-mentioned method, but can also be produced by exchanging each step according to the reaction. For example, it can be obtained by first subjecting compound a or compound e to the same substitution reaction of R ³ as described above, then reducing, and finally subjecting the same to a conversion reaction to R ⁴ as described above. .

For compounds having a substituent (for example, hydroxy, amino, etc.) that hinders the reaction, the group is protected with an appropriate protecting group in advance, and acid treatment or the like is performed at an appropriate stage. The protecting group may be removed according to the conventional method.

Examples of the hydroxy protecting group include lower alkyl, aralkyl (benzyl and the like), trialkylsilyl (tert-butyldimethylsilyl and the like), alkoxyalkyl (methoxymethyl and the like), tetrahydroviranyl, isyl (acetyl and the like), and alkylsulfonyl. (Methanesulfonyl, trifluoromethanesulfonyl, etc.).

Examples of the protecting group for amino include lower alkoxycarbonyl (such as tert-butylcarbonyl), diaralkyloxycarbonyl (such as benzyloxycarbonyl), and amide. (Phthalimid and the like).

The present compound (I) exhibits a strong NPY antagonistic activity and can be administered as a medicament to animals containing humans.

The compound of the present invention as an N P Y antagonist is applicable as an antifeedant, and is useful for the treatment and / or prevention of obesity, bulimia and anorexia nervous in which N P Y is involved. Also, cardiovascular diseases such as myocardial infarction, angina pectoris, congestive heart failure, hypertension, arrhythmia, arteriosclerosis, organ circulatory failure based on vasospasm, bronchial asthma, diabetes, schizophrenia, depression, Alzheimer's dementia , Parkinson's disease, sleep disorders, gastrointestinal motility disorders, sexual dysfunction, inflammation, respiratory diseases, hormonal abnormalities, etc., and can be used for Z or prevention.

When the compound (I) of the present invention is administered as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina, or a hypotensive agent, it can be administered either orally or parenterally. Oral administration may be carried out according to a conventional method by preparing a tablet, granule, powder, capsule, pill, liquid, syrup, buccal, sublingual or the like in a usual dosage form. For parenteral administration, any commonly used dosage form, such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents and inhalants, can be suitably administered. In particular, oral administration is preferred.

If necessary, an effective amount of the compound (I) of the present invention is mixed with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants and diluents which are suitable for the dosage form. It can be a pharmaceutical preparation. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.

Specifically, excipients such as lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose, binders such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone, disintegrants As carboxymethylcellulose, carboxymethylcellulose sodium, starch, sodium alginate, powdered agar or lauryl sulfate Lubricants include talc, magnesium stearate, and McGall gall. As a suppository base, cocoa butter, Mackerel gall, methyl cellulose, or the like can be used. When prepared as a liquid or emulsion or suspending injection, a commonly used solubilizing agent, suspending agent, emulsifier, stabilizer, preservative, isotonic agent, etc. may be appropriately used. It may be added, and in the case of oral administration, a flavoring agent, a fragrance and the like may be added.

The dose of the compound (I) of the present invention as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and an antihypertensive agent depends on the patient's age, body weight, type and degree of disease, administration route, and the like. It is desirable to set above, but for oral administration to adults, it is usually 0.05 to 100 mg Zk gZ days, preferably within the range of 0.1 to 1 O mg / kg / day . In the case of parenteral administration, the power varies greatly depending on the route of administration. Usually, it is in the range of 0.05 to 10 mgZkg / day, preferably in the range of 0.01 to 1 mgZkg / day. It may be administered once or several times a day.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the present invention. Example

Abbreviations used in the examples have the following meanings

B n benzyl

B o c t e r t —butoxycarbonyl

B u butyl

C b z benzyloxycarponyl

c-P cyclopropyl

E t etil

i-P-isopropyl

M e methyl M s methanesulfonyl

n-P r n—propyl

P h phenyl

t-B u t e r t —butyl

T e t tetrazolyl

T s Toluenesulfonyl

T r triphenylmethyl

T H P Tetrahidrobiranil

DME 1, 2—Dimetoxetane

D M F N, N-dimethylformamide

DM S O dimethyl sulfoxide

TBS tert Monobutyldimethylsilyl Example 1 1 — (3-(tert-butoxycarbonylamino benzyl))-3-(3-tylureido) 1, 2, 3, 4, 5-tetrahydro 1 H-1_- Synthesis of Benzozepine-2-one (1-1)

(Step 1) 3 _ (3-Methylureide) — 23,4,5—Tetrahydro H-1 monobenzazepine_2-one (Compound 2)

Under ice-cooling, methyl isocyanate was converted to the compound 1 (9.08 mmol) described in the literature (J. Org. Chem., 50, 348 (19985)). After dropwise addition to a dimethylformamide solution (20.0 ml), the mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, the resulting precipitate was filtered, and the residue was washed with a 10% aqueous sodium hydroxide solution, washed with water and dried to obtain the title compound. Yield 68.9% mp. 25 6-260 ° C (decomposition)

! H-NMRCCDCLs) δ: 1.85 (lH, m), 2.32 (lH, m), 2.50 (3H, s), 2.60-2.73 (2H, m), 4.08 (lH, m), 5.98 (lH, dd , J = 4.5 Hz, 8.6 Hz), 6.10 (lH, d, J = 8.1 Hz), 7.12 (lH, td, J = 1.5 Hz, 7.5 Hz), 7.23-7.30 (2H, m), 9.78 (lH , brs)

IR max (KBr): 3393, 3319, 3174,3140,3085, 2939,2853,1686,1658.1634,1561 cm "

Elemental analysis: (as C HisNsOs)

Obtained value: (, 61.52; 11, 6.56 ;: ^, 18.06

Calculated values: 0,61.79; 11, 6.48;: ^, 18.01

(2nd step) Compound (I 1)

Under ice cooling, potassium hydroxide powder (0.613 mmo :) was mixed with compound 2 (0.429 mmo1) obtained in the first step and tetra-n-butylammonium bromide. The reaction mixture was added to a solution of meta- (tert-butoxycarbonylamino) benzyl bromide in dimethylformamide (5.0 ml), and stirred at room temperature for 2 hours. The organic layer was washed with water, dried (anhydrous magnesium sulfate), and the solvent was distilled off.The residue was purified by silica gel chromatography (ethyl acetate, Zn-hexane = 30/1) to obtain the title compound.

The meta- (tert-butoxycarbonylamino) benzyl bromide used was synthesized by a conventional method using 3-aminobenzyl alcohol.

Yield 6 8.9% amorphus

! H-NMR (CDCl3) δ: 1.47 (9H, s), 2.00 (lH, m), 2.30-2.90 (3H, m), 2.53 (3H, s), 4.62 (lH: m), 4.68 (lH, d, J = 16.2Hz), 5.38 (lH, d, J = 16.0Hz), 6.19 (lH, m), 6.86 (lH, d, J = 7.8Hz) _: OAV £ yichi: fcyl re J i

IR v max (KBr): 3375, 3285, 2961, 2934, 1665, 1642, 1602, 1556 cm ¹ Elemental analysis: (as dsHMN Os.O.lSCHCl ³ )

Obtained value: (3, 59.77; 11, 7.25;, 15.52)

Calculated value: 〇, 59.83; 11,7.23; 1 ^ 15.38 Example 4 3- (3-Methyl-perido) 1-111 ((1-naphthyl) methyl) 1-2,3,4,5-tetrahydro-1H-1 —Total yield of benzozepine-1 2-one (1-4) 82.5% amorphous

O-NMRCCDCb) δ: 1.87 (lH, m) ₎ 2.34 (lH, m), 2.51 (2H, m), 2.71 (3H, d, J = 5.1Hz), 4.39 (lH, m), 4.54 (lH, m), 5.35 (lH, d, J = 15.3 Hz), 5.49 (lH, d, J = 8.1 Hz), 5.73 (lH, d, J = 15.3 Hz), 7.06-8.09 (llH, m)

IR record max (KBr): 3412,3368,2943,1635,1600,1546cm ¹

Elementary analysis: (as ^{_{^{_{_{C 2 3 H 2 3 N 3}}}}} O 2 .0.15H 2 O)

Found: C, 73.41; H, 6.34; N, 11.17

Calculated value: 〇, 73.44; 11,6.24; 1 ^, 11.17 Example 51 1— (4— (tert—butyl) benzyl) 13— (3-Methyl pereido) 12,3,4,5—tetrahydro-1 Synthesis of 1 H— 1 —Benzazepine-1-one (I-5)

Yield 92.5% m p -2 4 7 -2 49 ° C

! H-NMRCCDCh) δ: 1.28 (9H, s), 1.98 (lH, m), 2.44-2.60 (3H, m), 2.68 (3H, d, J = 4.5 Hz), 4.48 (lH, brs), 4.91 (lH, d, J = 14.7Hz), 5.09 (lH, d, J = 15.0Hz), 5.55 (lH, brs), 7.12-7.30 (8H, m)

IR v max (KBr): 3400, 3317, 2960, 1689, 1635, 1599, 1550cm- ¹

Elementary analysis: (as _{_{_{_{C 23 H 29 N 3 0 2}}}} ) Observed value: (:, 72.69; 11,7.76; 1 ^, 11.04

Calculated value: (:, 72.79; 11,7.70;, 11.07) Example 6 3 — (3-Methylureido) 1-1— (2-quinolylmethyl) —2,3,4,5—Tetrahydro-1H—1— Synthesis of Benzozepin-1-one (1-6) Yield 82.5% Amorphous

'.Eta. negation _{R (CDC1 3) (5:} 1.93-2.03 (lH, m), 2.57-2.68 (5H, m), 3.14-3.27 (lH, m), 4.47 (lH, b rs), 4.53-4.62 (lH, m), 5.27 (lH, d, J = 15.9Hz), 5.40 (lH, d, J = 15.9Hz), 5.51 (lH, brs), 7.1

2-7.23 (4H, m), 7.46 (lH, d, J = 8.4Hz), 7.51 (lH, t, J = 8.1Hz), 7.68 (lH, td, J = 1.5,8.1Hz),

7.79 (lH, d, J = 7.5Hz), 7.99 (lH, d, J = 8.4Hz), 8.13 (lH, d, J = 8.4Hz)

IR record max KBr SSTT ^ OSS ^ SS SGSJGASJGOC SOScm- ¹

Elementary analysis: (as _{_{^{_{C 22 H23N4O3.0.15C 6 Hi 4 .0.3H 2}}}} O)

Obtained value: (3, 69.64; 11, 6.30 ;; ^, 13.94

Calculated value:, 69.85;! ¾, 6.58 ^, 14.23 Example 7 1— (Bis (4-fluorophenyl) methyl-3— (3-methylperido) —2,3,4,5—Tetrahydro 1 H—1 —Synthesis of Benzazepine 1-2-one (I-17)

Yield 7 2.3% m p. 2 35-2 38 ° C

! H-NMRCCDCls) δ: 1.83-1.91 (lH, m), 2.39-2.48 (3H, m), 2.70 (3H, d, J = 5.1Hz), 4.37 (l

H, m), 4.48-4.56 (lH, m), 5.36 (lH, d, J = 8.1Hz), 6.86 (2H, t, J = 8.7Hz), 6.95 (lH, d, J = 7.5

Hz), 7.03-7.11 (7H, m), 7.28-7.32 (2H, m)

IR v max (KBr): 3416, 3295, 1651, 1604, 1556, 1508cm ¹

Elementary analysis: (as _{_{_{_{C 25 H 23 N 3 0 2}}}} F 2)

Found: C, 69.00; H, 5 · 58; N, 9 · 80; F, 8.73

Calculated: C, 68.95; H, 5.32; N, 9.65; F, 8.45 ΐ) 9 (∞'HI) 9S '(ra'HI) mu' (™ 'HS) 09-0 2'(∞'Ηΐ) 96 · ΐ: 9 ( ^ε ΐΟ (ΙΟ) called Ν.Ηι

Do 0 I 1-9 0 I-ci ui% 8 "6 L cable St ^ ω (0 I-I)-Z-<7 /, ^^ ΐ —H i —Mouth s' 'ε' ζ-( ^ ^ (-^^-£)-ε — (κ く (二 Qi ψ ^ κ, く) 一 Ν— ε)-I ~~ Wm ε6ε = + [Η + Μ]

_I .uioi _t .gx '^ 09T'lS9l' _i LZ _i 9T'i'SAlO8LlO86Z'ei88'8S ^ 8: (-ia¾) x¾∞ HI

( ^m 'H ^) l8'L-L9-A'(∞'H ^) Si''Z _i -8T'L '( ^z H9 "8T = f'P'HI) SS'9'(ZH0'8 = f'VHS) I9'S '(s>iq'HI)9''( ^ζ Η9 · εΐ = ΓΡ'ΗΤ) 3' (™ 'Ηΐ) 6 • 98't''( ^z H9' ^ = f '' HS) S ₁ L'S '( ^ra ' HS) 6i-3-8 ^ -S '(∞'Hl) S0-Z-68-I ^: P ( ^ε Ι3 (Ι0) Η Η- Hi ϋ I% I 9 South ¾ι

'' ε 'ζ -Ίί ^^ Η ϊ ΐΓ ^^-τ-(ίΐ ^ ί ^^-ζ) one ε ~~ 6ΈΜΜ i 9'H ^: S8'S / 3: ¾ 意 ^

(Tsuma 0 ^Ζ ΗΓΟ '"Η ⁹ 0 0 · εο ^ε Ν Η ⁹ ): ϊ! ½ Mine i-∞3nsi 9Sr τ' 9r 98s's Go ss: (jgra) xBra HI

(αι'ΗΙΐ) —M -ΪΓΖ ΟΗ

_{Z / -8 = p'p'HS) e8'9 '} (sjq'Hl) Ai''e' (z H ^ 'i'I = f'P'HT) TrS'(s' HS) T0'e '(zHA ^ I = f'P'HT) SZ'(∞'Ηί) ί ^ · '(zHZ S = f'P'HS) U'S'(∞'H £) 6 S '(∞'HT) S8 -I: 9 (αθ) so-called Ν

Otsu 1ίϊ% · 8 6 South Mr

^

(8-i) i- z-aa--T -HT-OH ^ 6 ^-S '' ε 'z one (H ^^ t ^ r-^^-s) one ε— (ir ^- ^ Γ ^ ν- ^)-ι 8 mm.

Z, 6S00 / 86df / XDd If6S £ / 86 OM

AV ½6S £ / O-I / l:> d

X 3Hΐ 99 Z

II

Ma S £ / OAV one 6soifcyJDd Yanagi SS ¥ ∞ ΐ L

w¾ 遴 ¾ί η ψ Ί times ε

00 CD

CD

¾-

Dimension I

O 〇

— Times

2- 19ί

¾ challenge ) (,), ddJ28HZHm =

(¾242333CWN0 t τFactory,

Observed: (3, 71.55; 11, 5.91; ^ 10.69

Calculated value: (, 71.80; 11, 5.77; ^^, 10.47

(Second step) 3- (3- (4-Benzyloxy) phenylureido) 1-1-1 (3-phthalimidopropyl) 1,2,3,4,5-tetrahydro-1H-1-Benazezepin-2-one (Compound 4)

In a nitrogen stream, at 0 ° C, sodium hydride (0.748 mm o 1) was added to a solution of compound 3 (0.665 mm o 1) obtained in the first step in dimethylformamide (5 O ml). ) Was added and the mixture was stirred at that temperature for 1 hour, and then N- (3-bromopropyl) phthalimide (0.778 mmol) was added in 30 minutes. After stirring at room temperature for 1 hour, bring the temperature to 0 ° C again, and add sodium hydride (0.325 mmol) and N— (3-bromopropyl) phthalimid (0.398 mmol) Then, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (form-form Z methanol = 56 Z 1).

Yield 80.0% amorphous

Ή-Maraudal R (CDC1 ₃ ) (5: 1.87-1.99 (3H, m), 2.54-2.66 (2H, m), 2.92 (3H, m), 3.54 (lH, m), 3.6 4 (2H, t, J = 7.5Hz), 4.39 (lH, m), 5.00 (2H, s), 6.87 (2H, d, J = 8.1Hz), 7.12-7.43 (llH, m), 7.67 (2H, m), 7.78 ( 2H, m)

IR record max (KBr): 3376,2940, 1771,1712, 1649, 1601,1546, 1509cm ¹

Elementary analysis: (as _{_{_{_{C 35 H 32 N4O 5 .0.lC 6}}}} Hi 4 .0.3H2O)

Found: 71.03; 11, 5.85; 9.13 Calculated values: J, 70.95; 11, 5.69;, 9.30

(Third step) Compound (1-16)

Hydrazine monohydrate (80 mg) was added to a solution of compound 4 (0.5 1 mmo 1) obtained in the second step in ethanol (10.O ml), and the solution was added at 110 ° C. Stirred for hours. After cooling, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate-methanol. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform form Z methanol = 10/1-5/1) to give the title compound.

Yield 72.0% amorphous

! H-NMRCCDCls) δ: 1.70 (2H, m), 1.90 (2H, m), 2.50-2.77 (6H, m), 3.57 (lH, m), 4.28 (l

H, m), 4.43 (lH _> m), 5.00 (2H, s), 6.17 (lH, brs), 6.87 (2H ₎ d, J = 9.0Hz, 7.16-7.43 (12H, m)

IR v max (KBr): 3398 , 3061,3033, 2932, 2862, 1648, 1601,1551,1509cm 1 Elementary analysis: (as _{_{_{_{C 27 H 30 N 4 O 3}}}} .0.2C 6 H 14 .1.3H 2 O )

Observed value: (2, 67.82; 11,7.39 ^, 11.59

Calculated value: (, 67.85; 11,7.15;, 11.22 Example 17 3-(3- (4-benzyloxy) phenylureido)-1-1 (3-

N ', N' 'one (Gee t rt —butoxy 7 nil)

3,4,5 —Synthesis of 1H—1—Benso'azepin-2-one (I—17)

Compound (1 — 16) (0.22 mmo 1) and compound N, Ν ′ described in literature (Tetrahedron. Lett., 34, 3389 (1993).) A solution of bis-Boc-amidinovirazole (0.243 mmo1) in dimethylformamide (3.0 ml) was stirred at room temperature for 1 week. The solvent was distilled off, and the residue was purified by silica gel chromatography (formin methanol = 150/1) to give the title compound.

Yield 64.2% amorphous

O-NMRCCDCh) (5: 1.47 (9H, s), 1.49 (9H, s), 1.82 (2H, m), 2.56-2.65 (2H, m), 2.83 (lH, m), 3.35-3.63 (3H, m), 4.30 (lH, m), 4.43 (lH, m), 5.02 (2H, s) ₎ 6.00 (lH, brs), 6.69 (lH, br s), 6.89 (2H, d, J = 8.6Hz) , 7.15-7.44 (llH, m), 8.40 (lH, m), 11.45 (lH, brs)

IR record max (KBr): 3324,2982,1717,1634,1511cm- ¹

Elemental analysis: (as C38H48N6O7.0.15C6HW.0.5H2O)

Observed: (], 64.85; 11,7.20; 1 ^, 11.85

Calculated value: (, 64.64; 11, 7.13; 1 ^, 11.64 Example 18 1 — (3-N ', N' '(di-tert-butoxycarbonyl) guanidinopropyl) 1 3 _ (3- (4-hydroxy) Hue: Nil-Reid 2, 3,

4,5—Tetrahydro-1-H 1 —Be: Synthesis of zazepin_2-2-one (I—18) Compound (1—17) (0.13 mmo 1) of methanol, ethanol (1 : 1) To the solution was added 10% palladium-carbon (34 mg), and the mixture was stirred in a hydrogen atmosphere under a pressure of 5.0 kg / cm ² for 18 hours. Then, the catalyst was filtered and the solvent was distilled off. The title compound was obtained. Yield 88.7% amorphous

! H-NMRiCDCb) δ: 1.47 (9H, s), 1.85 (3H, m), 2.62 (2H, m), 2.83 (lH, m), 2.82 (lH, m), 3.

39 (2H ₎ m), 3.56 (lH, m), 4.32 (2H _; m) ₎ 5.91 (lH, d, J = 7.8Hz), 6.56 (lH, s), 6.69 (2H, d, J =

8.6Hz), 7.04 (lH, d, J = 8.6Hz), 7.19-7.30 (4H, m), 8.38 (lH, brs), 11.43 (lH, brs)

IR v max (KBr): 3324,2982,2934,1717,1639,1511cm ¹

[M + H] ⁺ = 611 Example 19 9 1- (3-guanidinopropyl) -13- (3- (4-hydroxy) phenylureido) -12,3,4,5-tetrahydro-1H — [1] Synthesis of benzazepine — 2 —one (1 — 1 9)

To the compound (1-18) (0.09 mmo1), add a total of 5.0 m1 of 4 N hydrogen chloride / ethyl acetate solution under ice-cooling, stir at room temperature for 6 days, and remove the solvent. Was distilled off to obtain the title compound.

