JP2000191648A - Condensed cyclic compound, its production and agent thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new condensed cyclic compound having somatostatin receptor function regulating action. SOLUTION: This new compound is a compound of formula I [B-ring is a (substituted) cyclic hydrocarbon; Z is H or a (substituted) cyclic group; R1 is H, a (substituted) hydrocarbon, or the like; R2 is a (substituted) amino; D is a lone pair or bivalent group; E is a lone pair, CO, SO2, or the like; G and L are each a lone pair or bivalent group; A is H or a substituent;... indicates that a ring may be formed with R2 and the atoms on the B-ring], e.g. N-(2- fluorobenzyl)-1-(4-aminomethylphenyl)-5-(4-biphenylmethyl)-2,4-dioxo-2 ,3,4,5- tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride. The compound of formula I is obtained, for example, for a compound of formula II [R2a is a (protected) (substituted) amino], by reaction of pref. 0.5-2 molar equivalent of a compound of the formula NH(Ra)-G-Z (Ra is H or the like) with one mol of a compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a fused ring compound having a somatostatin receptor function regulating action, and a medicament containing the same.

[0002]

2. Description of the Related Art Somatostatin has been isolated from sheep hypothalamus tissue as a peptide consisting of 14 amino acids (SST-14) having a growth hormone secretion inhibitory action. At present, somatostatin (SST-28) consisting of 28 amino acids has been isolated and identified. This somatostatin is not only the hypothalamus, for example, cerebrum, limbic system, spinal cord, vagus nerve, autonomic ganglion, gastrointestinal mucosa, pancreatic Langerhans islet, brain and intestinal peptide widely distributed, Suppresses the secretion of pituitary and gastrointestinal hormones such as growth hormone, thyroid stimulating hormone, gastrin, insulin and glucagon. Also, gastric acid secretion,
It also suppresses pancreatic exocrine secretion, gastrointestinal motility and blood flow. Somatostatin receptors have been type 1 to 5 (SSTR1, SSTR2, SSTR3, SSTR4,
SSTR5) is known, and it has been recognized that they exhibit different expression at central and peripheral sites, respectively [1. Life Sciences, No. 57
Vol. 13, No. 1, p. 1249 (1995) Journal of Clinical Endocrinology and Metaboli
sm, Vol.80, No.6pp.1789-1793 3.The New England Journal of Medicine, Jan.25, 199
6 4. 4. Eur J Clin Pharmacol, 1996, 51, 139-144. Exp. Opin. Ther. Patents (1998) 8 (7): 855-870]. Currently, clinically, peptidic somatostatin analogs that suppress secretion of specific hormones are being developed.

[0003]

The compounds that are currently being developed as somatostatin receptor function modulators are peptidic compounds, and have a long action time, administration method, specificity,
There are many problems in terms of side effects. In terms of solving these problems, it is very significant to create and develop a compound that is a non-peptidic compound and has an excellent somatostatin receptor function regulating action.

[0004]

Means for Solving the Problems The present inventors have conducted various studies in view of the above-mentioned circumstances, and as a result, in the following formula (I), the cyclic hydrocarbon B has an amino group directly or via a divalent group. Formula (I) which has a chemical structural feature in being bonded:

Embedded image [Wherein, ring B is a cyclic hydrocarbon group which may have a substituent; Z is a hydrogen atom or a cyclic group which may have a substituent; R ¹ is a hydrogen atom or a substituent A hydrocarbon group which may be substituted, a heterocyclic group which may have a substituent or an acyl group; R ² represents an amino group which may be substituted;
Is a bond or a divalent group; E is a bond, -CO-, -CON (R ^a )
-,-COO-,-N (R ^a ) CON (R ^b )-,-N (R ^a ) COO-,-N (R ^a ) SO ₂ -,-N
(R ^a )-, -O-, -S-, -SO- or -SO _2- (R ^a and R ^b independently represent a hydrogen atom or a hydrocarbon group which may have a substituent) G represents a bond or a divalent group; L represents a bond or a divalent group; A represents a hydrogen atom or a substituent; X and Y each represent a hydrogen atom or an independent substituent;
‥‥ indicates that R ² and an atom on the B ring may form a ring. ] Or a salt thereof for the first time. Based on its unique chemical structure, this compound has excellent somatostatin receptor function regulation and low toxicity. The inventors have found that they have properties, and based on these, have completed the present invention.