Quantitative powder

'H-NMRCCDCb) δ: 1.89 (2H, m), 2.02 (lH, m), 2.43 (lH, m), 2.66-2.85 (2H, m), 3.22 (2H, t, J = 6.8Hz), 3.80 (lH, m), 4.12 (lH, m), 4.25 (lH, m), 6.68 (2H, d, J = 9.0Hz), 7.08 (2H, d, J = 8.6Hz), 7.35 (2H, m )

IR record max (KBr): 3377, 1653, 1600, 1559, 1516cm ¹

Elemental analysis value: (as C2iH27N ₆ O3C1.2.5HC1.0.4Na ₂ SO4.0.6H2O)

Observed: 〇, 44.31; 11,5.26; 1 ^, 14.76; (1,15.37

Calculated value: 0, 44.23; 11,5.43; 1 ^ 14.74; €! 1, 15.54 Example 20 3-(3- (4-benzyloxy) phenylureido) — 1 — (3-aminobenzyl) 1 2,3, Synthesis of 4,5-Tetrahydro-1H-1 monobenzazepin-12-one (1-20)

From compound 3 (0.5 mm o 1), N-alkyl was obtained in the same manner as in Example 1, Step 2. OAV £ /, 6soo / 86fc71d

5 «Dimension ZI

Π

Έ έ έ έ Π H H H 0 0 ヽ

§Η9 9- Synthesis of 3- (3- (4-hydroxy) phenylureido) -1,2,3,4,5-tetrahydro 1H—1-benzazepin—2_one (I-122) The title compound was obtained from 21) (0.1 mmo1) in the same manner as in Example 18.

Yield 47.0% mp.300 ° C or more

O-NMRCCDCls) δ: 1.50 (18H, s), 1.95 (1H, m), 2.46-2.65 (3H, m), 4.54 (1H, m), 4.86 (1H, d, J = 15.3Hz), 5.14 (lH, d, J = 14.4Hz), 6.02 (lH, brs), 6.63 (3H, m), 6.95 (3H, m), 7.18 (5H, m), 7.58 (lH, d, J = 8.4Hz)

IR record max KBr SSS ^ STS ^ S ^ m ^ lSA lSS ^ lSMcm. ¹

Elementary analysis: (as C ₃₅ H42N ₆ O7.0.3H ₂ O)

Observed value: 〇, 63.20; Ox, 6.64 ;: ^, 12.81

Calculated value: 0, 63.30; 11, 6.47; 1 ^, 12.65 Example 23 1- (3-guanidinobenzyl) -3- (3- (4-hydroxy) phenylureido) 1,2,3,4 Of 5,5-Tetrahydro-1H-1_benzazepin-12-one (1-23)

The compound (1-22) (0.061 mmo 1) was dissolved in 4 N—hydrogen chloride / ethyl acetate solution (2.5 ml) under ice cooling and stirred at room temperature for 36 hours. The resulting precipitate was dried to give the title compound.

Yield 84.8% amorphous

! H-NMRCCDaOD) δ: 2.00 (lH _; m), 2.43 (lH, m), 2.62-2.69 (2H, m), 4.37 (lH, m), 5.11 (2H, s), 6.68 (2H, d , J = 8.7Hz), 7.08 (2H, d, J = 8.7Hz) _; 7.16-7.38 (7H, m) ₎ 7.40 (lH, t, J = 7.5Hz)

IR v max (KBr): 3309, 2954, 1653, 1600, 1558, 1513cm ¹

Elementary analysis: (as _{_{_{_{C25H 26 N 6 O 3 .l.lHC1.0.5EtOAc.0.75H 2}}}} O)

Obtained: <3, 58.30; 1 !, 5.95; ^ 14.97; (1,6.78 Calculated value: 58.12; 11,5.92; 1 ^, 15.06; 01,6.79 Example 24 (3_cyanobenzyl) (3-phenylureido) 1 2,

Synthesis of 3,4.5—tetrahydro H-1—ben-2-one (24)

(Step 1) 3-Azido-1 — (3-Cyanobenzyl) 1-2,3,4,5-Tetrahydro-1H-1 —Benzozepin-2-one (Compound 6)

Using compound 5 (1.98 mmo 1) described in the literature (J. Med. Chem., 28, 1511 (19985).) And meta-cyanobenzyl bromide, Example 1 N-alkylation by the method of the second step afforded the title compound.

Yield 98.7% mp .90-91 ° C

O-NMRCCDCh) δ: 2.29-2.59 (4H, m), 3.76 (3H, m), 4.82 (lH, d, J = 15.0Hz), 5.30 (lH, d, J = 14.8Hz), 7.17-7.57 ( 8H, m)

IR v max (KBr): 3435, 2958, 2230, 2098, 1664, 160 lcm ¹

Elemental analysis: (as C ₁₈ Hi ₅ N50)

Found: C, 68.15; H, 4.96; N, 22 · 02

Calculated value: (:, 68.13; 13 :, 4.96; 1 ^, 22.07

(Second step) 3-amino 1- (3-cyanobenzyl) -1,2,3,4,5-tetrahydro-1H-1-benzo-azepin-12-one (Compound 7)

67 A tetrahydrofuran solution of the compound 6 (1.76 mmol) obtained in the first step and triphenylphosphine (1.94 mmol) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was heated under reflux for 2 hours. Then, tetrahydrofuran was distilled off, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water, dried (anhydrous magnesium sulfate), and the solvent was distilled off. Purification by silica gel chromatography (form: form / methanol = 1 Z4) gave the title compound quantitatively.

O-NMRCCDCIs) δ: 1.86 (lH, m), 2.29-2.48 (3H, m), 3.43 (lH, m), 4.85 (lH, d, J = 15.0Hz), 5.26 (lH, d, J = 14.7Hz), 7.18 (3H, m), 7.28 (lH, m), 7.39 (lH, m), 7.53 (3H, m)

IR level max (KBr): 2948,2228,1658,1599cm- ¹

(Third step) Compound (I-24)

Under ice-cooling, phenyl isocyanate was added dropwise to a solution of compound 7 (0.602 mmol) obtained in the second step in dimethylformamide (4.0 ml). Stirred for hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (ether / _n- hexane = 3 Z 2—2 / 1) to give the title compound. Yield 82.2% amorphous

! H-NMRCCDCls) δ: 1.92 (lH, m), 2.43-2.59 (3H, m), 4.57 (lH, m), 4.89 (lH, d, J = 14.8Hz), 5.20 (lH, d, J = 15.4Hz), 6.18 (lH, brs), 6.97-7.54 (14H, m)

IR v max (KBr): 3359,3058,2952,2929,2860,2229,1648,1600,1550cm- ¹

Elementary analysis: (as _{_{_{_{C 25 H 22 N 4 O 2}}}} .0.3C 6 H I.2H2O)

Observed value: (, 70.29; 11, 6.05; ^^ 12.23

Calculated value: 70.29; 11, 6.29; 12.23 Example 2 51 1- (3- (tert-butoxycarbonylamino) benzyl) -3- (3-phenylureido) 1-2,3,4,5-tetrahydro 1H — 1 —Synthesis of benzoxazepine—2-one (1 — 25)

(First step) 3 —Azido 1 — (3 — (tert-butoxycarbonylamino) benzyl) — 2,3,4,5-tetrahydro 1 H— 1 —Benzezepine-12-one (Compound 8)

Compound 5 (4.994 mm 01) was N-alkylated according to the method of Example 1, second step, to give the title compound.

Yield 79.0% amorphus

! H-NMRCCDCls) δ: 1.50 (9H, s), 2.24-2.70 (4H, m), 3.76 (lH, t, J = 9.0Hz), 4.85 (lH, d, J = 14.7Hz), 5.17 (lH , d, J = 14.7Hz), 6.43 (lH, s), 6.86 (lH ₁ d, J = 7.5Hz), 7.16-7.41 (7H, m)

(2nd step) Compound (I-I-25)

The compound 8 (9.47 mmo 1) obtained in the first step was reduced in the same manner as in Example 15 to obtain an amine compound (Compound 9). The title compound was obtained in a similar manner.

Yield 69.6% mp. 139 ° C (decomposition)

! H-NMRCCDCh) δ: 1.50 (9H, s), 1.99 (lH, m), 2.59 (2H, m), 2.80 (lH, m), 4.65 (lH, m), 4.79 (lH, d, J = 15.6Hz), 5.35 (lH, d, J = 15.6Hz), 6.54 (lH, brs), 6.80-7.03 (8H, m), 7.35 (lH, 99 對 Z ZS ZW ^^ (I o uiui g I ε-0) 0 T 呦 ^ ェェ

(9 2-D

! rao9eST'S6Sl'8S9T'LSAl'L0IS'I86S'LA6S'88S8 :( ^j a3) ^XBUI HI

(s'HI) 9S'8 '(ZH

= f'P'Hl) e6-L '(ra'HS) 0 ^' i-6rA '( ^z He-L'ZHe-I = f'PP'HT) ^ T-L'(zHS-A'zHS'I = P'P H ΐ) Α2, -9' (ζΗ8 · 'ζΗ8Ι = Γ'ΡΡΉΐ) 0Δ9'(ζΗΔ'ΐΊ = Γ'Ρ'ΗΤ) ϋ'δ '(ζΗ9 · 5 = Γ'Ρ'ΗΤ) Α ^ '5' (ζ ΗΔI = f'P'HI) 9S't '(∞'HI) 99'S'(∞'H)-06 06 (3'Η6) Δ2 · Ι: 9 ( ^ε ΐΟ (ΙΟ) Η 用-Hi

^-L ^ i ^% 6 'SS South ¾τ 呦导 :) vs fel ^ S%% ΐ mm ^^ & ^ U o uiui _ε 6 • S) Mouth /: Ki-3 og-j Ma ( I om 6 ■) S

(0 T ^}) one z—ku 33 · one i — HI —mouth 344 · ^ — s' 'ε' 2-(ir v (Mii # ^ + 4 .. ^.-1 J 3 u- z)-ι-.- (si τ

/, ^^ — τ — HI —Mouth = I ^ 4 ^ _ S '' ε — (^ 二乙一 ε) —

8 80ΐ'Ν ^: ΐ / 9'Η: 69 · 69 ': ε8 · 0ΐ'Ν: 68 · 9'Η ^: n 69'〇： Thigh

_I .rao8 ^ gT'009r6 ^ 9l'S2, T'TS6S ¹ 9A6S'LS08'8S8e: ( ^-i aE) ^x13ra ¾ ¾Q

A6S00 / 86df / XDd 6SS / 86 OA Yield 53.9% powder mp. 235 ° C

! H-NMRCCDCh) (3: 1.52 (9H, s), 1.73 (lH, m), 2.05-2.53 (3H, m), 4.45 (lH, m), 4.49 (lH, d, J = 14.6Hz), 5.42 (lH, d, J = 14.4Hz), 6.17 (lH, brs), 6.66 (lH, dd, J = 1.6Hz, 7.4Hz), 6.78 (lH, td, J = 1.2Hz, 7.4Hz), 6.99 -7.36 (13H, m), 7.80 (lH, d, J = 7.8Hz), 8.73 (lH, brs) IR -les-π ^ χίΚΒι ^^ ΑΤ ^ ί ^ , ΒΙ, ΠΙδ, ΙβΑδ, ΙδΟΙ, ΙδβΟοπι · 1

Elemental analysis: (as C29H32N4O4.O.IH2O)

Observed value: (, 69.53; 11,6.78; 1 ^ 11.24

Calculated value: C, 69.33; H, 6.46; N, 11.15 Example 27 1 — (3-amidinobenzyl) 1-3 — (3-phenyl peridode) — 2, 3, 4, 5, 5-tetrahydro 1 H — 1 _Synthesis of benzazepin-12-one hydrochloride (1 — 27)

The compound (1-24) (0.317 mm 01) was dissolved in dry ethanol (0.5 ml) and dry chloroform (10.0 ml) and stirred under ice-cooling. And saturated with hydrogen chloride gas. The mixture was alkalified with a 10 N sodium hydroxide solution, and the layers were separated. The foam layer was washed with water and an aqueous potassium carbonate solution, and the solvent was distilled off. Ammonium chloride (0.375 mmol) and 75% ethanol (10.0 ml) were added to the residue, and the mixture was heated and stirred at 70 ° C for 4 hours, and then stirred at room temperature for 16 hours. The ethanol was distilled off, and a precipitate formed by adding 10% hydrochloric acid and ethyl acetate was filtered, washed with ethyl acetate, and dried to obtain the title compound.

Yield 31.4% amorphous

! H-NMRCCDaOD) δ: 2.08 (lH ₎ m), 2.45 (lH, m), 2.70 (2H, m), 4.37 (lH, m), 4.96 (lH, d _> J = 15.9Hz), 5.36 (lH , d, J = 16.2Hz), 7.00 (lH, m), 7.04-7.32 (10H, m), 7.54-7.79 (3H, m), 8.67 (lH, s), 9.25 (lH, s)

IR v max (KBr): 3301,3074, 2864, 1663, 1599, 155 lcm ¹

Elementary analysis: (as _{_{_{_{C 25 H 25 N 5 O 2}}}} .HC1.0.1C4Hl0.0.6H2O) Obtained value: (, 63.20; 11,6.64; 1 ^ 12.81; €; 1,7.35

Calculated value: (3,63.27; 11,5.89; 1 ^, 14.52: (1,7.35 Example 2 8 3 — (3-benzylthiolide) 1 1— (3— (tert—butoxylponylamino) benzyl) 1 2 , 3,4,5 —Tetrahydro-1H-1 —Benzoazepine-2-one (1 — 28)

Example 25 25 From the compound obtained in the first step, the title compound was obtained in the same manner as in the second and third steps of Example 24.

Yield 98.8% amorphous

! H-NMRCCDCls) δ: 1.41 (9H, s), 1.71 (lH, m), 1.92 (lH, m), 2.48 (2H, m), 2.68 (lH, m), 4.08 (lH, m) , 4.38 (lH, dd, J = 6.4,15.0Hz), 4.67 (lH, d, J = 16.2Hz), 5.20 (lH, d, J = 15.6Hz), 5.42 (lH, brs), 6.10 (lH, brs), 6.80 (lH, d, J = 7.8Hz), 7.05 (lH, d, J = 7.5Hz), 7.12-7.21 (10H, m), 7.58 (lH, brd, J = 7.8Hz)

IR v max (KBr): 3384, 2975, 1725, 1642, 1603, 1548cm ¹

Elementary analysis: (as C ₃₀ H ₃₄ N4O4)

Found: 0, 69.93; 11, 6.88;}, 10.77

Calculated value: 〇, 70.02; 11,6.66; 1 ^, 10.89 Example 29 3-(3 — (4-benzyloxy) phenylureido) — 1 — (3 — (tert-butoxycarbonylamino) benzyl) 1 2, Synthesis of 3,4,5-Tetrahi 1-H-1 monobenzoazepine-2-one (1-29)

Example 25 5 Using compound 9 obtained in the second step, the title compound was obtained in the same manner as in Example 16, the first step.

Yield 8 0.2% amorphous

'H-NMRCCDCls) δ: 1.49 (9H, s), 1.96 (lH, m), 2.49-2.63 (2H, m), 2.75 (lH, m), 4.62 (lH, m), 4.80 (lH, d, J = 15.9Hz), 4.94 (2H _! S), 5.29 (lH, d _> J = 14.7Hz), 6.38 (lH, brs) _! 6.68 (2H, s) dd, J = 1.8Hz, 8.7Hz), 6.88 (3H, m), 7.12-7.39 (13H, m), 7.57 (lH, brd, J = 8.7Hz)

IR max maxiKBr SSTS TS ^ SL SJGAS'lGCH.lS T.lSlOcm ¹

Elementary analysis: (as _{_{_{_{C 26 H 27 N 3 0 3}}}} )

Observed value: 〇, 71.10; 11,6.58; 1 ^, 9.03

Calculated value: (:, 71.27; 11, 6.31; 1 ^, 9.23 Example 30-3— (3- (4-hydroxy) phenylureido) 1 1— (3— (tert—butoxycarbonylamino) Benzyl) Synthesis of 1,2,3,4,5-Tetrahydro-1H-1-benzazepin-2-one (1-30)

To a methanol solution of the compound (1-29) (0.211 mmo 1) was added 10% paradigmum carbon (18 mg), and the mixture was stirred in a hydrogen atmosphere for 3 hours. The solvent was distilled off to obtain the title compound.

Yield 94.5% amorphous

! H-NMRCCDCls) δ: 1.45 (9H, s), 1.98 (lH, m), 2.54 (3H, m), 4.54 (lH, m), 4.87 (lH, d, J =

15.6Hz), 5.02 (lH, d, J = 15.6Hz), 6.38 (lH, d, J = 7.8Hz), 6.46 (lH, d, J = 15.6Hz), 6.80 (3

H, m), 6.91 (lH, m), 7.34 (lH, d, J = 8.6Hz), 7.47-7.54 (lH, m), 7.04-7.54 (7H, m)

IR record max (KBr): 3361,2974,2931,1646,1605,1545,1513cm- ¹

Elemental analysis value: (as CSSH NAOS.O.ISCSHU.O.IHSO)

Obtained value: (:, 67.66; 11, 6.75; 10.51

Calculated value: 0, 67.59; 11, 6.51;] ^, 10.54 Example 3 1 1 (3- (tert-butoxycarbonylamino) benzyl) — 3- (3- (4-Sulfonyloxy) phenylureido) Synthesis of 1,2,3,4,5-tetrahydro 1H—1—benzazepin-12-one sodium salt (I—31) Compound (1—30) (0.21 1 mm o 1) To the pyridine solution was added a sulfur trioxide pyridin complex (0.97 mmo 1), and the mixture was stirred at room temperature for 110 hours. 09

( ^sj q'HI) 90'8 '(s'in) 6S'Z (∞'H6) SS'mu -8Γ' (ζ HS-L = f '^ q'Hl) l0-i'(sjq'HS ) 9A'9 '(∞'HS) Ae'e' (zHS "9T = f'P'HT) 69-f ''(ra'Hl)6e-'(∞'HI)06'S'(∞'HS)8-89'S'(∞'IH)S0'S'(s'H6)iS'I: 9 (αθ ^ε αθ + ^ε ΐθαθ) ΗΗΝ-Ηι

Y. ^-LM ^ k% 8-Z ^ Xtr

° ¾

Lolo)-C 口口 “ι 辛恵 ¾ 缀つ缀マ (ma * （^ 氺氺) 回回 τ ¾ 氺 ¾ ¾ 氺 ¾ 萆 n n tn z z 邈 'IY ¾ ^ :?? Ma ft

¾ § ェ

ω τ ν-

9 6 8 0 5-d 39 ^ (I ο uiui ^ ι χ ¹⁰ ) .3- V (^ Γ-3 one — /, Λ ΐ-Η I-I)-i-

TV— 9 6 L 8 0 3-d 3

'ε' z--y Λ ^ ί-^ c ((^ r-s-(-Λ ^-^-ED-)-£)-ε— (κ く ^ (/ mi two} J a) — ε)-I zH & WW

(∞'HU) Se-A-80-i '( ^z Hi''' L = P'P- ⁱ q'Hl) ^ 8'9 '(zH8 ^ I = f'^< HT) L2-e '(zHl ⁷ 'ei = i ⁱ ' P 'HT) S8- ^, (™ ^, HT) S8'(∞'H8)69-3-9S'S'(∞'HT)00-S'(s'H6) 6f I: 9 ( ^ε Ι0 (Ι.) so-called Ν · Ηι

% Ζ-0 S ¾¾τ 遨遨辛つ辛 1 っっっマ (マ 6 * マ M) One £ W times Z,-I, ^ ^

ェ: i i ·:: :: i (Iuis · ε) Tsu i 鄴 e ¥ W¾

Z.6S00 / 86 «If / IDd If6S £ / 86 OAV IR v max (KBr): 3384, 2977, 2930, 1647, 1601, 154 lcm- ¹

Elemental analysis: (as C3oH32N ₈ 04.0.2C _G H ".0.6H ₂₀ )

Obtained: 62.57; 11, 6.04; ^^ 18.69

Calculated value: C, 62.80; H, 6.08; N, 18.78 Example 3 31-(3 — (tert-butoxycarbonylamino) benzyl) — 3-(3- _4-(3 — chloropropoxy)) phenylurei C) Synthesis of 1,2,3,4,5-tetrahydro-1-H- 1-benzoazepin-2-one (1-33)

To a solution of the compound (1 — 30) (0.137 mm o 1) in acetone is added potassium carbonate (0.137 mm o 1) and 1-bromo-3-propane (0.27 mm o 1). After 1) was added and the mixture was heated under reflux for 24 hours, 1-bromo-3-chloropropane (0.27 mmo 1) was added, and the mixture was further heated under reflux for 24 hours, and then the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform / methanol = 50: 1) to give the title compound quantitatively.

Amorphous

! H-NMRCCDCh) δ: 1.50 (9H, s), 1.96 (lH, m), 2.19 (2H, m), 2.52-2.64 (2H, m), 2.78 (lH, m), 3.73 (2H, t, J = 6.4Hz), 4.02 (2H, d, J = 5.9Hz), 4.60 (2H, m), 4.85 (lH.dJ = 16.2Hz), 5.2

2 (lH, d, J = 16.2Hz), 5.17 (lH, s), 6.55 (lH, dd, J = 1.5Hz, 9.0Hz), 6.80 (lH, s), 6.87 (2H, d,

J = 8.7Hz), 6.95 (2H, dd, J = 1.8Hz _> 9.0Hz), 7.12-7.25 (5H, m) ₎ 7.55 (lH, brd, J = 6.9Hz),

IR max (KBr): 3382,2972,2932,1724,1651,1604,1543,1511cm- ¹

Elementary analysis: (as C ₃₂ H ₃₇ N4O ₅ C1.0.2H2O)

Found: C, 64 · 42; H, 6 · 40; N, 9 · 61; C1, 5.69

Calculated value: (3,64.41;! 1,6.32,9.39;, 5.94 Example 34 1- (3- (tert-butoxycarbonylamino) benzyl) -3-1 (3— (3-tetrahydropyran-1 2 _) Iloxy) phenylureido) 1 2,

V OAi 6

Bark ^ K% 9 blocks Dimensions £, 寸) Η) (ΗHεΐ620 (§) 3S) N2ΐ66 δδ --- ·. * d, J = 9.4Hz), 6.71 (3H, m), 6.93 (lH, brd, J = 7.8Hz), 7.05 (lH, brs), 7.17-7.39 (6H, m), 7.5 l (lH, d, J = 8.2Hz),

IR record max (KBr): 3387,2976,1648,1603,1548cm- ¹

Elemental analysis: (as C ₂₉ H ₃ 2N4O 5.0.3H ₂ O)

Obtained value: (, 66.69; 11,6.44;] ^, 10.81

Calculated value: (, 66.73; 11,6.29; ^ 10.73 Example 36 1- (3- (tert-butoxycarbonylamino) benzyl) -13- (3- (2-hydroxy) phenylureido) 1-2, 3. Synthesis of 4,5—Tetrahydro-1H-1 monobenzazepin-2-one (1—36)

(Step 1) 1- (3_ (tert-Butoxycarbonylamino) benzyl)-3- (3- (2-tert-butyl-dimethylsilyloxy) phenylperoxide) -2,3,4,5-tetrahi Dro-1H-1 -Benzozepin-2-one (Compound 11) Compound obtained by protecting the hydroxy group of ortho-nitrophenol with tert-butyldimethylsilyl group and reducing the ditro group in a conventional manner ( Performed using 2- (tert-butyldimethylsilicyloxy) aniline; 0.174 mmo 1) and Example 9 5 compound 9 (0.262 mmo 1) obtained in the second step The title compound was obtained by the method of Example 32.

Yield 70.7% amorphous

O-NMR CDCla) δ: 0.22 (6H, s), 1.01 (9H, s), 1.96 (lH, m), 2.45-2.65 (3H, m), 4.54 (lH, m), 5.01 (2H, s) , 6.68-6.92 (6H, m), 7.10-7.26 (6H, m), 7.44 (lH ₎ brd, J = 4.0Hz ₎ 7.82 (lH, m)

IR v max (KBr): 3415,2954,2930,2899, 1728, 1655, 1599, 1528cm- ¹

Elementary analysis: (as C ₃₅ H _4G N40 ₅ Si)

Obtained: C, 66.75; H, 7.63; N, 8.71

Calculated: 66.64; 11,7.35;] ^, 8.88 (2nd step) Compound (1 — 3 6)

A solution of the compound (0.127 mmo 1) obtained in the first step in tetrahydrofuran (2.0 m 1) was added under ice-cooling to tetrahydrofuran (1.Oml) of tetra-n-butylammonium fluoride. ) The solution was added dropwise, and after 5 minutes, the temperature was returned to room temperature and stirred for 1 hour. Ice water and a saturated aqueous solution of sodium carbonate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (form-form Z methanol = 50/1) to give the title compound.

Yield 82.3% amorphous

O-NMRCCDCls) o: 1.51 (9H, s), 2.00 (lH, m), 2.51-2.77 (3H, m), 4.56 (lH, m), 5.31 (2H, d, J = 15.4Hz), 6.62 ( lH ₎ m), 6.85 (4H, m), 7.08-7.23 (6H, m), 7.54-7.63 (2H, m)

IR max (KBr): 3384, 2976, 2931, 1726, 1647, 1602, 1542cm. ¹

Elemental analysis: (as C29H32N4O5.0.1C6H.0.3H2O)

Found: 〇, 67.11;! 1,6.75; 10.75

Calculated value: (, 67.00; 11,6.46; 1 ^ 10.56 Example 37 1-(3- (tert butoxycarbonylamino))

― (3- (Pyridin-3-yl) ureido) Synthesis of 1,2,3,4,5-tetrahydro-1H-1-benzazepin-12-one (1-37)

Using 3-amino-pyridine (0.289 mmo 1) and compound 9 (0.262 mmo 1) obtained in the second step in Example 25, the title compound was obtained in the same manner as in Example 32. I got Yield 25.9% amorphous

! H-NMIKCDCls) δ: 1.50 (9H, s), 1.97 (lH, m), 2.53-2.62 (2H, m), 2.74 (lH, m), 4.60 (lH, m) ₎ 4.90 (lH, d, J = 15.6Hz), 5.23 (lH, d, J = 15.3Hz), 6.54 (lH, d, J-7.5Hz), 6.87 (lH, d, J =

7.5 Hz), 6.97 (lH, m), 7.11 (lH, brs), 7.23 (5H _> m), 7.50 (2H, d, J = 8.4 Hz), 7.64 (lH, brs), 8.10 (lH, d, J = 3.9Hz), 8.29 (lH, brs) 99

6 呦导 ^ § ェ S S ¾ S S i-th ^ (i o mm o 0 S '0) —

V 5-9 ¾ 1 — /, mouth 4 9 Q

(6 ε-I) Ku ^ — 2 _ku 3 /, ku ^ Ι _Η ΐ —mouth

^ M 9 '' ε 'ζ-(ir ν (i ζ r-^ ^-i JS i)-ε)-τ-(Η -1 ^ (ir-9 -ΊΓ-, Α ν ν)-ε) -ε ~~ 6 ε \ Μ

SA-ST'N ^ 8'9'H ^: 8e-99'0: i!} ^ 4l 98 · 2Ι'Ν ^: 98 · 9'Η ^: 85 · 59Ό: ^} ^^ (1 Ο ΗΓ0 · ³ Ο ⁸ Ν "Η ^0ε Ο): ¾½ ^ ^ ^ ra: ^ si'oi9I 99rSS6S'I 6S'ISSS: (Ja: a) ^XBUI HI HI (s-tq'Hl) Ar8 '(sjq'Hl) ^ g-L '(zHS ^ = f'P'HT) 8 ^ -A' ( ^ra 'H9) 9S'A- ^ rL' ( ^z H8-i = f 'P'Hl) 88-9'(s' HT) SA-9 '(s'Hl) 0r9' ( ^z HA T = f'P'HT) 6re '(zHA- I = f'P'Hl) S6-l7' (∞ 'HI) S''(ra'HS) W .9 '(ra'HI) SO' ( ^S 'H6) 8' I '(s'H6) 6S'T: ρ ( ^E 10aO) HWN "Hi 乙乙 ·% · 0 9

呦 ^ G? 遨 im ω ζ z im ^ ^ (ι ◦ z g z · o) 6 s ¾ s z

7 (I o IUUI 6 Z0) ir-.. A-fr + ^-l -i s i-g-Z ^-S

^ 导

〇 (8 S— I) Ku ^ — Z—ku 3 /, Kuichi H T—Mouth s '' ε

'z-(κ く 2} ^{J 9} ^) — ε)-τ-(H ^

ε9'Η ^ 839'0: 翥 ε3'εΐ'Ν: 6 '9'Η: 9Γ99'0: | 1 嗨 (Emma 0— ⁶ HS'0 O ^S N ^IS H ^8S 0 ): ¾½ Hajime T.uiDgt, gi'909l'999T'S86S'9L6S'8908'S98C: (Ja¾) x ^ ∞ Λ ai

Z.6S00 / 86df / X3d 6SS / 86 OAV (0.262 mmo 1) to give the title compound by the method of Example 32.

Yield 50.0% amorphous

! H-NMRCCDCls) δ: 1.5 l (9H, s), 2.03 (lH, m), 2.60 (lH, m), 2.70 (lH, m), 2.86 (lH, m), 4.76 (lH, d , J = 15.9Hz), 5.48 (lH, d, J = 15.9Hz), 6.81 (lH, d, J = ll.lHz), 6.89 (lH, d, J = 8.4Hz), 6.99 (lH, d, J = 8.4Hz), 7.02 (lH, s), 7.19-7.35 (6H, m), 7.53 (lH, d, J = 9.0Hz), 7.58 (lH, d, J = 7.8Hz), 7.71 (lH , S), 8.61 (lH, s)

IR y max (KBr): 3358, 2977, 2930, 2930, 1653, 1602, 1550, 152 lcm ¹

Elemental analysis: (as CsoHsiNsC S.O ^ HsO;)

Observed: (2, 63.82; 11, 5.85; ^ 12.36; 8, 5.74

Calculated value: 63,79; 11,5.67; 1 ^, 12.40; 3,5.68 Example 40 3 _ (3- (benzotriazole-5-yl) ureido) -1-1 (3 — (tert- Butoxycarbonylamino) benzyl) Synthesis of 1,2,3,4,5-tetrahydro-1H-1-benzazepin-12-one (1-40)

6-Aminobenzotriazole (0.261 mmo1) obtained by reducing 5_nitrobenzotriazole by a conventional method and the compound 9 (0.252 mm) obtained in the second step of Example 25 The title compound was obtained by the method of Example 32 using o 1).

Yield 41.0% amorphous

! H-NMRiCDCls) 6: 1.20 (9H, d, J = 7.5 Hz), 2.11 (lH, m), 2.52-2.66 (2H, m), 2.81 (lH ₎ m), 4.66 (lH, m), 4.85 (lH, brs), 5.35 (lH ₎ brs) ₎ 6.63 (lH, brs), 6.94 (2H, d, J = 15.9Hz), 7.0 l (lH, brs), 7.22 (2H, m) 7.42 (2H, s), 7.51 (lH, br, s), 8.65 (2H, s),

IR v max (KBr): 3360, 2975, 2930, 1654, 1603, 1576, 1536cm ¹

Elementary analysis: (as _{_{_{_{C 29 H 3 iN7O 4 .0.1C6Hi4.0.4H 2}}}} O)

Obtained:, 63.87; 11, 6.21;, 17.67

Calculated: C, 63.79; H, 6.00; N, 17.58 Example 4 1 1- (3— (tert-butoxycarbonylamino) benzyl) — 3— (3— (1—para-tosyl-1H—benzoimidazoyl-1-5-yl) perido) -2,3 , 4.5—Synthesis of tetrahydro-1-H-1 benzoazepine-12-one (1-41)

1-para-tosyl-5-ditrobenzoimidazole which is a compound described in the literature (Roczniki Chem., 38, 1073 (19664).) 1-paratosyl — 5—Aminobenzoimidazole was obtained. Using the compound (0.720 mmo 1) and the compound 9 (0.655 mmo 1) obtained in the second step in Example 25, the title compound was obtained by the method of Example 32. Was.

Yield 4 1.0% amorphous

'H-NMI CDCls) δ: 1.50 (9H, s), 1.93 (lH, m), 2.36 (3H, s), 2.45-2.69 (3H, m), 4.57 (lH, m), 4.96 (lH, d , J = 7.8Hz), 5.06 (2H, d, J = 7.6Hz), 6.30 (lH, m), 6.63 (lH, s), 6.82 (lH, d, J =

7.8Hz), 7.82 (lH, d, J ^ 8.6Hz), 7.14-7.30 (10H, m), 7.45-7.58 (lH, m), 8.31 (lH, s)

IR v max (KBr): 3393,3087,2975,2930, 1719, 1655, 1599, 1543cm ¹

Elementary analysis: (as ^{_{_{_{C 37 H 38 N 6 O 6}}}} S.0.4H 2 O)

Found: 0, 63.37; 11, 5.72; 1 ^, 11.99

Calculated value: C, 63.30; H, 5.57; N, 11.97 Example 4 2 3 — (3 — (Benzoimidazole-5-yl) ureido) — 1 (3-(tert-butoxycarbonylamino) ) Synthesis of benzyl) _2,3,4,5-tetrahydro-1H-1-benzazepin-12-one (1-42)

10% potassium hydroxide / methanol (2.0 ml) was added dropwise to a solution of the compound (1-41) (0.115 mmo 1) in methanol (2.0 ml), and the mixture was stirred for 30 minutes. . The mixture was neutralized with 10% hydrochloric acid and extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform Z methanol == 10 Z 1) to give the title compound. Yield 64.3% amorphous

O-NMRCCDCls) δ: 1.48 (9H, s), 2.01 (lH, m), 2.49-2.61 (2H, m), 2.77 (lH, m), 4.60 (lH, m), 4.77 (lH, m), 5.28 (lH, brs), 6.69 (lH, brs), 6.88 (2H, brd, J = 8.4Hz), 7.10-7.26 (8H, m), 7.34 (lH, s), 7.47 (lH, m), 7.67 -7.81 (lH, m)

IR v max (KBr): 3387,2977,2933,1654,1602,1549cm " ¹

Elemental analysis: (as CSOH NGC -I I ^ O)

Observed value: (, 64.03; 11, 6.00;, 15.02

Calculated value: 0, 64.09, 6.17; 1 ^, 14.95 Example 4 33— (3- (2-((4-benzyloxy) phenyl) ethyl) ureido) —1— (3- (tert-butoxycarbonyl) Amino) benzyl) —2,3,4,5-tetrahydro-1H-1—benzazepin-2-one (1—43) Synthesis of 3- (4-benzyloxy) propionic acid (J. Chem) Soc., Perkin Trans. 1 185 (1988).) And an isocyanate (0.187 mmo 1) obtained according to the method of Example 25, 2nd step. The title compound was obtained by the method of Example 32 from compound 9 (0.170 mmo 1) obtained in the above.

Yield 82.3% amorphous

^{_{1 H-NMR (CDC1 3)}} δ: 1.42 (9H, s), 1.93 (lH, m), 2.41-2.60 (4H, m)) 2.72 (lH, m), 3.19 (lH, m), 3.35 (lH , M), 4.55 (lH, m), 4.72 (lH, d, J = 15.9Hz), 4.95 (lH, brs), 5.00 (2H, s), 5.11 (lH _> d, J = 15.6Hz), 5.88 (lH, brs), 6.81-6.89 (3H, m), 6.99-7.43 (14H, m), 7.58 (lH 1 brd, J = 8.4Hz)

IR v max (KBr): 3384,2974,2931,1724,1644,1606,1548,1512cm ¹

Elementary analysis: (as _{_{^{_{C 38 H 43 N 4 0 5}}}} )

Obtained: 71.51; 11,6.98;] ^, 8.80

Calculated values: 0, 71.79; 11,6.82; 8.81 Example 4 4 1 1 (3 — (tert-butoxycarbonylamino) benzyl) 1 3-(3 — (2 — ((4-hydroxy) phenyl) ethyl) ureido) — 2, 3, 4, 5 —Synthesis of —tetrahydro—1H—1—benzazepin-2-one (1—44) Using the compound (I—43; 0.10 mmo1), the title compound was obtained by the method of Example 30. I got

Yield 77.0% mp.128 ° C (decomposition)

! H-NMRCCDCls) δ: 1.26 (lH, t, J = 7.2 Hz), 1.44 (9H, s), 1.9 l (lH, m), 2.5 l (4H, m), 2.66 (lH, m), 3.24 (2H, m), 4.52 (lH, m), 4.76 (lH, d, J = 15.6Hz), 5.09 (lH, d, J = 15.6Hz), 5.19 (lH, brs), 6.06 (lH, brs) , 6.64 (2H, d, J = 8.1Hz), 6.83 (3H, t, J = 7.8Hz), 7.11 (lH, t, J = 7.8Hz), 7.13-7.19 (6H, m), 7.46 (lH , d, J = 7.8Hz)

IR record max (KBr): 3338,2974,2931,1724,1644,1608,1548,1517cm ¹

Elementary analysis: (as _{_{_{_{C 3 iH 37 N4O 5 .0.lC 6}}}} Hi4.0.3H2O)

Obtained: 0, 67.73; 11, 6.95; 1 ^, 9.87

Calculated value: (, 67.84; 11,6.99 ^, 10.01 Example 4 51,3—Bis— (1— (3— (tert—Butoxycarponylamino) benzyl) 1-2—oxo—2,3,4, 5—Tetrahydro-1H-benzo [b] azepine-1-3-yl) Perea (1-5)

Example 25 5 The title compound was obtained using Compound 9 (0.472 mmo 1) obtained in the second step and the isocyanate obtained by the method of Example 32.

Yield 18.6% amorphous

! H-NMRiCDCls) δ: 1.45 (18H, s), 1.91 (2H, m), 2.31-2.61 (6H, m), 4.37 (2H, m), 4.84 (2H, d, J = 14.8Hz), 5.16 (2H, d, J = 15.2Hz), 6.15 (2H, brs), 6.75 (2H, d, J = 7.6Hz), 6.97-7.16 (14H, m), 7.52 (2H, brd, J = 7.8Hz) )

IR v max (KBr): 3397,2931,1725,1655,1603,1541cm ¹

Elementary analysis: (as _{_{_{_{C 45 H 5 2N 6 O7.0.lC6Hi4.0.8H 2}}}} O) Obtained: (, 67.34; 11,6.85; 10.12

Calculated value: C, 67.45; H, 6.83; N, 10.35 Example 4 61— (3- (tert-butoxycarbonylamino) benzyl) —31-((4-carboxy) phenylureido) —2,3, 4,5-Tetrahydro-1H-1—benzazepin-12-one (Synthesis of 1—46 丄 _

Example 25 Compound 9 (0.183 mo 1) obtained in the second step and literature (J. Chem. Soc., Chem. Commun., 82 (197) 3) A solution of 4-phenoxycarbonylaminobenzoic acid (0.195 mmo 1) in dimethylformamide as described in

Triethylamine (0.028 ml) was added dropwise to (3.0 ml), and the mixture was stirred at room temperature for 18 hours. Ice water and 10% hydrochloric acid were poured into the reaction mixture, the resulting precipitate was acidified, and the resulting precipitate was collected by filtration. The residue was subjected to silica gel chromatography (form-Z methanol = 20 /

Purification by 1) afforded the title compound.

Yield 46.2% amorphous

_{'H-NMR (CDC1 3)} (5: 1.45 (18H, s), 1.91 (2H, m), 2.31-2.61 (6H, m), 4.37 (2H, m), 4.84 (2 H, d, J = 14.8Hz), 5.16 (2H, d, J = 15.2Hz), 6.15 (2H, brs), 6.75 (2H, d, J = 7.6Hz), 6.97-7.16 (14H, m), 7.52 (2H, brd, J = 7.8Hz)

IR record max (KBr): 3397,2931, 1725, 1655, 1603, 1541cm- ¹

Elemental analysis value: (as C45H52N6O7.O.IC6HW.O.8H2O)

Observed value: (3,67.34; 11,6.85;, 10.12.

Calculated value: (:, 67.45; 11,6.83; 10.35 Example 4 71 1- (3- (tert-Butoxycarbonylamino) benzyl) -3- (3-dimethylureido) 1-2,3,4,5- Synthesis of tetrahydro_1H—1-benzazepine-12-one (1—47)

Example 25 5 To a solution of compound 9 (0.524 mol) obtained in the second step in acetonitrile (6.0 m 1) was added carbonyldiimidazole (1.05 mm o 1), and the mixture was added at room temperature for 1 hour. Stirred. Ice water was poured into the reaction mixture, and the solvent was distilled off. After extraction with ethyl acetate twice, the organic layer was washed with water, dried (anhydrous magnesium sulfate), and the solvent was distilled off. A 1 M-dimethylamine Z tetrahydrofuran solution (0.25 ml) was added to the obtained residue (0.251 mmo 1), and the mixture was stirred at room temperature for 18 hours. The mixture was acidified with 10% hydrochloric acid and extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off to obtain the title compound.