That is, the present invention relates to (1) the compound (I) or a salt thereof; (2) E represents -CO-, -CON (R ^a )-, -COO-, -N (R ^a ) CON (R ^b )-,-N (R
^a ) COO-,-N (R ^a ) SO ₂ -,-N (R ^a )-,-O-,-S-,-SO- or -SO _2-
(R ^a and R ^{b each} independently represent a hydrogen atom or a hydrocarbon group which may have a substituent). (3) wherein L is [1] a bond or [ 2] i) C _1-6 alkyl group, ii) halogeno-C _1-6 alkyl group, iii) phenyl group, iv) benzyl group, v) optionally substituted amino group, vi) substituent And vii) a C _1-6 alkyl group, a phenyl group which may have a substituent or a heterocyclic group which may have a substituent. May have 1 to 5 substituents selected from a carbamoyl group or a thiocarbamoyl group;
The compound according to the above (1), which is a divalent hydrocarbon group optionally via O— or —S—; (4) the above (1), wherein Z is a cyclic group optionally having a substituent. (5) The compound according to (1), wherein D is a divalent group bonded to the ring via a carbon atom; (6) a benzene ring, wherein ring B may have a substituent; L is the a C _1-6 alkylene group (1) the compound according; (7) G represents a divalent hydrocarbon group which may have a substituent, and ring B and R ² and ring (8) A is a hydrogen atom, B is a benzene ring, Z is a phenyl group substituted with halogen, and R ¹ is (1) hydroxy;
(2) phenyl, (3) C _1-6 alkyl-carbonyl or C
_6-14 aryl-carbonyl, and (4) C _1-6 alkyl-
The above-mentioned (1), which is a C _1-6 alkyl or C _7-14 aralkyl group which may be substituted with a substituent selected from an amino group which may be substituted with sulfonyl or C _6-14 aryl-sulfonyl, respectively. (9) X and Y independently represent a hydrogen atom, halogen, hydroxy, C _1-6 alkoxy, halogeno-C _1-6 alkoxy, C
_7-14 aralkyloxy, benzoyl-C _1-6 alkoxy, hydroxy-C _1-6 alkoxy, C _1-6 alkoxy-
Carbonyl -C _1-6 alkoxy, C _3-14 cycloalkyl -C _1-6 alkoxy, imidazol-1-yl -C _1-6 alkoxy, C _{7 - 14} aralkyloxy - carbonyl -C
_1-6 alkoxy or hydroxyphenyl-C _1-6 alkoxy; a benzene ring in which ring B may be substituted with C _1-6 alkoxy, or a tetrahydroisoquinoline or isoindoline ring formed by bonding with R ² ; Z represents one or three substituents each optionally having 1 to 3 substituents selected from halogen, formyl, halogeno-C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-carbonyl, oxo and pyrrolidinyl. _6-14 aryl group, C _3-10 cycloalkyl group, piperidyl group, thienyl group, furyl group, pyridyl group, thiazolyl group, indanyl group or indolyl group; A is a hydrogen atom; D is C _1-6 alkylene group; There bond or phenylene may also contain, and a C _1-6 alkylene group optionally substituted by phenyl,; R ¹ is a hydrogen atom, (1) halogen, (2) Toro, (3) C _1-6 alkyl - substituted carbonyl C _1-6 alkyl,
Amino, (4) (i) hydroxy, C _1-6 alkyl-carbonyl, carboxy or C _1- which may have one or two substituents selected from benzoyloxycarbonyl and C _1-6 alkylsulfonyl C _1-6 alkyl optionally substituted with ₆ alkoxy-carbonyl, (ii) phenyl optionally substituted with hydroxy, (iii) benzoyl or (iv) mono- or di-C _1-6 alkylamino- Hydroxy optionally substituted with carbonyl, (5)
C _3-6 cycloalkyl, (6) hydroxy or halogeno-
Phenyl optionally substituted with C _1-6 alkyl and
(7) thienyl, furyl, thiazolyl, indolyl or benzyloxy each substituted group selected from carbonyl piperidyl optionally substituted C _1-6 alkyl group,
C _2-6 alkenyl group, C _6-14 aryl group or C _7-14 aralkyl group; R ² is (1) an unsubstituted amino group, (2) piperidyl group or (3) (i) benzyl, (ii) C _1-6 alkyl optionally substituted with amino or phenyl, (iii) mono- or di-C _1-6 alkyl-carbamoyl, or mono-
Or di-C _1-6 alkyl-thiocarbamoyl, (iv) C
1 or 2 selected from _1-6 alkoxy-carbonyl, (v) C _1-6 alkyl-sulfonyl, (vi) piperidylcarbonyl and (vii) C _1-6 alkyl-carbonyl optionally substituted with halogen or amino. Which may have one or more substituents; E is a bond, -CON (R ^a )-,
^{-N (R a) CO -,} - N (R a) CON (R b) - (R a and R ^b are each a hydrogen atom or a C _1-6 alkyl group); L is even via the -O- (1) which is a C _1-6 alkylene group which may be substituted with C _1-6 alkyl
(10) X and Y independently represent a hydrogen atom, halogen, hydroxy or C _1-6 alkoxy; a ring B bonded to a benzene ring or R ² to form a tetrahydroisoquinoline ring or isoindoline ring; A optionally substituted phenyl group, D is a C _1-6 alkylene group, G is a C _1-6 alkylene group;
R ¹ is (1) hydroxy, (2) phenyl and (3) C _1-6 alkyl - substituted respectively carbonyl or C _1-6 alkylsulfonyl substituent selected from amino optionally substituted by A C _1-6 alkyl group or C _7-14
An aralkyl group; R ² is an unsubstituted amino group; E is —CON
H-; a compound according to the above (1), wherein L is a C _1-6 alkylene group; (11) a prodrug of the compound according to the above (1) or a salt thereof; (12) a formula (IIa):