Yield 46.2% mp. 197-199 ° C

! H-NMRCCDCls) <5: 1.49 (9H, s), 2.00 (lH, m), 2.48-2.58 (2H, m), 2.73 (lH, m), 4.53 (lH, m), 4.83 (lH, d , J = 15.3Hz), 5.19 (lH, d, J = 15.6Hz), 6.85 (lH, d, J = 7.8Hz) ₁ 6.99 (lH, s), 7.07-7.27 (7H, m), 7.37 (lH, brd, J = 7.5Hz)

IR v max (KBr): 3421,3310, 2974, 2937, 1728, 1664, 1635, 1603, 1541cm ¹

Elementary analysis: (as ^{_{^{^{C 25 H 3 2 N 4 O}}}} 4 .0.3H 2 O)

Observed value: 〇, 65.57; 11, 7.17; ^^, 12.25

Calculated value: 〇, 65.57 ;: «, 7.18; 1 ^ 12.23 Example 4 81- (3-aminobenzyl) —3- (3-phenylureido) —2,3,4,5-tetrahydro-1H— 1 _Synthesis of Benzozepine 1-2-one (1-48)

Compound (I-25) (0.640 mm o 门) was prepared in the same manner as in Example 23.

) 8HZ (, (,,, HmJCDC 683Hm HdNMR =- ((() ,, 〇 HN R〇D 06H 94lH Hmm-

7 X% 4〇.

ί # ¾

N

() ,,,, 83lffi 6HZ HdJ HdJ Hz 6 6.86 == 0 (lH, m), 4.96 (lH, d, J = 15.2Hz), 5.09 (lH, d, J = 15.2Hz), 6.17 (lH, brs), 6.91 (2H, t, J = 7.

0Hz), 7.15-7.26 (1 lH, m), 7.63 (lH, m)

IR v max (KBr): 3380, 1645, 1598, 1545cm ¹

[M + H] ⁺ = 508 Example 5 1 1-(3-(3 -Cyan- 2 -phenylisoureido) benzyl) 1 3-(Phenylperido)-2, 3.4, 5 —Tetrahydro Synthesis of 1 1H— 1 —Benzozepine 1 2 _ 1 (1 — 5 2)

(1) A solution of the compound (1-52) (I-488) (0.498 mmo 1) in dry tetrahydrofuran (3.0 ml) was added to a solution of diphenylcyanocarboimidate (J. Heterocyc 1. Add Chem. —1 9—, 125 (1 1982)) (0.546 mmol), stir at 50 ° C for 5 days, cool, and evaporate the solvent did. The residue was purified by silica gel chromatography (formaldehyde acetone: 6/1) to give the title compound. Yield 95.1% amorphous

! H-NMRCCDCls) δ: 1.89 (lH, m), 2.32-2.61 (lH, m), 4.53 (lH, m) ₁ 4.63 (2H, s), 6.43 (lH, d, J = 7.8Hz), 6.85 -7.48 (llH, m), 7.72 (lH, s) ₁ 9.50 (lH, brs)

IR v max (KBr): 3361, 6058, 2952, 2196, 1636, 1599, 1549cm ¹

Elemental analysis: (as C32H28N6O3.0.25CHC13.0.25C6HW.0.75H2O)

Observed value: (, 66.51; 11, 5.48; 1 ^ 13.90

Calculated values: (3, 66.50; 11,5.50, 13.79 Example 5 2- (3- (1-Methylthio-1-2-nitrothenylenylamino) benzyl) (phenylureido) -1,2,3,4.5-tetrahydro-1-H-1—benzozopine-2_ On (1 — 5 3) synthesis

Compound (1 — 48) (0.623 mmo 1) in dry tetrahydrofuran (7.0 ml) solution was mixed with 1,1 dimercapto-12-nitroethane (Chem. Ber. 10

Add 0_, 5999 (19667)) (0.763 mmo1), stir at 70 ° C for 5 days, and at 80 ° C for 2 days, cool, and evaporate the solvent. I left. The residue was purified by silica gel chromatography (chloroform form Z acetone = 10/1) to obtain the title compound.

Yield 84.7% m p. 1 25-1 27 ° C

_{'H-NMR (CDC1 3)} δ: 1.94 (lH, m), 2.27 (3H, s), 2.48-2.59 (3H, m), 4.57 (lH, m), 4.90 (lH, d, J = 14.4Hz ), 5.15 (2H, d, J = 15.3Hz), 6.19 (lH, brs), 6.63 (lH, s), 7.00 (lH, brs), 7.17-7.34 (12H, m), 11.77 (lH, s)

IR v max (KBr): 3352, 3144, 3056, 2929, 1655, 1599, 1550cm ¹

Elementary analysis: (as C _₂₇ H ₂₇ N ₅ 04S)

Obtained: 0, 62.76; 11, 5.28;] ^, 13.73; 3, 5.96

Calculated value: (, 62.65; 11,5.28; 1 ^, 13.53; 3,6.20 Example 5 31 1- (3- (Ν'-cyano N ', — methyl) guanidinobenzyl) 13- (phenylureido ) Synthesis of 1, 2, 3, 4, 5 —Tetrahi draw 1 Η— 1 —Benzoazepine—2—one (1—5 4)

To a solution of compound (I-52) (0.127 mmo 1) in methanol (2.0 ml) was added 40% methylamine / methanol solution (2.5 m 1), and the mixture was allowed to stand at room temperature for 18 hours. After stirring, the mixture was concentrated. The residue was purified by PTLC (chloroform / methanol = 20Z1) to give the title compound.

Yield 6 0.6% m p. 23 4-23 36 ° C

! H-NMRCCDCla) δ: 2.03 (lH, m), 2.5 l-2.66 (3H, m), 2.77 (3H, d, J = 4.8Hz), 4.53 (lH, m), 4.61 (2H ₎ s), 4.82 (lH, brs), 6.64 (lH, d, J = 7.8Hz), 6.92 (2H, t, J = 8.7Hz), 7.03 (lH, d, J

= 7.8Hz), 7.14-7.29 (10H, m), 7.86 (lH, s), 8.26 (lH, s)

IR max (KBr): 3339, 2953,2171, 1654, 1600, 1556cm ¹

Elementary analysis: (as _{_{_{_{C 2 7H27N 7 O 2 .0.lC 3}}}} H 8 O.0.2H 2 O)

Observed value: (:, 66.76; 11, 5.79; ^^ 19.78

Calculated value: 〇, 66.91; 11,5.98; 1 ^ 19.96 Example 5 41- (3- (1-methylamino-2-nitroethenyl) aminobenzyl) -3- (phenylphenyl) 1-2,3, Synthesis of 4, 5-tetrahydro-1H-1-benzozepine-2 -one (1-55)

To a solution of compound (1-53) (0.17 mmo1) in methanol (2.0 ml) was added 40% methanol solution of methylamine Z (3.0 ml), and the mixture was stirred at room temperature for 18 hours. Thereafter, the mixture was stirred at 60 ° C for 6 hours and concentrated. The residue was purified by silica gel chromatography (chloroform Z acetone = 2 Z 1) to give the title compound.

Yield 4 1.0% mp. 235 ° C (decomposition)

! H-NMRCCDCh + CDsOD) δ: 2.00 (lH, m), 2.55 (lH, m), 2.60 (lH, d, J = 3.6Hz), 2.81 (2H, m), 4.49 (lH, m), 4.82 (lH, brs), 5.19 (lH, brs), 6.97 (lH, d, J = 6.6Hz), 7.08-7.34 (13H, m)

IR v max (KBr): 3324, 3134, 3067,2952, 1698, 1647, 1600, 1552cm ¹

Elemental ^{^{_{analysis: (C 27 H 2 8 N}}} ( as 50 ⁴ .1.2H ² 0)

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Z.6S00 / 86df / X3d 6S £ 786 OAV A solution of phenylisothiocyanate in dimethylformamide (0.46 ml) was added to the solution of formamide (1.0 ml) and stirred at room temperature for 30 minutes, followed by stirring at 60 ° C for 6 hours. Concentrated. The residue was purified by silica gel chromatography (chloroform form Z methanol = 50Z 1) to give the title compound.

Yield 92.9% Amorphous

^{_{1 H-NMR (CDC1 3)}} (5: 1.50 (9H, s), 1.89 (lH, s), 2.51-2.81 (3H, m), 4.43-4.52 (lH, m), 4.65 (lH, brs), 4.72 (lH ₎ brs), 4.78 (lH, d, J = 15.6Hz) ₎ 5.12 (lH, d, J = 15.2Hz), 6.77 (lH, brs), 6.85 (lH, d, J = 7.8Hz), 7.12-7.41 (12H, m)

IR v max (KBr): 3335,3062,6031,2975,2929, 1725, 1650, 1604, 1535cm ¹

Elemental analysis: (as C ₃ oH ₃ 4N40 ₃ S)

Observed: (3,67.82; 11,6.62; ^ 1,10.42; 3,6.19

Calculated value: (, 67.90 ;: ^ 1, 6.46;] ^, 10.56; 3,6.04 Example 5 8 1— (3— (tert—butoxycarbonylamino)

—Synthesis of 3-methoxy-3- (3-methylureido) -1,2,3,4,5-tetrahydro-1H—1-benzazepine-12-one (1-59)

(Step 1) 3-Azide-1 (3- (tert-butoxycarbonylamino) benzyl) 1-7-Methoxy 2,3,4,5-tetrahydro-1H-1-benzazepine-2 ON (Compound 15)

NHBoc

The title compound was obtained from compound 14 (0.157 mmo 1) described in WO 9216,524 by the same method as in Example 12. 6si o: u 6so] o / 86fevld

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% 8-8 8 尜 St °

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Example 2 5 Compound 9 (0.786 mmo1) obtained in the second step and compound 17 (1.11 mmo1) obtained in the first step were added to 2-propanol (1 2 m 1) was added and the mixture was heated under reflux for 11 days, and then concentrated. The residue was purified by PTLC (cloth form Z methanol = 5/1) to give the title compound.

Yield 4.0% mp. 124 ° C (decomposition)

! H-NMRCCDCls) δ: 1.40 (9H, s), 2.01 (lH, m), 2.52-2.72 (3H, m), 2.77 (lH, m), 4.86 (lH, d, J = 15.3Hz), 5.13 (lH, d, J = 15.3Hz), 5.94 (lH, brs), 6.57 (lH, d, J = 3.9Hz), 6.63 (lH, s),

6.89 (2H, d, J = 7.2Hz), 6.96 (lH, brs), 7.14-7.29 (7H ₎ m), 7.37 (lH ₎ d, J = 8.4Hz)

IR record max KBi ^ SSgS'SgTG. LGSSJSlSJS lcm. ¹

Elemental analysis: (as C ₂₆ H ₃₀ N ₆ O ₃ S.0.2H ₂ O)

Observed: (3,61.26; 11,6.18; ^ 1,16.33; 3,6.38

Calculated value: 〇, 61.20; 11,6.01, 16.47; 8,6.28 Example 6 _0 _ 3 -amino-5-(3-(tert-butoxycarbonylamino) -be 2,3,4,5-tetrahydro 1—1,5—Benzothiazepine _4—one

Synthesis of (1-6 1)

(First step) 3 — (3 —phenylureido) — 2,3,4,5-tetrahydro-1,5 benzothiazepine_4-one (compound 19)

Ψ2

80'9'S ^: S9'0I'N ^: 00'9'H ^: SrS9'〇: 寬 Τΰ9'8 · '69 · 0ΐ'Ν ^ χ · 9'Η ^: ζδ'59Ό: ΐ!} [Ι¾¾ 7 ⁱ "H ⁹ OrO-S ⁹ O ^ N ^ H ^9s O) ^: 5} ½ ^ ¾ ^

(zH8'A = f'P'HT) 9t '"i' (a ⁱ 'HS) S ^ -A-08'L'(∞'H8)9S-Z--80" L '(∞'HS) S6-9 '(sjq'H2) S9-9 ^, (zHS'9I = f'P'Hl) 9 ^ -S'(zH9'ST = f'P'HT) 68 '^'(∞'HS) 6A ''(zHS'n'8'9 = f'PP'HI) 6 'S'(zHS'U = f ';' HI) Z6'S '(s'H6) 6fI: Q ( ⁸ IOaO) HWN "Ht LM ^ c% 9 · S 9 South ¾i. ^ Q ¾ ¾ ^ G) Countermeasure 2 ¾ ί ί ^ 3ϊ ^ ¾ ^ (I o UIUI 6 ε ζ-0) 6 ΐ 呦 ^! I ¾

(T 9-I) 呦 (si z

^ Γ0Γ3: εε · εΓΝ: 98 '' Η ^: M 6'09'〇: Meaning £ 6'6'8 ^: 1 81 '^ ^: 98 '15 ^: 91'"[9'0 ^: 1!} 嗨 (Χ Ο ^ε ΗΓ0 · 8 ^ε Ο ^ε Ν ^5Ι Η ^9Ι Ο): 碟 ^^ mine τ∞39ζ, 9ΐΊ96ζΊίΌεΌ6ΐεΌ92ε'2ΐεε'8ΐ'εε: (· ^Ι 9¾) ^{χ¾Ι11 HIHI}

(zHS-9 = f'P'HI) S9-Z (∞'H (H) 8S '-96'9'(∞'Ηΐ) ε · 9 '(∞'Ηΐ) 69 ·'(ζΗΟ'ΐΐ' ζΗ 9'9 = f'P 'HT) S8-8 ^, ( ^z HSOT = f' HT) e6'S '(s-iq'HS) 8A-S: ρ ((ΙΟ ^ε (ΙΟ + ^ε ΐθαθ) Ηι

(¾-^) a ε ε s · d ui% 9 's 9 south a 呦 ^ 蘿 ^ ω IM ω ω ω ω 3 〇 Ren 2 :) 1 2 ^ 1 0 ^ 6 OM, 6S00 / 86df / XDd 6SS / 86 OAV Example 6 (S) -5- (3- (tert-butoxycarbonylamino) benzyl) 3- (3-phenylureido) -1,2,3,4,5-tetrahydro-1,1,5-benzothiazepine Synthesis of 4 _ on (1 — 6 2)

(First step) (S) — 3-Amino — 5— (3- (tert-Butoxycarbonylamino) benzyl) 1,2,3,4,5-tetrahydro-1,5 -— [5] benzothiazepin-4-one (Compound 21)

From the compound 20 (0.43 mmo 1) described in the literature (Chem. Pharm. Bu 3 4, 1128 (1986)), the same as Example 12 was obtained. After N-alkylation by the method, deprotection was carried out in the same manner as in Example 16, Step 3, to give the title compound.

Yield 80.7% amorphous

O-NMRiCDC) δ: 1.50 (9H, s), 1.80 (2H, brs), 2.80-2.94 (lH, m), 3.52-3.66 (2H ₁ m), 5.06 (2H, s), 6.47 (lh , brs), 6.95 (lH, d, J = 7.4Hz) ₎ 7.12 (6H, m), 7.58 (lH, dd ₇ J = 1.6Hz.7.4Hz)

IR v max (KBr): 3351, 2974, 2927, 1723, 1662, 1610, 1544cm ¹

Elemental analysis: (as C ²⁶ H ³⁴ N ⁴ O ⁶ S.0.2C ³ H ⁸ O.0.3H ² O)

Obtained: J, 62.62; 11, 6.62; ^ 10.25; 3, 7.64

Calculated values: C, 62 · 38; H, 6.63; N, 10.01; S, 7.57

(2nd step) Compound (1 — 6 2)

(1-62) The title compound was obtained from compound 21 (0.133 mmo 1) obtained in the first step, in the same manner as in Example 24, third step.

Yield 94.2% amorphus

! H-NMRCCDCla) δ: 1.49 (9H, s), 2.91 (lH, t, J = l 1.4Hz), 3.82 (lH, dd, J = 6.6, 11.4Ηζ), 4.

80 (2H, m), 5.31 (lH, d, J = 15.9Hz), 6.60 (lH, brs), 6.68 (lH, s), 6.93 (lH, brs) ₎ 6.94 (2H, d,

J = 7.5Hz), 7.03 (2H, t, J = 7.5Hz), 7.10 (lH, t ₎ J = 6.9Hz), 7.19-7.26 (4H ₎ m), 7.35 (lH, t, J =

6.6Hz), 7.47 (lH, brd, J = 8.1Hz), 7.64 (lH, d, J = 7.2Hz)

IR v max (KBr): 3377,2976,2927,1652,1600cm- ¹

Elementary analysis: (as _{_{_{_{C 26 H 34 N 4 O 6}}}} S.0.1C 6 H 14)

Obtained: 〇, 65.19; 11,6.12;] ^, 10.71; 3,5.89

Calculated value: (:, 65.15; 11,6.00 ;: ^, 10.63; 3,6.08 Example 6 21-(3- (tert-butylacetylacetylamino) benzyl) 13- (2- (N-nitroguanidino) ) Synthesis of acetylamino) 1,2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (I-63)

(First step) 3-Amino-1- (3- (tert-butylacetylamino) benzyl) 1,2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (compound twenty two )

Compound 5 (0.717 mmo 1) was N-alkylated in the same manner as in Example 12 and then reduced in the manner of Example 15 to obtain the title compound.

Yield 88.3% Amorphous 6 £ / S ::, 6oo / s86dT / ld

H (sqHH NH sS o day 2 --.--

O

isNiJ: H0 69z / 9s6ssii:-* .- " Example 6 31-((4-benzyloxy) benzyl) 1-3- (2- (N-nitroguanidine) acetylamino) 1,2,3,4,5-tetrahydro-1H-1 -benzazepine 1-2 On (1 — 6 4) composition

(First step) 3 _Amino 1 — ((4-benzyloxy) benzyl) — 2,3,4,5-tetrahydro-1 H—1 —Benzazepine 12 _one (Compound 23) Compound 5 (0.29 N-alkylation was carried out from 6 mmo 1) in the same manner as in Example 12, and then reduced in the same manner as in Example 24, Step 2, to obtain the title compound.

Yield 90.0% amorphous

! H-NMRCCDCh) δ: 1.61 (2H, brs), 1.82 (lH, m), 2.24-2.48 (3H, m), 3.37 (lH, m), 4.74 (lH, d, J = 14.4Hz) ₎ 5.00 (2H, s), 5.26 (lH, d, J = 14.4Hz) _> 6.84 (2H, d, J = 8.4Hz), 7.13-7.41 (l lH, m)

IR v max (KBr): 3016,3006, 1654, 1601,1508cm ¹

(2nd step) Compound (1- 64)

From compound 23 (0.720 mmo 1) obtained in the first step, the title compound was obtained in the same manner as in Example 62, the second step.

Yield 20.7% amorphous

! H-NMRCCDCla) δ: 2.03 (lH, m), 2.42 (3H, m), 3.99 (2H, m), 4.36 (lH, m) ₎ 4.71 (lH, d, J = 14.4Hz), 4.96 (lH , s), 5.18 (lH, d, J = 14.8Hz), 6.71 (2H, d, J = 7.0Hz), 7.06-7.38 (llH, m), 7.74 (2H, brs)

IR max (KBr): 3399,3329、1648,1510cm ¹

Elementary analysis: (as _{_{_{_{C 27 H 28 N 6 0 5}}}} )

Observed value: (3,63.75; 11, 6.38 ;: ^, 14.74

Calculated value: (2,63.77; 11, 3.35; 1 ^ 14.87 Example 6 41- (3- (tert-butylacetylamino) benzyl) -1-((2 —Guanidino) acetylamino) Synthesis of 1,2,3,4,5—tetrahydro 1 H—1 —benzazepine 1 2—one (1—65)

A 10% palladium-carbon (16 mg) was added to a 10% acetic acid / methanol solution (4.4 ml) of the compound (1 to 63) (0.115 mmo1), and hydrogen atmosphere was added. After stirring for 13 hours in the middle, the catalyst was filtered and the solvent was distilled off. The residue was purified by PTLC (cloth form Z methanol ZNH 4 OH = 60/101) to obtain the title compound.