Embedded image [In the formula, R ^2a may be protected, an amino group which may be substituted, and other symbols have the same meanings as described in the above (1). And a reactive derivative or a salt thereof represented by the formula (III):

Embedded image [The symbols in the formula are as defined above. By reacting the compound represented by the formula (Ia-
a):

Embedded image [The symbols in the formula are as defined above. A compound of the formula (Ia), which is optionally subjected to a deprotection reaction:

Embedded image [The symbols in the formula are as defined above. [13] a method for producing a compound or a salt thereof; (13) a pharmaceutical composition comprising the compound or a salt thereof according to the above (1); (15) the pharmaceutical composition of (14), wherein the somatostatin receptor function modulator is a somatostatin receptor agonist; (16) prevention or treatment of diabetes, obesity, diabetic complications or intractable diarrhea The pharmaceutical composition according to the above (13), which is an agent.

In the above formula, the ring B represents a cyclic hydrocarbon group which may have a substituent. As the ring B, for example, an aromatic hydrocarbon group which may have a substituent is preferable, and a phenyl group which may have a substituent is particularly preferable.
Examples of the cyclic hydrocarbon group represented by ring B include an alicyclic hydrocarbon group composed of 3 to 14 carbon atoms or an aromatic hydrocarbon group composed of 6 to 14 carbon atoms. No. As the “alicyclic hydrocarbon group”, for example, a C _3-14 cycloalkyl group (for example,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _3-14 cycloalkenyl group (for example,
Cyclopentenyl, cyclohexenyl, etc.), _C5-14 cycloalkadienyl group (e.g., 2,4-cyclopentadienyl, 1,3-cyclohexadienyl, etc.), indanyl group and the like. An alicyclic hydrocarbon group composed of carbon atoms is preferred. The “aromatic hydrocarbon group” includes, for example, an aromatic hydrocarbon group composed of 6 to 14 carbon atoms (for example, C 4 such as phenyl, naphthyl, anthranyl, phenanthryl and the like).
_6-14 aryl group), among which an aromatic hydrocarbon group composed of 6 to 10 carbon atoms is preferable. Among them, a phenyl group is preferred.

A cyclic hydrocarbon group as ring B
Examples of the substituent and the substituent of A include, for example, halogen
Atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6Alkyl groups (eg, methyl, ethyl, propyl,
Butyl, sec-butyl, t-butyl, isopropyl, etc.),
Halogeno-C_1-6Alkyl groups (eg, 1 to 5
C substituted with the "halogen atom"_1-6Alkyl group and the like;
Eg trifluoromethyl), phenyl group, benzyl
Group, C_1-6Alkoxy groups (eg, methoxy, ethoxy,
Si, propoxy, butoxy, sec-butoxy, t-butoxy
, Isopropoxy, etc.), halogeno-C_1-6Alkoxy
Group (eg, substituted with one to five such "halogen atoms")
Done C_1-6Alkoxy group; trifluoromethoxy,
Loropropyloxy, etc.), phenoxy group, C_7-14Aral
Killoxy groups (eg, benzyloxy, phenethyl
Xy, phenylpropyloxy, etc.), formyloxy
Group, C _1-6An alkyl-carbonyloxy group (for example,
Cetyloxy, etc.), C_1-6Alkylthio group (for example,
Tylthio, ethylthio, propylthio, butylthio, se
c-butylthio, t-butylthio, isopropylthio
Etc.), halogeno-C_1-6An alkylthio group (eg,
5 carbon atoms substituted with 5 such "halogen atoms"_1-6Al
Alkylthio group; for example, trifluoromethylthio, etc.),
Droxy, mercapto, cyano, nitro,
Boxyl group, formyl group, C_1-6Alkyl-carbonyl
Groups (eg, acetyl, propionyl, etc.), benzoyl
Group, C_1-6An alkoxy-carbonyl group (e.g., methoxy
Cicarbonyl, ethoxycarbonyl, propoxycarbo
Phenoxycarbonyl group, amino group, mono-
Or di-C_1-6Alkylamino groups (eg, methyl
Mino, ethylamino, dimethylamino, diethylamino
Etc.), formylamino group, C_1-6Alkyl-carbonyl
Amino groups (eg, acetylamino, propionylamido)
, Butyrylamino, etc.), carbamoyl group, thiocarba
Moyl group, mono- or di-C_1-6Alkyl-carbamo
Yl group (for example, N-methylcarbamoyl, N-ethyl
Carbamoyl, N, N-dimethylcarbamoyl, N, N
-Diethylcarbamoyl etc.), mono- or di-C_1-6
Alkyl-thiocarbamoyl group (for example, N-methylthio)
Ocarbamoyl, N-ethylthiocarbamoyl, N, N
-Dimethylthiocarbamoyl, N, N-diethylthioca
Rubamoyl, etc.), sulfo group, C_1-6Alkylsulfonyl
Groups (eg, methylsulfonyl, ethylsulfonyl,
Ropylsulfonyl, etc.), benzoyl-C_1-6Alkoxy
Groups (eg, benzoylmethyloxy, etc.), hydroxy
-C_1-6An alkoxy group (eg, hydroxyethyloxy)
Etc.), C_1-6Alkoxy-carbonyl-C_1-6Alkoki
Si group (for example, methoxycarbonylmethyloxy and the like),
C_3-14Cycloalkyl-C_1-6An alkoxy group (eg,
Cyclohexylmethyloxy, etc.), imidazole-1-
Il-C_1-6Alkoxy group (for example, imidazole-1
-Ylpropyloxy, etc.), C_7-14Aralkyloxy-
Carbonyl-C_1-6Alkoxy groups (eg, benzylo
Hydroxycarbonylmethyloxy, etc.), hydroxyphenyl
-C_1-6An alkoxy group (for example, [3- (4-hydroxy
Ciphenyl) propyl] oxy, etc.), C_7-14Aralkyl
An oxy-carbonyl group (e.g., benzyloxycarbo)
Nil, etc.), mono- or di-C_1-6Alkylamino-C
_1-6Alkoxy (for example, methylaminomethoxy,
Tylaminoethoxy, dimethylaminomethoxy, etc.),
No or di-C_1-6Alkylamino-carbonyloxy
(For example, methylaminocarbonyloxy, ethyl alcohol
Minocarbonyloxy, dimethylaminocarbonyloxy
And the like). A cyclic hydrocarbon group as ring B and
And are 1 to 4 positions selected from these substituents
It may have a substituent. A is a hydrogen atom
preferable.