Yield 36.3% amorphous

'H-NMRCCDCb) (5: 1.05 (9H, s), 1.90 (3H, s), 2.20 (2H, s), 2.05-2.76 (4H, m), 3.95 (2H, d, J = 2.0 Hz), 4.37 (lH, m), 4.81 (lH, d, J = 15.0Hz), 5.31 (lH, d ₎ J = 14.8Hz), 6.96 (lH, d, J = 8.4Hz), 7.14-7.48 (9H, m)

IR v max (KBr): 3330,2955, 1657, 1600, 155 lcm ¹

Elementary analysis: (as _{_{_{_{C26H27N 3 O 3 .0.1C6Hi4.0.3CHCl 3 .1.8H 2}}}} O)

Observed value: (:, 56.47; 11, 6.79; 1, 13.35

Calculated value: 〇, 56.40; 11,7.09 ;: ^ 13.65 Example 6 51-((4-benzyloxy) benzyl) —3-(((2-guanidino) acetylamino) —2,3,4,5-tetrahydro Synthesis of 1H-1 and 1-benzazepine-2-one (1 to 66)

The title compound was obtained from the compound (1-64) (0.140 mmo 1) in the same manner as in Example 64.

Yield 33.7% amorphus

! H-NMRCCDaOD) δ: 1.92 (3H ₁ s) ₎ 2.02-2.51 (4H, m) ₎ 3.94 (lH, d _> J = 1.8Hz), 4.33 (lH, dd, J = 7.6Hz, 11.6Hz), 4.67 (lH ₎ d, J = 14.6Hz), 5.26 (lH ₎ d, J = 14.4Hz), 6.63 (lH, d, J = 8.2Hz), 7.01 (2H, d, J = 8.6Hz), 7.20 ( 2H, m), 7.36 (2H, m)

IR v max (KBr): 3373, 1654, 1601,1552, 1515cm ¹

Elemental analysis: (as C ² oH ² ₃ N ⁵ 0 ₃ .C ² H ⁴ 0 ² .1.3H ² 0) OAV t6S £ //-6oo / 86DlsfcyJ «One

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≠ 2 Synthesis of 1- (3-carbomethoxyamino) -1,2,3,4,5-tetrahydro-1-H-1-benzazepin-2-one (1-74)

Example 2 5 A solution of compound 9 (0.131 mmo1) obtained in the second step in ethyl acetate (3.0 Oml) was added to potassium carbonate (0.39 mmo1) and water (1. 5 ml), add methyl carbonate (0.39 mmol) under cooling with water, stir at room temperature for 15 hours, add water and 10% hydrochloric acid, and extract twice with ethyl acetate. did. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue was purified by silica gel chromatography (form: methanol / methanol = 40: 1) to obtain the title compound.

Yield 93.8% m p. 18 3— 18 4 ° C

! H-NMRCCDCh) δ: 1.49 (9H, s), 1.96 (lH, m), 2.46-2.69 (lH, m), 3.36 (lH, s), 4.32 (lH, m), 5.00 (2H, s) , 5.66 (lH, brd, J = 7.8Hz), 6.66 (lH, s), 6.85 (lH, brd, J = 7.5Hz), 7.12-7.22 (2H, m), 7.45 (lH, d, J = 8.4 Hz)

IR record π ^ χίΚΒι ^^ ΑΤ ^ δΒ ^ δΒ,, δΙ, ΙΒ ΙδΑβϋπι- ¹

Elementary analysis: (as ^{^{^{^{C 24 H 29 N 3 O 5}}}} .0.15H 2 O;)

Obtained:, 65.19; 11, 6.74; 1 ^, 9.54

Calculated value: 65.19, 6.68; 9.50 Example 7 4 1 — (3- (tert-butoxycarbonylamino) benzyl) — 3- (2-mercapto-3_phenylpropionylamino) 1,2,3,4, Synthesis of 5-tetrahydro-1H-1-benzazepin-1-one (1-75)

H, brs), 4.50 (lH, d, J = 14.4Hz), 8.48 (lH, d, J = 6.6Hz)

IR v max (KBr): 3254, 1721,1653, 1609, 1543cm ¹

Elementary analysis: (as _{_{_{_{C 2 4H 3 oN 4 0 4}}}} .0.25CHCl 3 .1.0H 2 0)

Obtained: 60.52; 11,7.09; 1 ^, 11.06

Calculated values: 〇, 60.61, 6.90; ^ 11.20

(2nd step) Compound (1 — 7 6)

The title compound was obtained from the compound (0.177 mmo 1) obtained in the first step in the same manner as in Example 62, the second step.

Yield 65.6% amorphous

O-NMRCCDCls) δ: 1.50 (9H, s), 1.63 (lH, m), 1.98 (lH, m), 2.40-2.65 (3H, m), 3.09 (2H, m), 3.50 (lH, m), 4.44 (lH, m), 4.91 (lH, dd, J = 4.2,15.0Hz), 5.06 (lH, d, J = 15.0Hz), 6.56 (lH, brs), 6.83 (lH, d, J = 7.8Hz ), 6.91 (lH, brs), 7.12-7.27 (13H, m), 7.40 (lH, d, J = 8.1H z)

IR v max (KBr): 3324,2977,2931, 1725, 1652, 1604, 1533cm ¹

Elemental analysis: (as CWH NSC S.O.II ^ O)

Observed: 0, 67.44; 1 ^ 6.57; 1 ^, 7.67; 8, 5.88

Calculated value: (, 67.34; 6.53;, 7.60; 8,5.80 Example 7 6 1 — (3- (tert-butoxycarbonylamino) benzyl) — 3--(3- (3-methanesulfonylamino) propionyla Synthesis of Mino) — 2,3,4,5 —Tetrahydro-1H-1 —Benzazepine-2-one (1 — 77)

Under ice-cooling, a solution of compound 24 (0.177 mmol) obtained in the first step in tetrahydrofuran (2.0 ml) was added to a solution of mesyl chloride (0.21 mmol) in tetrahydrofuran (2.0 ml). A solution of lahydrofuran (1.0 ml) was added and stirred at that temperature for 30 minutes. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off. The residue is subjected to silica gel chromatography.

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Example 8 35- (3- (tert-Butoxycarbonylamino) benzyl) -3- (3- (benzyloxycarbonylamino) propionylamino) -2,3,4,5-tetrahydro-5- Synthesis of benzothiazepine—4-one— (I—_84)

Example 6 1 From compound 21 (0.204 mmo 1) obtained in the first step and N—C bz — / 3 —alanine (0.235 mmol), Example 6 2 second step The title compound was obtained in the same manner as in.

Yield 6 1.6% mp. 86 ° C (decomposition)

! H- negation _{R (CDC1 3) δ: 1.50} (9H, s)) 2.43 (2H, t, J = 5.5Hz), 2.84 (lH t, J = 11.2Hz), 3.44 (2H, m)> 3.74 ( lH, dd, J = 6.6,11.0Hz), 4.68 (lH ₎ m), 4.97 (lH, d, J = 15.4Hz), 5.07 (2H, s), 5.09 (lH, d, J = 15.0Hz), 5.37 (lH, brs), 6.57-6.69 (2H, m), 6.93 (lH, d, J = 7.6Hz), 7.16-7.39 (lH, m), 7.59-7.63 (lH, m)

IR record max (KBr): 3322,2975,2930,1722,1654,1610,1535cm- ¹

Elemental analysis: (as C ₃₀ H ₃ 4N4O ₃ S)

Found: 0, 63.69; 11, 6.36; 1 ^ 9.26; 3, 5.30

Calculated value: (, 63.65; 11,6.16; 1 ^, 9.11; 3,5.21 Example 8 4 (R) -3- (3-benzyloxycarbonylaminoaminopropionylna) -5— (3— (tert (Butoxycarbonylamino) benzyl) one

2,3,4,5—Tetrahi draw 1,5—Benzoxazepine--4--4-one (I—

8 5) Synthesis (First step) (R) — 3— (3- (benzyloxycarbonylamino) propionylamino) 1,2,3,4,5—tetrahydro-1 15—benzobenzoazepine—4-one (Compound 27)

Compound 26 (0.466 mmol) and N—Cbz described in the literature (Chem. Phram. Bui, 34, 1128 (1986)). The title compound was obtained from / 3-aranine (0.560 mmo 1) in the same manner as in Example 62, the second step.

Yield 6 1.6% mp. 178-179 ° C

O-NMRCCDCh) δ: 2.52 (2H, t, J = 6.0 Hz), 3.47 (2H, q, J = 6.3 Hz), 4.17 (lH, t, J = 10.5 Hz), 4.64-4.69 (lH, m ), 5.42 (lH, brt, J = 4.9Hz), 6.87 (lH, brd, J = 6.0Hz), 6.99-7.21 (4H, m), 7.32 (5H, s), 8.06 (lH, s)

IR v max (KBr): 3315,3247, 1710, 1680, 1647, 1603cm- ¹

Elemental analysis: (as C ₂₀ H ₂₁ N ₃ O ₅ )

Found: C, 62.43; H, 5.58; N, 11.14

Calculated value: (], 62.65; 11,5.52;] ^, 10.96

(2nd step) Compound (I-185)

Using compound 27 (0.250 mmo 1) obtained in the first step and meta- (tert-butoxycarbonylamino) benzyl bromide (0.3000 mmo 1), The title compound was obtained in the same manner as in 12.

Yield 7 2.1% amorphous O-NMRiCDCIs) (5: 1.49 (9H, s), 2.46 (2H, m), 3.45 (2H, q, J = 6.0Hz), 4.16 (0.5H, d, J = 7.2Hz), 4.20 (0.5 H, d, J = 6.9Hz), 4.63 (0.5H, d, J = 7.5Hz), 4.66 (0.5H, d, J = 7.2Hz), 4.98 (lH, m), 5.05 (lH, s) , 5.07 (lH, s), 5.34 (lH, brs), 6.50 (lH, brs), 6.58 (lH, d, J = 7.5Hz), 6.89 (lH, d, J = 7.13-7.35 (llH, m)

IR max (KBr): 3326, 1707, 1655, 1610, 1597, 1534cm. ¹

Elemental analysis: (as CSSH ^ NAOT.O.SCSHW.O.SHSO)

Observed value: (, 65.15; 11,6.53;] ^, 9.19

Calculated value:, 65.23; 11,6.50; 1 ^, 9.17 Example 8 51- (3- (3-isopropylureido) benzyl) — 3— (N′-methyl-N ′ ′ — 4-hydroxyhydroxy Synthesis of 1,2,3,4,5-tetrahydro- 1 H- 1 -benzazepin-12-one (1-86)

(First step) 3-Azido-1- (3_ (N'-isopropylureido) benzyl)-2,3,4,5-tetrahydro-1H-1 -benzazepin-2-one (Compound 29)

Compound 5 (13.5 g) was suspended in 160 ml of tetrahydrofuran, and 3- (3-isopropyl) peridobenzylbromide (compound 28; 20.8 g), n was added under a nitrogen stream and ice cooling. —Tetrabutylammonium bromide (2.15 g) and powdered hydroxide (4.81 g) were sequentially added, followed by vigorous stirring. The mixture was further stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate and ice water, the ethyl acetate layer was washed with brine, dried, dried under reduced pressure, the residue was purified by gel chromatography, and the compound was crystallized from ethyl acetate and hexane. 29 (21.0 g) was obtained. mp. 9 9-10 3 ° C

NMR (300M) (CD ₃ OD) δ: 1.15 (6H, d, J = 6.6), 2.20 (lH, m), 2.36 (lH, m), 2.56 (2H, m), 2.84 (2H, m ), 4.76 (lH, d, J = 14.7), 2.84 (2H, m), 4.76 (lH, d, J = 14.7), 5.33 (lH, d, J = 14.7), 6.80 (lH, d, J = 7.5), 7.11 (lH, t, J = 7.5), 7.20 (3H, m), 7.30 (3H, m).

Elementary analysis: (as _{_{_{_{C 2 iH 2 4N 6 0 2}}}} O.ICH3CO2C2H5)

Obtained value: 〇, 64.33; 11, 6.29; 1 ^, 20.65

Calculated value: 64.03; 11, 6.24; 1 ^, 20.90

(Second step) 3-amino-1 (3- (3-isopropylureido) benzyl)

2,3,4.5-Tetrahydro-1H-1 _benzazepin-12-one (Compound 3

0)

Compound 29 (20.5 g) and 10% palladium-carbon (2.0 g) were transferred into methanol (500 ml), subjected to normal pressure catalytic reduction, filtered, and the filtrate was dried under reduced pressure. As a result, a foamy compound 30 (18.3 g) was obtained.

NMR (300M) (CD ₃ OD) δ: 1.15 (6H, d, J = 6.6), 1.86 (lH, m), 2.3 l (lH, m), 2.40-2.65 (2H, m), 3.36 (lH, dd, J = 7.5,11.7), 3.85 (lH, m), 4.82 (lH, d, J = 14.7), 5.24 (lH ₁ d, J = 14.7) ₎ 6.8

3 (lH, d, J = 7.5), 7.14 (lH, t, J = 7.5), 7.2 (6H, m).

Elemental analysis: (as C ₂ iH ₂₆ N4O ₂ 0.2H ₂ O)

Measured value: 〇, 68.09, 7.19; 1 ^, 15.14

Calculated value: (, 68.16; 11,7.22;] ^, 15.20

(3rd step) 1- (3- (3-isopropylureido) benzyl) 1-3- (N '-(4-Methoxymethyloxyphenyl) thiourede) — 2,3,4,5-tetra Hydro-1H-1 -Benzozepin-2-one (Compound 32) NHCONH-i-

Compound 30 (1.22 g) was dissolved in 12 ml of acetonitrile, and thiocarbonyldiimidazole (1.40 g) was added under cooling at 50 ° C, and the mixture was further allowed to stand at room temperature for 10 minutes. Stirred for 10 minutes under. To this was added paramethoxymethyloxyaniline (2.60 g), and the mixture was stirred for 1 hour. Ethyl acetate and water were added to the reaction solution, and the mixture was shaken. The ethyl acetate layer was dried, dried under reduced pressure, and then subjected to silica gel chromatography to obtain Compound 32 (3.50 g). NMR (300M) (CD ₃ OD) δ: 1.14 (6H, d, J = 6.3), 1.95 (lH, m), 2.5-2.7 (3H, m), 3.43 (3H, s), 3.85 (lH, m ), 4.83 (lH, d, 15.2), 5.00 (lH) dd, J = 6.0,10.0), 5.17 (2H 1 s), 5.21 (lH, d, J = 15. 2), 6.86 (lH, d, J = 7.0), 7.0-7.4 (llH, m)

(Fourth step) 3— (3— (4-Hydroxyphenyl) thioureido) 1-1— (3— (3-Isopropylperido) benzyl) 1-2,3,4,5—Tetrahydro-1H— 1 Benzozepine—2-one (Compound 33)

32 33

The compound 32 (2.50 g) obtained in the third step was dissolved in 10 ml of methylene chloride, trifluoroacetic acid (5 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Toluene (5 ml) was added, and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate. The crystals were washed with water, dried and evaporated to dryness under reduced pressure to obtain a foamy compound 33 (1.90 g). NMR (300 M) (CD ₃ OD) δ: 1.13 (6H, J = 6.3), 1.95 (lH, m), 2.5-2.7 (3H, m), 3.85 (lH, m), 4.81 (lH, d , J = 14.7), 4.99 (lH, dd, 6.9,10.8), 5.22 (lH, J = 14.7), 6.81 (2H, d, J = 8.7), 6.83 (lH, d, J = 7.0), 7.10 (lH, m), 7.11 (2H, d, J = 8.7), 7.2-7.4 (6H, m).

(Step 5) 3- (3- (4-Hydroxyphenyl) -12-methylisothioperide) 1-111 (3- (3-isopropylureido) benzyl) 1-2,3,4,5- Tetrahydro—1H—1—Benazepine—2—one (Compound 34)

Compound 33 (1.80 g) obtained above was dissolved in acetonitrile (30 ml), and methyl iodide (3 ml) was added, followed by stirring at room temperature for 3 hours. After the reaction solution was evaporated to dryness under reduced pressure, it was dissolved in ethyl acetate and shaken vigorously with aqueous sodium carbonate. The ethyl acetate layer was dried and dried under reduced pressure to obtain a foamed compound 34 (1.56 g).

NMR (300M) (CD ₃ OD) δ: 1.14 (6H, J = 6.3), 2.l (lH, m), 2.3 l (3H, s), 2.5-2.7 (3H, m), 3.86 (lH , m), 4.97 (lH, d, J = 15.0), 5.11 (lH, d, J = 15.0), 6.5-6.7 (4H, m), 6.89 (lH, d, J = 7.2), 7.01 (lH, t, J = 7.8), 7.1-7.3 (6H, m).

(Step 6) Compound (I_86)

The compound 34 (200 mg) obtained above was dissolved in a 20% methylamine solution in ethanol (2 ml), heated in a sealed tube at 70 ° C for 6 hours, and dried under reduced pressure. The residue was developed and eluted with butanol-acetic acid / water (5: 1: 1) using silica gel thin layer chromatography. The product is shaken with ethyl acetate and sodium carbonate water, and the ethyl acetate layer is dried under reduced pressure to give a foamy compound.

(1 — 86) (52 mg) was obtained.

(1 — 8 6) p owd e r

NMR (CD ₃ OD) δ: 1.13 (6H, dd, J = 6.3, 1.8), 2.05 (lH, m), 2.5-2.7 (3H, m), 2.82 (3H, s), 3.8 3 (lH, m ), 4.30 (lH, dd, J = 7.2,10.0), 4.85 (lH, d, J = 15.0), 5.20 (lH, d, J = 15.0), 6.63 (2H, d, J = 8.7), 6.75 ( 2H, d, J = 8.7) , 6.80 (lH, t, J = 7.5), 7.07 (lH, t, J = 7.5), 7.2-7.4 (6H, m) elemental analysis: (C ₂₉ H ₃ 4N _G O ₃ .0.5H ₂ O)

Obtained: (, 66.22; 11, 6.75;] ^, 15.77

Calculated value: 0, 66.52; 11, 6.74; 1 ^, 16.05 Reference Example 1 Synthesis of Compound 28

(First step) 3- (3-Isopropyl peridode) benzyl alcohol (Compound 36)

35 36

Dissolve 3-aminobenzyl alcohol (compound 35; 25 g) in 455 ml of acetonitrile, and cool isopropyl isocyanate (22.O ml) in acetonitrile under ice-cooling. The (60 ml) solution was added over 10 minutes. The mixture was further stirred at room temperature for 45 minutes and at 50 ° C for 2 hours and 30 minutes. Ethyl acetate (300 ml) was added to the reaction solution, and the mixture was left for 30 minutes. The precipitated crystals were collected by filtration to obtain compound 36 (35.3 g).

m p. 144 1 5 ° C

NMR (300M) (CD ₃ OD) δ: 1.17 (6H, d, J = 6.6), 3.88 (lH, m, J = 6.6), 4.55 (2H, s), 6.96 (lH, d, J = 6.9) , 7.24 (2H, m), 7.32 (lH, s).

(2nd step) 3- (Methanesulfonyloxymethyl) -N- (isopropylaminocarbonyl) aniline (Compound 37) sCI-Et ₃ N

NHCONH-i-Pr NHCONH-i-Pr

36 Compound 36 (2.34 g) was dissolved in dimethylformamide (23 ml), and triethylamine (2.04 ml) and methanesulfonyl chloride (1.13 ml) were added under ice-cooling. And stirred for 1 hour. The reaction solution was transferred to a mixture of ethyl acetate and ice water, and after shaking, the ethyl acetate layer was washed with water, dried, the solvent was distilled off, and the residue was crystallized from ether to give compound 37

(2.66 g) was obtained.

m p. 1 1 δ-1 18 ° C

NMR (300M) (CD ₃ OD) δ: 1.17 (6H, d, J = 6.6), 3.03 (3H, s), 3.88 (lH, m, J = 6.6), 5.20 (2H, s), 7.04 (lH , m), 7.32 (2H, m), 7.50 (lH, m).

Elementary analysis: (as C ₁₂ H ₁₈ N ₂ 04S)

Found: C, 50.14; H, 6.27; N, 9.69; S, 11.21

Calculated values: (, 50.33; 11,6.34; 9.78; 8,11.20

(Step 3) Compound 2 8

37

Compound 37 (2.60 g) was dissolved in dimethylformamide (20 ml), and lithium bromide (1.21 g) was added under ice cooling, and the mixture was heated at the same temperature for 1 hour and 20 minutes. Stirred. After adding ethyl acetate and water to the reaction solution and shaking, the ethyl acetate layer was washed with water, dried and evaporated to dryness under reduced pressure. The residue was crystallized from ether to obtain Compound 28 (2.38 g).

m p. 1 62-16 5 ° C

NMR (300M) (CD ₃ OD) δ: 1.17 (6H, d, J = 6.6), 3.88 (lH, m, J = 6.6), 4.50 (2H, s), 7.01 (lH, m), 7.23 (2H , m), 7.45 (lH, m).