[0008] Especially as the B ring, a benzene ring or a cycloalkane and the like are preferable have a substituent, respectively, among others C _1-6 alkoxy (preferably methoxy, etc.) is a benzene ring optionally or substituted with A cyclohexane ring or the like is more preferred, and an unsubstituted benzene ring or cyclohexane ring is most preferred. Further, R ² and an atom on the B ring may form a ring, and the B ring is, for example,
B adjacent to the atom forming the B ring to which L is bonded
The atoms forming the ring may be bonded to the amino group represented by R ² or a substituent of the amino group to form a nitrogen-containing heterocyclic ring which may have a substituent.
When such a nitrogen-containing heterocyclic ring is formed, R
The nitrogen atom of the amino group ² may be directly bonded to the atom forming the ring B, or may be bonded via a spacer. This spacer means a part or all of the substituent of the amino group of R ² . Examples of the "nitrogen-containing heterocycle optionally having a substituent" formed together with the ring B include, for example,
A cyclic hydrocarbon (for example, a benzene ring or the like) which may have a substituent represented by ring B, and at least one nitrogen atom, and one or two selected from a nitrogen atom, an oxygen atom and a sulfur atom A bicyclic fused nitrogen-containing heterocyclic ring (preferably a monocyclic non-aromatic heterocyclic ring) formed by condensing a 5- or 6-membered monocyclic heterocyclic ring (preferably a monocyclic non-aromatic heterocyclic ring) optionally having a heteroatom Bicyclic non-aromatic condensed nitrogen-containing heterocycle) and the like, and specifically, for example, tetrahydroisoquinoline (eg, 1,2,3,4-tetrahydroisoquinoline), tetrahydroquinoline (eg, 1,2,3,4)
-Tetrahydroquinoline), isoindoline, indoline, 2,3-dihydrobenzothiazole, 2,3-dihydrobenzoxazole, 3,4-dihydro-2H-1,4
Benzothiazine, 3,4-dihydro-2H-1,4-benzoxazine, 1,2,3,4-tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1,4-benzoxazepine and the like are used And among them, tetrahydroisoquinoline or isoindoline is preferable. Examples of the substituent that the “nitrogen-containing heterocyclic ring optionally having” which is formed together with the ring B may have, for example, the above “cyclic hydrocarbon” in the ring B may have Examples of the substituent include the same as those described above. The “nitrogen-containing heterocyclic ring optionally having substituent (s)” may be selected from 1 to 4 selected from these substituents.
May have one or more substituents.

In the above formula, Z represents a hydrogen atom or a cyclic group which may have a substituent (preferably a cyclic group which may have a substituent). Examples of the “cyclic group” represented by Z include a cyclic hydrocarbon group and a heterocyclic group.
Z is preferably, for example, an aromatic hydrocarbon group which may have a substituent, an aromatic heterocyclic group which may have a substituent or the like, and particularly preferably a phenyl group which may have a substituent. Are preferred. Examples of the “cyclic hydrocarbon group” for Z include an alicyclic hydrocarbon group composed of 3 to 14 carbon atoms, an aromatic hydrocarbon group composed of 6 to 14 carbon atoms, and the like. . Examples of the “alicyclic hydrocarbon group” include a C _3-14 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, etc.), C _3-14 cycloalkenyl group (eg, cyclopentenyl, cyclohexenyl, etc.), C _5-14
Cycloalkadienyl group (for example, 2,4-cyclopentadienyl, 1,3-cyclohexadienyl and the like), indanyl group and the like, among which alicyclic hydrocarbons having 6 to 10 carbon atoms Groups are preferred. Examples of the “aromatic hydrocarbon group” include a C _6-14 aryl group (eg, phenyl, naphthyl, anthranyl, phenanthryl, etc.), among which an aromatic hydrocarbon having 6 to 10 carbon atoms Groups are preferred. Examples of the “heterocyclic group” for Z include a monocyclic heterocyclic group, a polycyclic fused heterocyclic group, and the like. As the "monocyclic heterocyclic group",
Examples thereof include a 5- or 6-membered monocyclic heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, and specifically,
For example, a monocyclic aromatic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl, etc.), monocyclic non-aromatic Heterocyclic groups (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
Thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like). Examples of the “polycyclic fused heterocyclic group” include, for example, and a bicyclic or tricyclic fused aromatic heterocyclic group formed by condensing two or three of the “monocyclic aromatic heterocycle”; A condensed bicyclic or tricyclic aromatic heterocyclic group formed by condensing one or two monocyclic aromatic heterocycles with a benzene ring (preferably a monocyclic aromatic heterocyclic group) Bicyclic or tricyclic fused aromatic heterocyclic group formed by the condensation of one or two benzene rings) and their partially reduced forms, and the like. Ring groups (e.g., benzofuryl, isobenzofuryl, benzo [b] thienyl, indanyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl,
Benzothiazolyl, 1,2-benzisothiazolyl, 1
H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl Inyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-
a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-a] pyridazinyl, imidazo [1,2-
a] pyrimidinyl, 1,2,4-triazolo [4,3-
a] Pyridyl, 1,2,4-triazolo [4,3-b]
Pyridazinyl, etc.), polycyclic non-aromatic condensed heterocycles (eg, isochromanyl, chromanyl, indolyl, isoindolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl) Are used. Examples of the substituent that the cyclic group represented by Z may have include, for example, the same substituents as those that the “cyclic hydrocarbon” in the ring B may have, and the like.
An oxo group and a thioxo group are exemplified. "Cyclic group" of Z
May have 1 to 5 substituents selected from these substituents. Z is halogen, formyl, halogeno-C _1-6 alkyl, C _1-6 alkoxy, C
_A C _6-14 aryl group (preferably phenyl or the like) which may have 1 to 3 substituents selected from _1-6 alkyl-carbonyl, oxo and pyrrolidinyl, respectively;
C _3-10 cycloalkyl group, piperidyl group, thienyl group,
Furyl, pyridyl, thiazolyl, indanyl,
An indolyl group and the like are preferred, and a phenyl group and the like substituted with halogen (preferably fluorine and the like) are particularly preferred. The substitution position of the substituent in the cyclic group represented by Z is Z
Is a phenyl group, the ortho position is preferred, and the number of substituents is preferably 1.