Elemental analysis: (as CuH ₁₅ N ₂ OBr) Obtained: (, 48.72, 5.59; 1 ^, 10.36 ;: 81 ", 29.18

Calculated value: (:, 48.73; 11,5.58; 1 ^, 10.33;: 61:, 29.47 Example 8 61— (3- (3-Isopropylureido) benzyl) —3— (3-phenylureido) Synthesis of 1,2,3.4,5—Tetrahydro 1H—1—Benazepine-12-one (1—87)

30 (1-87)

Example 8 5 The compound 30 (lOOmg) obtained in the second step was dissolved in 1 ml of acetonitrile, phenylisocyanate (50 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction solution, and the mixture was allowed to stand. The precipitated crystals were collected by filtration to obtain a compound (1-87) (97 mg).

(1-87) m p. 22 9-230 ° C

NMR (CD30D) (5: 1.14 (6H, d, J = 6.3), 2.00 (lH, m), 2.4-2.7 (3H, m), 3.85 (lH, m) ₎ 4.36 (lH, dd, J = 7.3, 11.3), 4.84 (lH, d, J = 15.0), 5.26 (lH, d, J = 15.0), 6.84 (lH, d, J = 7.8), 6.97 (lH, t, J = 7.6), 7.1-7.4 (llH, m)

Elemental _{_{_{analysis: (C 28 H 31 N 5}}} 0 3 as.)

Observed value: (3,69.25; 11,6.47; 1 ^, 14.40

Calculated value: 69.26; 11, 6.43; 1 ^, 14.42 Example 8 7 1 — (3 — (3 — isopropyl ureido) benzyl) 3 3 — (3 — benzothiazolyl 6 — yl) ureide ) Synthesis of 1, 2,3,4,5 -tetrahydro-1H-1 -benzazepine-2 -one (1-8 8)

(Step 1) 1 1 (3 — (N'-Isopropylureide) benzyl) — 3 — ( οττ

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(8 8— 1)

. S ¾ (S in S S ΐ) (8 8-1) Tsuchi C) T1f "^ —: r— 1i—, ^

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(88-Ι) 8ε

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Z.6S00 / 86df / X3d [6Se / 86 O did. After drying under reduced pressure, ethyl acetate and sodium carbonate water were added to the residue, and the mixture was vigorously shaken. The ethyl acetate layer was washed with water, dried and dried under reduced pressure. The residue was washed with ether, purified by thin-layer silica gel chromatography using acetate nitrile-methanol, and crystallized from ether to give the title compound (72 mg).

(1-89) m p. 1 32-1 35 ° C

NMR (CD ₃ OD) δ: 1.49 (9H, s), 2.00 (lH, m), 2.56 (2H, m), 2.69 (lH, m), 4.45 (lH, dd, J = 7.8,12.3) , 4.95 (lH, d, J = 15.3), 5.15 (lH, d, J = 15.3), 6.85 (lH, d, J = 8.0), 6.9-7.1 (5H, m), 7.l-7.4 (7H , m)

Elemental _{_{analysis: (. C 29 H 33 N5O}} 3 .0.5 (C2H5) as a ₂ O)

Found: C, 69.25; H, 7.10; N, 12.95.

Calculated value: (3, 69.38; 11, 7.14; 1 ^, 13.05

Example 8 9 1- (3- (3-Isopropylureido) benzyl) -3- (3-phenylthioureido) 1-2,3.4,5-tetrahydro-1H-1 Benzozepine-2 —On (1 — 90) synthesis

30 (1-90)

Example 8 Compound 30 (300 m) obtained in the second step was dissolved in 1 ml of acetonitrile, phenylisothiocyanate (135 mg) was added under ice-cooling, and the mixture was stirred at room temperature. Stir for 1 hour. The precipitated crystals were collected by filtration to give the compound (1-90) (360 mg).

(1-90) m p. 195-197 ° C

_{NMR (CD 3 0D) δ:} 1.15 (6H, d, J = 6.3), 1.95 (lH, m), s), 2.5-2.7 (3H, m), 3.86 (lH, m), 4.88 (lH, d , J = 15.0), 5.03 (lH, dd, J = 7.2,10.1), 5.17 (lH, d, J = 15.0) _I 6.86 (lH, d, J = 7.5), 7.13 (lH, t, J = 8 .!), 7.2-7.4 (1 lH, m). Elementary analysis: (as _{_{_{_{C 28 H 31 N 5 0 2}}}} S.)

^ fl C, 67.01; H, 6.32; N, 13.94; S, 6.48

Calculated value: 65.18; 11,6.18; ^ 1,14.62; 3,6.39 Example 9 0 1 — (3- (3-isopropylpropyl) benzyl) — 3 _ (N 'Feniru N' ' — Tirguazidino) 1 2, 3, 4, 5 ——Tetrahydro 1 H

Synthesis of 1 _benzazepine-2-one (1-9 1)

(First step) 1 1 (3- (3-Isopropylureido) benzyl)-3- (S-methyl-3-phenylisothioureido) 1-2,3,4,5-tetrahydro-1H-1- Benzozepine 1-one (compound 4 1)

The compound (1-90; 300 mg) was suspended in 3 ml of acetonitrile, methyl iodide (0.3 ml) was added, and the mixture was stirred for 1 hour. After drying under reduced pressure, add ethyl acetate and sodium carbonate water to the residue and shake vigorously. Wash the ethyl acetate layer with water, dry and dry under reduced pressure to obtain a foamy compound (compound 41; 290) mg).

NMR (300M) (CD ₃ OD) δ: 1.15 (6H, d, J = 6.6), 2.13 (lH, m), 2.30 (3H, s), 2.4-2.7 (3H, m), 3.85 (lH, m ), 4.51 (lH, dd, J = 7.0,10.2), 4.97 (lH, d, J = 15.0), 5.08 (lH, d, J = 15.0), 6.73 (2H, d, J = 7.5), 5.9 -7.0 (3H, m), 7.1-7.3 (8H ₎ m).

(2nd step) Compound (I-I-91)

41 (1-91)

To 40 l of the compound (230 mg) was added lml of a 40% solution of methylamine in methanol, and the mixture was heated at 80 ° C for 4 hours in a sealed tube. After drying under reduced pressure, the residue was purified by thin-layer silica gel chromatography using acetonitrile-methanol acetic acid (3: 1: 0.2) to obtain the title compound (140 mg) as a powder.

(1 — 9 1) p owd e r

NMR (CDsOD) δ: 1.14 (6H, d, J = 6.3), 1.98 (lH, m), 2.4-2.7 (3H, m), 2.73 (3H, s), 3.83 (lH, m), 4.30 ( lH, dd, J = 7.2,10.4), 4.88 (lH, d, J = 15.3), 5.14 (lH, d, J = 15.0), 6.83 (3H, m), 6.91 (lH, t, J = 7.5) , 7.03 (lH, t, J = 7.5), 7.1-7.4 (8H, m)

Elementary analysis: (as _{_{_{_{C 28 H 3 2N 6 O 2}}}} .0.3H 2 O)

Found: C, 69.36; H, 6.99; N, 16.41.

Calculated value: 〇, 69.11; 11,6.92; 16.67 Example 9 1 1— (3- (3-tert-butyl-butyl) benzyl) -1-3- (3-phenylureido) 1-2,3,4,5-tetrahydro- 1 H— 1—Ben

Synthesis of one-two-on (1-9 2)

(Step 1) 1 _ (3-aminobenzyl) — 3-azido 2,3,4,5-tetrahydro 1H—1—benzazepine-12-one (compound 42)

8 42

Example 25 5 Compound 8 (1.50 g) obtained in the first step was added to 10 ml of methylene chloride. S £ / OAV: Amazing

R top i ¥ Π ^! Dimensions :: * b /: b: ku

Dimension

CO

Dimensions

Daughter (H ¾ΛA H

() a ΐ Ί ΐ Λ 口、- 6i / s! I:

(First step)

— 7 —

2 — ON

Compound 1 (

Lomid (5.7

Obtained.

Yield 7 5.δ

'H-NMR (CDC1 ₃₎

3.95 (1H, m). 4.

d, J = l. oHz), 6.

IR v max (KBr)

Elemental _{_{_{analysis: (C 22 H 26 N 6}}} 0 3 0. 1H 2 0 0. 1 CHC1 3 as) Found: C, 60. 85; H, 6. 18;, 19. 09

Calculated: C, 60.85; H, 6.07;, 19.27.

(2nd step)

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6S00 / 86df / I d lf6S £ / 86 O 3—Chloro 1— (3- (3_Isopropylureido) benzyl) —2,3,4,5-tetrahydro-1H— [1] Benzozepin-12—one (0.775 mm o 1) 4,5-Diphenyl-1-methyl-1H-imidazole-2-thiol (0.799 mmol) and sodium iodide (0 ml) were added to a dry methanol solution (6 ml). After cooling to 0 ° C., 20 ml of a 1 M sodium methoxide methanol solution was added. The reaction solution was heated under reflux for 48 hours, cooled, added with water, extracted with ethyl acetate, washed with water and concentrated. The residue was purified by silica gel chromatography (form: form Z acetone = 60 Z 1) to give the title compound.

Yield 12.6% m p. 23 8-240 ° C

_{'H-NMR (CDC1 3)} δ: 1.05 (6H, d, J = 6.3Hz), 2.37-2.48 (lH, m), 2.55-2.89 (3H, m), 3.41 (l H, s), 3.71 ( lH, m), 3.83-3.94 (lH, m), 4.67 (lH _! d, J = 13.8Hz) _; 4.69 (2H, brs), 5.21 (lH, d, J = 14.1Hz), 6.79 (lH, d , J = 7.8Hz), 6.96 (2H, brs), 7.10-7.21 (8H, m), 7.24-7.28 (lH, m), 7.38-7.44 (6H, m).

IR record max (KBr): 3326,2971,1652,1601cm ¹

Elementary analysis: (as _{_{_{_{C 37 H 3 7N 5 0 2}}}} S O.8H2O)

Observed: 〇, 70.52; 11,6.17, 11.11; 8,5.09

Calculated value:, 70.52,6.31;] ^, 10.98,3,4.85 Example 9 63- (5-amino-2-phenyl-2H— [1,2,4] triazole-3-yl-amino) Synthesis of 1 1 — (3- (3-Isopropylureido) benzyl) 1, 2,3,4,5-tetrahydro 1H_ [1] -benzazepin-12-one (I 1167)

46 (1-167) The title compound was obtained from compound 46 (0.783 mmo 1) and phenylhydrazine (2.35 mmo 1) in the same manner as in Example 94, step 1.

Yield 15.6% amorphous

_{'H-NMR (CDC1 3)} δ:. \ 09 (6Η, d, J = 6.6Hz) .1.94-2.05 (1H, m), 2.47-2.70 (. 3H m), 3.90 (1 H, m), 4.33 (1H, m), 4.77 (1H, d,] = 14.8Hz) .4.98 (2H.brs), 5.11 (1H, d, 1 = 15.2Hz), 5.30 (1H, brs), 6.80 (1H, d , J = 7.OHz), 7.01-7.16 (7H, m), 7.23-7.29 (iH.m), 7.38-7.45 (6H, m).

IR v raax (KBr): 3368. 1660cm— ¹

Elemental analysis: (as C ₂₉ H ₃ iN ₈ 02 O.ICGHH O.8H2O)

Observed value: (3,65.13; 11,6.27; 1 ^ 20.48

Calculated value: 65.04; 11, 6.27 ^, 20.50 Example 973- (5-Ami-1 monomethyl-2H— [1,2,4] triazole

3-yl-amino) 1-11 (3- (3-isopropylureido) benzyl)

3,4,5-tetrahydro- 1H— [1] benzene—2- (I—168 and 3— (5-amino-2-methyl-2H— [1,2,4] triazo Ill-3yl-amino (3-isopropylureido) benzyl) — 2,3,

Synthesis of 5-tetrahydro 1 H— [1] benzene 1 2 —one (I169)

46 (1-168) (1-169)

The following compounds were obtained from compound 46 (0.842 mmoI) and methylhydrazine (5.05 mmo1) in the same manner as in Example 94, the first step.

(1-1 6 8) Yield 9.5% mp. 159 ° C (dec.)

Marauder R (CDCl3) δ: 1.09 (6H, t, J = 6.0Hz), l.95-2.05 (1H, m), 2.46-2.73 (3H, m), 3.30 (3H, s), 3.92 (lH , m), 4.22 (lH, m), 4.62 (lH, d, J = 14.4Hz), 4.81 (2H, brs), 5.19 (2H, m), 6.82 (lH, d, J = 7.5Hz), 7.06 -7.18 (6H, m), 7.44 (lH, d, J = 7.5Hz), 7.71 (lH, m).

IR record max (KBr): 3367、2967、2933、1656,1600cm ¹

Elemental analysis: (as C ₂₄ H ₃₀ N _s O ₂ 0.7H ₂₀ )

Found: C.60.75; H, 6.69; N, 23.71.

Calculated: C, 60.67; H, 6.66; N, 23.58

(1 — 1 6 9)

Yield 90.0% mp.153-157 ° C

_{'H-NMR (CDC1 3)} (5: 1.09-1.13 (6H, m), 2.01-2.11 (lH, m), 2.48-2.62 (2H, m), 2.73 (lH, m), 3.37 (3H, s ), 3.94 (lH, m), 4.06 (2H, brs), 4.36-4.46 (lH, m), 4.57 (lH, d, J = 15.9Hz), 5.

25 (lH, m), 5.36 (lH, d, J = 15.6Hz), 6.81 (lH, d, J = 7.5Hz), 6.85 (lH, s), 6.98 (lH, brs), 7.0

8-7.23 (5H, m), 7.69 (lH, d, J = 7.8Hz).

IR record max (KBr): 3330,2869, 1659, 1603cm ¹

Elementary analysis: (as _{_{_{_{C24H 30 N 8 O 2 0.4C4Hi 0}}}} O'0.6H 2 O)

Found: C, 61.24; H, 6.91;, 23.06

Calculated value: C, 61.01; H, 6.85; N, 22.95 Example 98 8-16 4 Synthesis of other compounds

Hereinafter, other compounds were synthesized in the same manner. The compounds synthesized and physical properties are shown below. table 1

R ³ n

RRR ⁴ X

I-2 HH-CH ₂ C〇0 small Bu NHCONHMe CH ₂

| -3 HH-CH ₂ CONH-t-Bu NHCONHMe CH ₂

I-4 HH CO NHCONHMe CH ₂ ₁

CH ₂ ₁

1-12 HH CH ₂

-CH ₂ C0-Q NHCONHMe

¹¹

1-13 HH NHCONHMe CH ₂

1-14 HH NHCONHMe CH ₂

NHCONH-

1-16 HH-(CH ₂ ) ₃ NH ₂ C ₆ H ₄ -p-OBn CH ₂

NHBoc NHCONH-

1-17 HH — (CH ₂ ) ₃ HN NBoc C ₆ H ₄ -p-OBn CH ₂

NHBoc

NHCONH-

1-18 HH CH ₂

-(CH ₂ ) ₃ HN NBoc C ₆ H ₄ -p-OH

NH ₂ NHCONH-

1-19 HH-(CH ₂ ) ₃ HN NH HCI C ₆ H ₄ -p-OH CH ₂ Table 2

R ¹ R ² R ³ 'R ⁴ X n

1-1 HH m-NHBoc NHCONHMe CH _{2 1} 59 H 7-OMe m-NHBoc NHCONHMe CH ₂ ¹

! -28 HH m-NHBoc NHCONHBn CH ₂

¹¹

I-43 HH m-NHBoc NHCONH (CH ₂ ) ₂ -CH ₂

¹ C ₆ H ₄ -p-OBn

I-44 HH m-NHBoc NHCONH (CH ₂ ) ₂ -CH ₂

C ₆ H ₄ -p-OH ¹

I-47 HH m-NHBoc NHCONMe ₂ CH ₂ 1

I -93 HH m-NHBoc NHCONH-i-Pr CH ₂

I-94 HH m-NHBoc NHCONH-t-Bu CH ₂

¹¹

I-25 HH m-NHBoc NHCONHPh CH ₂ 26 HH o-NHBoc NHCONHPh CH ₂

I-95 H H m-NHBoc NHCONHPh 0

I-46 HH m-NHBoc NHCONH- CH ₂

C ₆ H ₄ -p-COOH

I-32 HH m-NHBoc NHCONH- CH ₂

C ₆ H ₄ -p-Tet

1-31 HH m-NHBoc NHCONH- CH ₂

C ₆ H ₄ -p-OS0 ₃ Na

Table 4

R ¹ R ² R ³ 'R ⁴ X n

1-38 HH m-NHBoc CH ₂ 1

1-39 HH m-NHBoc CH ₂ 1

To NHCONH I N

1-40 HH m-NHBoc I, N CH ₂ 1

HCONH ^^ N

Ts

_{1-41 HH m-NHBoc I CH 2} 1

NHCONH N

I-97 HH m-NHBoc NHCONH.Ό CH ₂ 1

I-98 HH m-NHBoc CH ₂ 1

U 99 HH m-NHBoc NHCONHCOPh CH ₂ 1

1-100 HH m-NHBoc NHCONHS0 ₂ P CH ₂ 1

R ¹ R ² R ³ 'R ⁴ X n

1-5 HH pt-Bu NHCONHMe CH ₂

¹¹

1-8 HH p-OBn NHCONHMe CH ₂

¹¹

I- I u H H m-NHCbz NHCONHMe i 12

1-1 1 HH m-NHC〇CH ₂ Small Bu NHCONHMe 2

1-15 HH p-OH NHCONHMe CH ₂ 24 HH m-CN NHCONHPh CH ₂

I -48 HH m-NH ₂ NHCONHPh CH ₂

I-49 HH m-NHS0 ₂ Me NHCONHPh CH ₂

I-50 HH mN (S0 ₂ e) ₂ NHCONHPh CH ₂

_{1-51 HH m-NHS0 2 -i-} Pr NHCONHPh CH 2 -101 HH m-NHCO-N 0 NHCONHPh CH 2 -102 HH mN (Boc) Me NHCONHPh CH 2 Table 6

R ¹ R ² R ³ 'R ⁴ X n

NHCONHC ₆ H ₄

1-20 HH m-NH ₂ CH ₂

-p-OBn 1

NHBoc NHCONHC ₆ H ₄

1-21 HH CH ₂

To m-NH NBoc -p-OBn 1

NHBoc NHCONHC ₆ H ₄

I -22 H H

To m-NH NBoc -p-OH CH ₂ 1

NH ₂ NHCONHC ₆ H ₄

Ι-23 HH CH ₂

-NH NH ^HCI -p-OH 1 m

OPh

Ι-52 H H

ΓΤΙ-ΝΗ ^Λ ΝΟΝ NHCONHPh CH ₂ 1

NHMe

Ι-54 H H NHCONHPh

m-NH CN CH ₂ 1

SMe

Ι-53 HH NHCONHPh CH ₂ 1 m-NH ^N 〇2

NHMe

Ι-55 HH _m-NH N0 ₂ NHCONHPh CH ₂ 1

Ι-27 HH NH ₂

NHCONHPh CH ₂ 1 m ^ NH HCI 〇

Table 10

R R R H to n

NN0 ₂

m MHPO

I-63 H H Π2

-CH ₂ small Bu NHCOCH ₂ NH NH ₂

NNUp

I-64 HH p-OBn 义 CH ₂

NHCOCH ₂ NH NH ₂ ¹

NH

m-NHCO

I-65 H H then Π2

-CH ₂ small Bu NHC〇CH ₂ NH NH ₂

NH

U 66 HH p-OH CH ₂

NHC〇CH ₂ NH NH ₂

I-67 HH m-NHBoc NHCOCH ₂ NHCbz CH ₂

I-68 HH m-NHBoc NHCO (CH ₂ ) ₂ NHCbz CH ₂ 69 HH m-NHBoc NHCO (CH ₂ ) ₃ NHCbz CH ₂

I-70 HH m-NHBoc NHCO (CH ₂ ) ₄ NHCbz CH ₂

1-71 HH m-NHBoc NHCO (CH ₂ ) ₅ NHCbz CH ₂

I-76 HH m-NHBoc NHCO (CH ₂ ) ₂ NHCOMe CH ₂

I-77 HH m-NHBoc NHCO (CH ₂ ) ₂ NHS0 ₂ Me CH ₂

I-78 HH m-NHBoc NHCO (CH ₂ ) ₂ NHCONHMe CH ₂

I-79 HH m-NHBoc NHCO (CH ₂ ) ₂ NHCONHBn CH ₂

I-80 HH m-NHBoc NHCO (CH ₂ ) ₂ NHCONH-n-Pr CH ₂ CO

Jay x

NHC〇〇 N8HNH 〇〇ο〇〇 HNH

NHroo

O 〇〇 X X x

6oo / 8.s6df / 13d

Η * t6oo86 $ y OAV.s / K76S-1 13d

Ητ〇 Η) εοΗ) α3) ΐ266ε

Calculated values: 〇, 69.53; 11, 6.69; ^> 1, 10.81

(1-10 3) m p. 2 1 0— 2 15 ° C

NMR (CDsOD) δ: 2.01 (lH ₎ m), 2.4-2.6 (2H, m), 2.65 (lH, m), 4.36 (lH.dd, J = 7.4, 11.7) _> 4.83 (lH, d, J = 14.7), 5.28 (lH, d, J = 14.7), 6.87 (lH, d, J = 6.3), 6.96 (lH, t, J = 6.6), 7.14 (lH, t, J = 7.0), 7.1- 7.4 (10H, m).

Elemental analysis: (as C H NSOSSL)

Observed value: (:, 67.66; 11, 5.77; 1 ^, 15.63

Calculated value: (, 67.71; 11,5.68; 1 »1,15.79

(1-104) m p-2 3 8-2 39 ° C

_{_{NMR (CD 3 0D-CDC1 3}} ) δ: 2.05 (lH, m), 2.5-2.8 (3H, m), 2.76 (3H> s)) 4.42 (lH, dd, J = 7.5, 11.4), 4.93 (lH , d, J = 15.0), 5.15 (lH ₎ d, J = 15.0), 6.86 (lH, d, J = 7.6), 6.96 (lH, t, J = 7.6), 7.l-7.4 (HH, m ).

Elementary analysis: (as _{_{_{_{C 26 H 27 N 5 0 3}}}} )

Observed value: 〇, 67.99; 11,6.01;] ^, 15.16

Calculated: C, 68.25; H, 5.95; N, 15.31

(1-105) mp.> 230 ° C

NMR (CD ₃ OD) δ: 0.5 (2H, m), 0.73 (2H, m), 2.0 (lH, m), 2.4-2.8 (2H, m), 4.52 (lH, dd, J = 7.5,11.7) , 4.74 (lH, d, J = 15.3), 5.26 (lH, d, J = 15.3), 6.82 (lH, d, J = 8.1), 6.96-7.03 (2H, m), 7.1-7.3 (9H, m ), 7.65 (lH, d, J = 8.1).

Elemental analysis: (C ²⁸ H ²⁹ N; as 5O ³ .0.5H ² O)

Obtained: (3,68.35; 11,6.08; ^, 14.07

Calculated values: 0, 68.27; 11, 6.14; 1 ^, 14.22

Mass: m / z [M + H] ⁺ 484 (1-106) mp. 180-180. C

NMR (CD ₃ OD) δ: 1.33 (9H, s), 1.95 (lH, m), 2.33 (lH, m), 2.55 (2H, m), 2.65 (3H, s), 4.29 (lH, dd, J = 7.5,10.0), 4.85 (lH, d, J = 15.0), 5.18 (lH, d, J = 15.0), 6.81 (lH, d, J = 7.8), 7.1-7.4 (7H, m). value: (as _{_{_{_{C 2 4H 31 N 5 O 3}}}} .0.4.AcOEt)

Found: 0, 65.07; 1 !, 7.29 ;: ^, 14.96

Calculated: 65.07; 11, 7.29 ^, 14.81

(1 — 1 0 7) p owd e r

NMR (CD ₃ OD) δ: 0.93 (3H, t, J = 6.6), 1.1 K3H, d, J = 6.6), 1.46 (2H, dq, J = 6.6, 6.6), 2.0 (lH, m), 2.38-2.72 (3H, m), 3.66 (lH, m), 4.36 (lH, dd, J = 7.5, H.8), 4.83 (lH, d, J = 14.7), 5.26 (lH, d, J = 14.7), 6.84 (lH, d, J = 7.5), 6.95 (lH, m), 7.1-7.4 (llH, m).

Elementary analysis: (as _{_{_{_{C 29 H 33 N 5 O 3}}}} .0.2H 2 O)

Obtained value: 〇, 69.07; 11, 6.64; 1 ^, 13.80

Calculated value: (, 69.21; 11,6.69;] ^, 13.91

Mass: m / z [M + H] ⁺ 500

(1-10 8) mp. 1 5 7 — 1 60 ° C

NMR (CD ₃ OD) δ: 2.04 (lH, m), 2.50 (2H ₎ m), 2.70 (lH, m), 4.38 (lH, dd, J = 7.5 ₎ 11.5), 4.88 (111, (1 = 15.0), 5.28 (111, (1 ^ = 15.0), 6.9-7.1 (311, £ 1,1 ^, 7.1-7.5 (1511,1 ^ Elemental analysis: (0

3lH29N ₅ 0 _3. )

Observed value: (, 71.67; 11,5.71; 1 ^, 13.48

Calculated values: 〇, 71.66; 11,5.63; 1 ^, 13.48

(1-10 9) m p. 2 3 7— 2 39.5 ° C

NMR (CD ₃ OD-DMSO-d ₆ ) δ: 1.13 (6H, d, J = 6.6), 3.82 (lH, m), 4.30 (lH, m), 4.55 (lH,

NMR (CD ₃ OD) δ: 1.14 (6H, d, J = 6.6), 2.0 (lH, m), 2.4-2.7 (3H, m), 3.85 (lH, m), 4.35 (l

H, dd, J = 7.2, ll.l), 4.83 (lH, d, J = 14.7), 5.28 (lH, d, J = 14.7), 6.84 (2H, d, J = 7.8), 7.12 (l

H, t, J = 7.8), 7.2-7.4 (7H, m), 7.53 (2H, d, J = 9.3), 8.11 (2H, d, J = 9.3).

Elementary analysis: (as _{_{_{_{C2 8 H 30 N 6 O 5}}}} .0.5H 2 O)

Observed: (, 62.31; 11,5.92; 15.74

Calculated values: 〇, 62.33; 11,5.79 ^, 15.57

Mass: m / z [M + H] ⁺ 531

(1-1 1 3) mp. 2 1 0— 2 16 ° C

NMR (DMSO-d _G ) δ: 1.07 (6H, d, J = 6.6), 1.9 (lH, m), 2.3 (lH, m), 2.45-2.7 (2H, m), 2.79 (6H, s) , 3.7 (lH, m), 4.2 (lH, m), 4.74 (lH, d, J = 15.0), 5.26 (lH, d, J = 15.0), 5.92 (lH, d, J = 7.5), 6.33 (lH, d, J = 8.1), 6.63 (2H, d, J = 9.0), 6.71 (lH, d, J = 7.5), 7.07 (lH, t, J = 7.5), 7.13 (2H, d , J = 9.0), 7.25 (4H, m), 7.32 (lH, dt, J = 2.5,7.5) ₎ 7.420 (lH, d, J = 7.5), 8.25 (lH, s), 8.37 (lH, s) .

Elementary analysis: (as _{_{_{_{C 30 H 3G N 6 O 3}}}} .0.5SiO 2)

Obtained value: (, 64.47; 11, 6.61 ^, 14.91

Calculated: 64.50; 11,6.49;] ^, 15.04

Mass: m / z [M + H] ⁺ 529

(1 — 1 1 4) mp. 2 3 3-2 3 7 ° C

NMR (CD ₃ OD) 6: 1.14 (6H, d, J = 6.6), 2.00 (lH, m), 2.34-2.74 (3H, m), 3.85 (lH, m), 4.35 (lH, dd, J = 7.8,11.7), 4.83 (lH, d, J = 14.7), 5.25 (lH, d, J = 14.7), 6.84 (lH, d, J = 7.8), 6.95 (2H, t, J = 9.0), 7.12 (lH, t, J = 7.8), 7.16-7.38 (8H, m).

Elemental analysis: (as C ₂₈ H ₃₀ N ₅ O ₃ F)

Found: 〇, 66.78; 11, 6.01; 13.91, 3.77

Calculated values: (3,66.81; 11,6.01; 13.84,3.79 a 6 6 T-Z 6 Tdi (8 T ΐ-I)

OSS ₊ [H +] ^Z / ∞ ^{: S} SBPM '(rS = f''HT)AL'8' (A-8 ^ = f'PP'Hl) 0r8 '(ra'H8) f'8-A' ( ra'HS) LT-A '(S'Z _i = f'P'Hl) ^ 8-9' (i '^ T = f'P'Hl) 6S-S' (^^ T = f'P ' HT) 38 ''(e-TTO'Z _i = f'PP'HT) 9 ''(∞'HI)S8'S'(∞'HS) iZ Sf ^'(∞'Ηΐ) 90 '(S'9 = f'P'H9) ri: 9 (σθ ^ε σθ) Η1Α [Ν

j 3 p M. o d (I I-I)

Γ9ΐ'Ν ^: 0ε9'Η''εΓ99'Ο: Kake i 3'9 "['9'1 ^ 0" [^ 9'0: Thigh

(1 ?? 0 ⁹ Ν ^ζε Η ⁸² 0) ^: ϋ} ½ ^ ¾ ^ • (s'HT) 69-8 '(s ^, HT) ^ 3'8' (8 = f'P'Hl) 60 -8 '(Hl) 0A'L' ( 8-A = f'P'H T) S ^ 'A' (i ra'Hl) 88'A <(UI 'Ht') SS "L '(9' L = f 'HT) 80'Z,'(∞'HS)Si'9'(8"A = f'P'Hl) eQ ^, 9' (8L = P'P'Hl) T6'S '(9I -f'P'Hl) LS "S '(8-eT = P'P'Hl) eA ^' (« i'Hl) 0S '^'(s'He) LZ, '8'(∞'H ΐ ) Z S '(∞'HS) 6S'(∞'Ηΐ) εε (∞'Ηΐ) 00 '(S-9 = f'P'H9 0'? ( ⁹ P "OSHa) ¾lA [N

2 S 2-8 Z Z-d ui (9 T I-I)

I9-9'S ^: LI'9l'N ^: A6'e'H ^: L6'09'3: 5} ^ + I ΐ2 · 9'8 ^: 90 · Δΐ ' ^: εΖ,' 9Ή ^: 96 · 09Ό: ΐ!} Ρϊ ^ (in? S ^S 0 ⁹ N ^8S H ^SZ 0): Cor ½, Mine

'Hl) 08'L'(∞'HS) 8S-Z, -9rA '(8'Z, = r'VHT) 80'i' ( ^ra 'HT) 90'L'(9'8 = f'P 'HT) T0'i' (eL = f 'P'Hl) Si'9' (SA = f'P'HT) 06'9 '(9T = f'P'Hl) 0e'S' (SI = f'P 'Hl) ^ L'(∞'Hl) TS ''(ra'H I) S S '(∞'HS) 09' (™ 'HI) 8S'(∞'HI) t6 '"I' (9 ' 9 = f'P'H9) time 0ΐ: ρ ( ⁹ P-OSWa) HWN

J 3 Ρ ο d (9 I I-I)

6SOO / 86df / 1 d If6S € / 86 O OAV One

e

οαο I (α) AS H 8 ΐ

eoe ₊ [H + H] ^z / ^{m: ssB}

9 9I'N ^: S0'9'H ^: 68'S9'O ^: relax · 9ΐ'Ν ^: λΟ'9'Η ^ 8'ε9'0 '· ΗΗ (one? Ο ^ Ηε-Ο-' Ό ^ οεΗ ^ θ) ^} ^ ¾? Ί • ( ^{s [} q'HT) 9ril '( ^s ' Hl) 6S'8' ( ^s ' Hl) ^ S "8 '(LS = f'P'Hl) 8t'-A '(8'Z, = f'P'HT) S' i '(∞'H 9) 9S',-rL '(0-8 = f'VHl) ₁ 0-L' (SL = f'P'Hl) '9' (8-L = f'P'HT) L '9' (9.6 = Γ'Ρ'ΗΙ) 8 S-9 '(8'Z _i = f'P' Hl) l6-9 '(8-9T = f'P'HT) A2'S' (S-SI = f'P'HT) ^ A ^ '( ^ra ' HT) ei '^'(ra'Hl) SL • S '(∞'HS) 8S -9'(∞'HI) 0S '(∞'HI) SG'"['(S'9 = f'P'H9) 0 0: 9 ( ⁹ P" OSHa ) HWN ao z-ε ο ζd ui (gs τ-I)

9i + [H + IA [] ^z / ∞ ^{: SSB} W 9r0S'N ^: SS'9'H ^: 9S 9 ': Tough i IS'0' N ^: S 9'H ^: 0S'S9'O:?! ii? (in? (^ Η · 0 ' ^ε ΟΝ ^6ε Η 0) ^: ^、, Mine

"5 = i ⁱ 'P'Hl) SS-L'(∞'He) 88-L-iri '(0-8 = P ⁱ Hl) 80'L' (eA = f'P'HT) Si'9 '( ^sj q'H3) SS-9' (SL = f'P'HT) 86 "S '(8" I = f'P'HS) 08 "e'(8'ST = f'P'Hl) 9S'S '(8-ST = f'P'HT) Li '(ra' HI) (ui'HI) Z S '(∞'HS) S9' ( 'Η3) ΐε'(S'9 = f'P ' H9 0-I:? ( ⁹ P-OS a) HIA [N

j 3 p Mod (

99-ST'N ^: T0-9'H: 8e-69'D: i!} Ri¾ (1ma · ^ε0 ⁹ ^ε ^εε ^Ηιε Ο): Ul ½ Mine 3 ^ (e ^ ^< SI = f 'PP'Hl)S9'8^< (∞ ⁱ HT) 9T-8 '(^-S = f'P'HI) 66-A'(0'6 = f'P'Hl) 88'A '(0- 6 ^ -S = f'PP'HT) 09-A '(0-8'0 ^ = f'PP'HT) ^^' L '( ^UI ' He) Se-L '(∞'H8) SS- A '(0-8 = f' HT) eT-L '(8

^ 6S00 / 86df / XDd 6SC / 86 OAV 6 la 9 I-8 3 I 'd ui (6 2 I-I)

9f ΟΙ ' ^: 9'9'Η ^: 65 · 89'0 · | 1 ^ + | SS'0I'N ^: 9S'9'H ^: 69— 89'O: The first thigh?

• (∞'HSI) · Α-ΓΖ (8

= f'P'Hl) 88-9 '(0-ei = f'P'Hl) S ^' e '(s'HS) ^ 0-S' (0-9T = f'P'HT) 88- t ''(A'Il'e'A = f'PP'H l) 9ri ''(∞'Hl) ^ 8'8 '(∞'HS) S'2' (ra ^< Hl) S ^ '( ∞'Hl) l'2 '( ^s ' H9) ^ T'I ^: 9 (αθ ^ε αθ) ΗΗΝ ΐ ZI-89 I-d (82 I-I)

_{^{Τ05 + [Η + Μ] Ζ}} / ∞: 85Β Μ -time ^{6 · 3ΐ'Ν · '9 9'Η:} 8ΐ · 99'0:! Ϊ meaning

36-SrN ^: 99 "9'H ^: S3-99'0: |]} fi | g

(ェ 0 ^S H 0'Ο 3SS.0 ' ^s O ⁹ N Η ^8Ε 0): ¾½ ^ draft ^

• (ui

'H6) i'-i-rL'(∞'H ^) 88 ^, 9 '(0'ST = f'P'Hl) S ^ 'e' (0 "ST = f'P'Hl) S8 '( i'irr8 = f'PP'H SS ''(UI'HI)S'S'(ra'HS) M-· 2' (™ 'Ηΐ) 0' (9-9 = f'P'H9) W [: 9 ((ΙΟ ^ε αθ) ϊ [

J s pA o d (S I-I)

0 '31' ^{^:} 96-9'1 ^ 93 9'0: Hiroshi ^{^{^{00-51 'N: S6'9'H;8A'S9'0:}}} ¾K ^ (1 wife O ^z Hf Ο ^ Ο ^^ Η ^ Ο) · !!!! ^^^^ (ra'H) '-r // (8 = f'P'HI) S8'9' (i I = f'P'H l) 0S'e '(A ^ T = f''HT) e8 ^'(S-TI'A'A = f ^< PP'Hl) 6S'i ' ^, ( ^UI ' Hl) S8-8 '(∞'HS) Se- e '(∞ ^, HS) 6rS' (™ 'HS) Z S-S'S' (™ 'HI) SS'(∞'HI)S6'r(S'9 = f'P'H9) Sri: ρ (αθ ^ί: αθ) ΗΗΝ

J 9 ρ ο d (9 2 Τ-I)

6S00 / 86dfAIDd 6S £ / 86 OAV ε / OAV one

Η [ί] / f + ζαΙ M O

m) Η) 5 (Ho0ΐ69)) (aao lior6s) I ∞s «"-* · Εΐ'Ν ^: 99 · 9'Η ^ 0 · 89'Ο: Hana

0 · εΓΝ ^: "9'Η ^: 8 ム 9'0: 嗨嗨 (ιη? · ^ 0 ³ Ν ^5ε Η ^οε θ) ^: ϋ½ ^^ 3ί (∞'Ηεΐ)--S'9 '(0'SI = f'P'HI) M o's '(o'si = P'P'HT) e8 ^' ( ^ra 'Hl) 0r ^ ^, (s'H8) 99 ^, S'(ra'HS)A'3-S ^ '(™' Hl) 86-i: 9 (αθ ^ε αθ) ΗΙΑ [Ν j 9 pod (g ε T-I)

SI9 ₊ [H + lA [] ^z / ^rass¾ P \ [

-(m'H

0l) SS-Z _i -0'Z, '(S'i = r'P'H2) t'6-9' (Gi = f'p'Hl) A8 "9 ⁱ (0-QI = f'P 'HT) 0S "e' (0-SI = i ¹ 'P'Hl) 06 ^ ^< (T'Tl'2'i = f'PP'HT) T ^''(∞'He)9-S' ( ^ra 'Hl) S0-S'(s'H6) 6 ^ -T: 9 ((ΙΟ ^ε αθ) N j 9 pod (ε ι _ ι) i-ie ₊ [H + H] ^z / ^mssB M

S9'SI'N ^: 6rZ H6.9 · 9'0: |!} Pl? Towing

(χη? ο¾ε · ^ " ^ε ο ⁵ Ν ^3ε Η ^οε ο) ^: ΐ!} ½ ^^ 3ί

^, (ra'HSl) i'-i-0-i '(i''L = f'P'HS) 8-9 ^< (8 ^ I = f'P'Hl) S ^ -S' (8 ^ T = P'P'Hl) 8 ^ '(f'"ir9'A = f'PP'HT) ie '^'(∞'H8)S6-'( ^ra ' H8) 8'5 ^^ '(∞ 'HT) S "S' ( ^s ' H6) 8 ^ -i: Q (αθ ^ί: αθ) ΗΙΑ [Ν

-i 3 AV o d (ε ε T-I)

^^ • SI'N- S "A'H ^: ITO9'0 ^: @> ^-| SI'N ^: 66'9'H: 0S'09'O: lHii (1 7 O ^s HS ' ^s O ^s N ⁶ 0): Hajime ½

(ui'He) SZ, -S'A '(ra'H8) G'L-S'L' (r8 = f '^ HT) iri' (9-L = r'P'HT) 88-9 ' (^ -TT = i ^> 'P'HT) SS-S' (^ 'TI = P'P'Hl) 8A'i''(S-3T'e

Z, 6S00 / 86df / I3d ϊ »-6δε / 86 OW (1-1 3 6) mp. 150-15 3 ° C

_{NMR (CDC1 3) δ: 1.50} (9H, s), 1.95 (lH, m), 2.5-2.8 (3H, m), 4.30 (2H, m), 4.70 (lH, d, J = 2 0.0), 5.32 (lH, d, J = 20.0), 6.8-7.4 (13H, m)

Elemental _{_{_{analysis: (C 29 H 33 N 5}}} O4..0.2 (C2H 5) as. 2O)

Measured value: (, 67.84, 6.65, 13.20

Calculated value: (, 67.65; 11,6.63; 1 ^ 13.00

Massm / z [M + H] ⁺ 516

(1 — 1 3 7) p owd e r

NMR (CDsOD) δ: 1.49 (9H, s), 1.95 (lH, m), 2.15 (lH, m), 2.34 (lH, m), 2.52 (lH, m), 2.89 (6H, s), 3.99 ( lH, dd, J = 7.5,11.5), 4.77 (lH, d, J = 15.0), 5.09 (lH, d _! J = 15.0), 6.61 (2H, d, J = 7.2), 6.69 (2H, d, J = 7.2), 6.77 (lH, d, J = 7.2), 6.9-7.3 (9H, m)

Elementary analysis: (as _{_{_{^{C 29 H 33 N 5 O4..0.2H 2}}}} O)

Observed value: (, 70.03; 11,7.12; ^ «1,13.00

Calculated value:. , 70.09;! 1,7.10; ^^ 13.18

(1-1 3 8) p owd e r

NMR (CDsOD) 0: 1.47 (9H, s), 1.94 (lH, m), 2.10 (lH, m), 2.38 (lH, m), 2.50 (lH, m), 3.15 (4H, m), 3.55 ( 4H, m) ₁ 3.97 (lH, dd, J = 7.5,10.5), 4.78 (lH, d, J = 14.5), 5.10 (lH, d, J-14.5), 6.69 (2H, d, J = 6.9), 6.78 (lH, d, J = 6.9) _> 6.72 (lH, t, J = 7.0), 7.0-7.3 (9H, m)

Elementary analysis: (as _{_{^{^{C 3 3H 3 9 N 6 O}}}} 4 .0.5H 2 O)

Obtained: (, 68.63, 7.04; 11.75

Calculated values: 0, 68.49; 11, 6.97 ;: ^, 12.00

(1-1 3 9) p owd er ir t6S £ / 6 6sod1 o υ

₉₃₉₃

6+ H) a〇ΐο (.) Painting δ "

S s) 99 Ma V u 6soo / 86yD OAfcId

o

00

Hs (s9) 0ΐ

H H day *

(qΐ) (ΐ09 Η) H6ΐ8 (SJ date 0/86 6S0MV1.

O

: Η) 6ΐ days-¾H / eN¾H0SISS

η? (0Ν9 O or £ / AV6si S .:

6SI f'P'HT) 8S "Z, '( ^UI ' H8) TS-i-eri '(8 = f' HT) 0rL '(Z _< '8'9-T = f'PP'HT) tO- i '(8'L = f'P ^, HS) L9-9'(8'5T = f'P'HT) irS ^< (r8 = f'P'Hl) 88 '(SI-f'P ^< Hl) iA '( ^ra ' HT) 6 ^^ '( ^ra ' Hl) S 6'8 '(s'H8) 88 "8' ( ^ra 'H8) t'9-S-98-S' ( ^ra 'HT) S8-T '(9'9'l'e = f'PP'H9) e0-T: ( ⁸ IOaO) HlA [N

(0 9 ΐ-I)

999 AU + m) ^z / ^{m SSB} M 09'S'S'SrZJ'N ^: 86'S'H-'S6 '9' ^: Intention 1 85'3'8 ^: 69'91'1 ^ ^: M 0'9'1 ^ 11 '89'0 ^: 1! Thigh

(Put: O ^Z H

• (s'Hl) S0'6 '(A'8 = P'P'Hl) t'8-Z i' (8-I = f'P'HT) li''A '(ra' H8) eZ 'L-96'9'(∞'HT) S8-9 '(0-9I = f'P'Hl) irS'(0'9T = P'P'HT) ^ 8- ^: {'' (t '-IT'S'i = P'PP'HT) t'S-f '' (« ^I 'H l) S8'8'(∞'H8)LA'S'(∞'H8) OA ^ -9S-2' ( ^ra 'Hl ) eO ^ '(9-9 = P'P'H9) en: (aO ^f; aO) aiA [N j 9 p A od (63 I-I)

L9 + (H + PV) ^z / ^{ra SSB} 9 'S'S ^: 0rSi:' N ^: 6 S'H ^: S 9'0: Hana}

(Emm S ^s O ⁹ N ^zs H ^0S O) ^: ^ 挲 ( ^s 'Hl) ^ 0'6' (f ⁷ ^ = f'P'HT) 6r8 '(A-8 = r'P' HT) 68'L '( ^ra ' H8) 98-L-8S--'(ra'HS) i'ri-80'L' ( ^ra 'Hl) 08-9' (T ^ I = f'P ' HT) 6S'S '(r ^ I = F'P'HT) 09 ^' ( ^ra 'Hl) 80 ^' ( ^ra 'HT) 88-8'(∞'H ΐ) 05 · ^ '(∞Ή2) ε0 '' (∞Ή2) ε8'ΐ '( ^ιΙΙ ΉΤ) ΐ5'Τ ^, (9 · 988Ι = Γ'ΡΡ ^, Η9) ετΤΤ (σθ ^ε αθ) ΗΙΜΝ

D „9 I C-Ζ I 2 'd ui (8 S ΐ-I)

^{^{^{'S8'ST'N: 3r9'H: Le'99'0: #}}} ^ + | ■ 88' ^ Τ'Ν: 6Τ · 9'Η · '8ζ · 99'0: ίιϊ ^ (: L one Ma ^s O ^s N ^{£ S} H ^0S O)-l!} ½ ^ ¾5i .6S00 / 86df / X3d [6SC / 86 O 09τ ς Q g 'LSI' ux n IUI o 3. Sa s Λ do 1 g · ui aoo 1 g

^ 晕 112 · ^ 玆 ^ ΐ people d N ΐ ^ 鄉 ^ f9 + (Η +) ^ζ / ^{ω SSB}

E8'e's ^: 8s-Qi'N ^; e9'e'H ^: ee-89'o ^: i!} ^ + I

• 88-e'S ^: T0 "Sl'N ^: 69'S'H ^: ^ -89'O: affile

(One? O ^z i / f

'(s'HI) IO'S' (8 = Ρ'Ρ'Η

X) _iL 9- _i '(ui'H0l) 0 ^'L-0T'L'(QL = f'P'HT) 06-9' (Z, T = f'P'HT) 0S'e '( L-i'I = P'P'Hl) e8 "'(ΐΐ'8' Muni f'PP'IH) 6S't '(s'H9) S'S' (™ 'HS) Mun-8ε'2' (™ 'Ηΐ) 00 · δ: (αθ ^ε αθ) ΗΜΝ j 9 p AV od (29 I-I)

SS'S'S ^: S6'SI'N ^: 9Z S'H ^: I8'S9'0 ^: ¾Rg

(i? O ^Z HS / I

• (∞'ΗΤ) 66 · Δ '(8 · Τ = Γ'Ρ'Ηΐ)

98Ζ / (∞'Η3) ΙΖ -S9'Z (S = f'P'in) 9S '丄'(∞'H9) W -Sr / (8 = f HT) 0r '(8'A = i ⁾ 'P' Hl) ^ 8'9 '(A'i'I = f'P'Hl) t' ^ '5' (^ 'f'I = f'P'Hl) i ^^' (L 'irS'A = f'PP'Hl) e8 ^' ( ^UI 'HT) ^ 8' e '(s'H8) S6-S'(∞'H8)SA-S-9S'S'( ^ra ' HT) ^ 0 ^ '(9-9'eI = f'PP'H9) ST'T: (aO ^e aO) HlAtN

(T 9 I-I)

SS-5'S ^: 89-n'N ^: 99-g'H ^: I8'S9'0 ^: @} g -I8S'S'S ^ S '"II'N ^: I9'S'H ^: SS'S9O ^: Thigh O ^z H9 / ZS ^s O ^s N ^ss H 0): ¾

'( ^ra ' HS) S6'i-88-L '(S

Ϊ́ = Γ'Ρ'ΗΤ) Α8 · '(Τ'8'9Ι = Γ'ΡΡ'Ηΐ) 8ΔΑΑ' (^ · 8 = f'P'Hl) Te-A '(ra'H2 ) 8f''L-6e'L '(r5 =

L6S00 / 86df / IDd If6Se / 86 OAV Using SK—N—MC cells (manufactured by American Type Culture Collection) cultured by the method described in 157 1 (1992), in the presence of the compound (I) of the present invention, or was incubated for 1 hour ^{1 2 5} I one labeled base peptide YY (about 5 0 0 0 0 cpm) in 3 7 ° C in the absence. ^{1 2 5} I - labeled peptide YY is peptide YY - the (D u P ont N ew Ltd. E ngland N uc 1 ear Inc.) was used as the ^{1 2 5} I labeled by a conventional method. After completion of the reaction, the glass fiber filter paper ^{1 2 5} bound to cells I - labeled base peptide YY separated, was boss measure the radioactivity in gamma prime counter evening one. Specific binding was determined by subtracting the non-specific binding which was obtained nonradioactive NPY under conditions comprising 1 0- ⁷ M. ^{1 2 5} I on cells - IC as the concentration of the compound of the present invention that specifically binds to inhibition 50% of the labeled base peptide YY (I) _5. Values were calculated. The results are shown below.

Compound name IC ₅ 0 (// M)

I I 1 1 .3

1-1 0 1 0

1-1 1 6.9

1-2 3 7.4

1-2 5 0. 8 7

1-2 8 1 .3

1-3 0 0. 3 6

1-3 1 4.5

1-3 2 2.6

1-3 5 2. 3

1-3 6 6.4

1-3 7 2.4

1-3 8 2.4

1-3 9 0. 1 8

1-4 0 0.7

1-4 2 1.0

1-5 6 2.6

1-5 8 6.4

1-5 9 1.6

1-6 0 0.5

1-6 1 1.5

1-6 21.0

1-6 3 6.0

1-6 4 4.5

1-6 5 2. 3 Compound name IC _s (/ i M)

1-1 4 0 3.3-1 1 1 0. 0 9 0

1-1 4 3 0 .0 4 0-1 1 2 0 .0 9 7

1-1 4 4 0 .0 0 8 0-1 1 3 0 .0 7 3

1 — 1 4 5 0 .0 7 2-1 1 4 0 .0 3 2

丄 1 4 t) Π π 1/1-1 1 5 0. 1 8

U U o b-1 1 6 0 .0 6 9 Π o o

U. U Z o-1 1 7 0. 7 6

U 1-1 1 8 0. 1 7 1

I — 1 b U u. (J l y-1 1 9 0 .5 4

1 — 1 b 1. U U o 4-1 2 0 0. 0 9 1

Ub-1 2 1 0 .2 6 1b b U. (J 14-1 2 2 0 .3 0 1/1

U —— 丄 b 4 u. U 1 I y-1 2 3 0. 0 6 2

1 — 1 0 0 U. U U ob

1-1 2 5 0 .6 0

丄 —— 丄 b> U. U Ό

1-1 2 6 8.5. 5 1

丄 —— 丄 b Π U. N U Π U

1-1 2 7 0 .4 4

U 丄 b ϋ U. U 丄 t)

1-1 2 8 0. 3 5 1 Q

D Π π Π

1-1 2 9 0 .2 3

1-1 6 0 0 .0 0 4 3

1-1 3 0 0. 3 4

1-1 6 1 0 .0 0 3 2

1-1 3 1 0 .0 4 3

1-1 6 2 0 .0 0 5 8

1-1 3 2 0. 3 5 1 — 1 6 3 0. 1

1-1 3 3 0 .0 8 1

1 — 1 6 4 0. 0 9

1-1 3 4 0 .9 0

1-1 6 5 1 .2

1-1 3 6 1. 4

1-1 6 7 0 .1 2

1-1 3 9 4. 2

1-1 6 8 0 .8 0

1-1 6 9 3 .7 Formulation example Tablet

Compound of the present invention 15 mg

1 5 mg

Lactose 15 mg

Crystalline cellulose 19 mg

Polyvinyl alcohol 3 mg

30 ml of distilled water

Calcium stearate 3 mg

Components other than calcium stearate were uniformly mixed, crushed, granulated and dried to obtain granules of an appropriate size. Next, calcium stearate was added and compression molded to obtain tablets. Industrial applicability

As is clear from the above test examples, the compounds of the present invention show strong N P Y antagonistic activity. Therefore, the compound of the present invention is very useful as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and a hypotensive agent.

Claims

Claims Formula (I):

R ³

I) lower alkyl optionally having substituent (s)

(However, excluding unsubstituted methyl. Here, the substituents are (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl, ( 7) lower alkoxycarbonyl, (8) which may have a substituent Ashiru, (9) amino, (1 0) nitro, (1 1) Shiano, (1 2) - NHC (= NR ^{1 8)} NR ¹⁹ R ^20, wherein R ¹⁸ , R ¹⁹ and R ^{2 Q} are each independently hydrogen, hydroxy or lower alkoxycarbonyl, or () a force optionally substituted by lower alkyl. ),

II) aryl lower alkyl optionally having substituent (s)

(Here, the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) substituent (where the substituent means lower alkoxycarbonyl, acyl, aryl, substituted amino or imino) (5) lower alkoxy optionally having a substituent, (6) carboxy, (7) lower alkoxycarbonyl, (8) Shiano, (9) Nitro, (10) Asil,

(11) amino which may have a substituent (here, the substituent means lower alkyl, aryl lower alkyl which may have a substituent, heterocyclyl lower alkyl, heterocyclyl carbonyl, acyl (However, acetyl is excluded), lower alkoxyl power rubonyl, arylalkoxycarbonyl, lower alkylsulfonyl, optionally substituted rubamoyl),

(12)-NHC (= R ¹⁶ ) R ¹⁷

(13) Heterocyclyl lower alkyl

Or

(14) aryl which may have a substituent) or

III) heterocyclyl lower alkyl optionally having substituent (s),

R ⁴

I) NHCOR ⁵

[Where R ⁵ is

Lower alkyl optionally having substituent (s)

(Where the substituents are (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro, (1 0) Shiano, (1 1) Single ^{^{NHC (= NR 6) NR 7}} R 8 ( wherein R ⁶ is hydrogen, Shiano or nitro, R ⁷ and R ⁸ are each Independently hydrogen or lower alkyl) or (12) i) benzyloxycarbonyl, ii) acyl (excluding formyl), iii) lower alkylsulfonyl, or iv) carbamino which may have a substituent. ,

Aryl lower alkyl optionally having substituent (s)

Lower alkoxy optionally having a substituent,

Aryl which may have a substituent,

Aryloxy optionally having a substituent or

Aryl lower alkoxy optionally having substituents],

II) NHCONR ⁹ R ¹⁰

(Wherein R ⁹ and R ¹ are each independently hydrogen, hydroxy, halogen, acyl, lower alkyl optionally having substituent (s), lower alkyl optionally having substituent (s), substituent (s) Aryl, which may have a substituent, heterocyclyl, which may have a substituent, lower alkyl, which may have a substituent, cycloalkyl which may have a substituent, Arylsulfonyl which may have or amino which may have a substituent)

III) NHC (= NR n) NR ^{1 2} R ^{1 3}

(Where R ¹¹ is hydrogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), amino which may have substituent (s), or substituent (s) Aryl which may be substituted, lower alkyl which may have a substituent or heterocyclyl which may have a substituent,

R ¹² and R ¹³ are each independently hydrogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), may have substituent (s) Amino, optionally substituted aryl, optionally substituted Aryl lower alkyl, aryloxy optionally having substituent (s), heterocyclyl optionally having substituent (s), or heterocyclyl lower alkyl optionally having substituent (s), or R ^{1 2} and R ¹³ together form an optionally substituted heterocyclyl),

IV) NH CSNR ¹⁴ R ¹⁵

(Where R ¹⁴ and R ¹⁵ are each independently hydrogen, lower alkyl which may have a substituent, aryl which may have a substituent, or aryl which may have a substituent Lower alkyl),

V) lower alkyl optionally having substituent (s),

VI) an optionally substituted acyl,

VII) optionally substituted heterocyclylamino or

VIII) heterocyclylthio optionally having a substituent,

X is CH ₂ , S or 0;

n is 1 or 2.

However, when R ³ is lower alkyl which may have a substituent, R ⁴ is NH C ONR ⁹ R ^{1 Q} , and R ⁹ and R ^{1 Q} each may have a substituent. Not really,

When R ³ is unsubstituted arylalkyl lower alkyl, and R ⁴ is NHC OR ⁵ , R ⁵ is not lower alkyl which may have a substituent,

When R ³ is heterocyclyl lower alkyl which may have a substituent, R ⁵ is NH CON R ⁹ R ¹⁰ . )

Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. R ³ is an aryl lower alkyl which may have a substituent, and the substituent is

(2) hydroxy, (3) benzyloxy,

(11) optionally substituted amino

(Here, the substituent means a lower alkyl, an aryl which may have a substituent. Alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl or optionally substituted rubamoyl) or

(12) 'One NHC (= R ¹⁶ ') R ¹⁷ '

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof.

3. R ⁴

I) NHC OR ⁵ '

[Where R ⁵ 'is

Lower alkyl optionally having substituent (s)

(Here, the substituents are (1) nodogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, ( 8) cycloalkenyl, (9) nitro, (10) cyano,

(12) i) benzyloxycarbonyl, ii) acyl (excluding formyl), iii) lower alkylsulfonyl or iv) amino having any of carbamoyl which may have a substituent),

Lower alkoxy, aryloxy or aryl lower alkoxy], II) NH CONR ^9, R ¹ ° '

(Wherein R ⁹ ′ and R ¹ each independently represent hydrogen, acyl, lower alkyl optionally having substituent (s), lower alkyl optionally having substituent (s), Optionally substituted aryl, optionally substituted heterocyclyl, heterocyclyl lower alkyl, cycloalkyl, arylsulfonyl or optionally substituted amino),

III) NHC (= NR ^{1 1 1} ) NR ^{1 2} 'R ^{1 3} '

IV) NHCSNR ^{1 4} 'R ^{1 5} '

(Wherein R ¹⁴ ′ and R ¹⁵ ′ are each independently hydrogen, an optionally substituted aryl or an optionally substituted lower alkyl. 2. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

4. R ¹ and R ² are each independently hydrogen, hydroxy or a lower alkoxy optionally having substituent (s),

R ³ is optionally lower arylalkyl which may have a substituent

(Here, the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) lower alkyl which may have a substituent (where the substituent is lower alkoxycarbonyl, Acyl, aryl, substituted amino or imino),

(5) lower alkoxy which may have a substituent, (6) carbonyl, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl,

(11) optionally substituted amino

(Here, the substituents include lower alkyl, arylalkyl which may have a substituent, lower alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxyl propyl, aryl) Alkoxycarbonyl, lower alkylsulfonyl or optionally substituted radicals ),

(12)-NHC (= R ¹⁶ ) R ¹⁷

(Where R ¹⁶ is a substituent (where the substituent is lower alkoxycarbonyl or cyano) or an imino or a substituent that may have a substituent (where the substituent is cyano or nitro) R ¹⁷ is a lower alkylene which may have a substituent (where the substituent is a lower alkoxycarbonyl or a lower alkyl), an amino, a lower alkylthio or an aryloxy which may have a substituent. Is) or

(13) heterocyclyl lower alkyl)

R ⁴

I) NH COR ⁵ '

[Where R ⁵ 'is

Lower alkyl optionally having substituent (s)

(Here, the substituents are (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8 ) Cycloalkenyl, (9) nitro, (10) cyano,

Lower alkoxy, aryloxy or aryl lower alkoxy], II) NH C ON R ⁹ 'R ¹ o'

(Where R ⁹ ′ and R ^{1 Q} ′ each independently represent a hydrogen, an acyl, a lower alkyl optionally having a substituent, an aryl lower alkyl optionally having a substituent, or a substituent Optionally substituted, heterocyclyl optionally substituted, hetero Cyclyl lower alkyl, cycloalkyl, arylsulfonyl or optionally substituted amino)),

III) NHC (-NR ^{1 1} ') NR ^{1 2} ' R ^{1 3} '

IV) NH CS NR ¹⁴ 'R ¹⁵ '

(Wherein, R ¹⁴ ′ and R ¹⁵ ′ are each independently hydrogen, an optionally substituted aryl or an optionally substituted lower alkyl) The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

5. R ³ -lower alkyl optionally substituted with R ³ [where the substituent means a substituent (lubamoyl, lower alkyl lubamoyl, lower alkylaminocarbamoyl or tert-butoxycarbonyl) May be possessed], and R ⁴ is

II) NHC〇NR ^9. , R ¹⁰ .

(Where one of R ⁹ ′ ″ and R ^{1 G} ″ ′ is hydrogen and the other is (1) lower alkyl, (2) phenyl or phenyl optionally substituted with halogen, hydroxy, nitro or lower alkylamino. (3) heterocyclyl),

III) NHC (= NR ^{1 1} ''') NR ^{1 2} ''' R ^{1 3} '.'

(Where R ¹¹ ′ ″ is hydrogen or lower alkyl optionally having hydroxy, R ¹² ′ ″ and R ¹³ ′ ″ ′ are one hydrogen and the other is hydrogen, Phenyl or benzylthiazolyl, optionally having hydroxy) or

^{IV) NH CSNR 1 4..} . R 1 5,..

_2. The compound according to claim 1, wherein X is CH ₂ , or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

6. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

7. A neuropeptide Y antagonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

8. An antifeedant comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

9. A therapeutic agent for myocardial infarction comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

10. A therapeutic agent for angina pectoris comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

11. An antihypertensive comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.