In the above formula, D represents a bond or a divalent group, and the divalent group may have, for example, a substituent, and may be -O-, -S-, or -N (R ^a )-(Ra represents ^a hydrogen atom or ^a hydrocarbon group which may have a substituent). Among them, a divalent group bonded to a ring via a carbon atom is preferable, and a divalent hydrocarbon group which may have a substituent is particularly preferable. Examples of the divalent group represented by D include, for example, those having 1 to 10 carbon atoms.
For example, a C _1-10 alkylene group (eg, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, peptamethylene, octamethylene) is used. And the like, and a C _1-6 alkylene group (eg, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, etc.) is particularly preferable. The “divalent group” may be, for example, C _3-6 cycloalkylene (for example, 1,4-cyclohexylene), phenylene (for example, 1,4-phenylene, 1,2-phenylene) at any position. Etc. may be included. Examples of the substituent which the divalent group represented by D may have include, for example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), a halogeno-C _1-6 alkyl group ( For example, a C _1-6 alkyl group substituted with 1 to 5 “halogen atoms”; for example, trifluoromethyl and the like), a phenyl group, a benzyl group, an amino group which may have a substituent, a substituent And a carbamoyl group which may have a substituent and a thiocarbamoyl group which may have a substituent. The “divalent group” may have 1 to 3 of these substituents. In particular, D is preferably a C _1-6 alkylene group (eg, methylene, ethylene, propylene, etc., preferably methylene, etc.). In the above formula, G represents a bond or a divalent group. As the “divalent group” represented by G, for example, those similar to the aforementioned “divalent group” represented by D and the like are used. G may contain, for example, a bond, or phenylene;
A C _1-6 alkylene group which may be substituted with phenyl is preferable, and for example, a C _1-6 alkylene group (eg, methylene, ethylene, propylene, etc.) is generally used. Here, the C _1-6 alkylene group represented by G may have phenylene interposed between the C _1-6 alkylene group and E or Z;
Phenylene may be present in the C _1-6 alkylene group.

In the above formula, R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent or an acyl group. R ¹ is preferably a hydrocarbon group or an acyl group which may have a substituent. Examples of the hydrocarbon group represented by R ¹ include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aralkyl group, and the like, and an aliphatic hydrocarbon group and the like are particularly preferable. Examples of the aliphatic hydrocarbon group for R ¹ include an aliphatic hydrocarbon group having 1 to 10 carbon atoms (eg, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, etc.). No. Examples of the “C _1-10 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,
Isopentyl, neopentyl, 1-methylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,
2-dimethylbutyl, 3,3-dimethylbutyl, 3,3
-Dimethylpropyl, 2-ethylbutyl, heptyl and the like, preferably a _C3-5 alkyl group (for example, propyl, isopropyl, isobutyl, neopentyl and the like), and particularly preferably isobutyl and neopentyl. Examples of the “C _2-10 alkenyl group” include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,
-Methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-2-butenyl, 1-
Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like, in particular, C _{2- 6} alkenyl groups (for example, vinyl, allyl, isopropenyl, 2-
Methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, etc.) and the like. Examples of the “C _2-10 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-
Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like, Particularly, a C _2-6 alkynyl group (eg, ethynyl, 1-propynyl, 2-propynyl, etc.) and the like are preferable.

As the alicyclic hydrocarbon group for R ¹ , for example, an alicyclic hydrocarbon group having 3 to 10 carbon atoms (for example, C
_3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C
_5-10 cycloalkadienyl group). Examples of the “C _3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. The “C _3-10 cycloalkenyl group”
As 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1- And the like. Examples of the “C _5-10 cycloalkadienyl group” include 2,4-cyclopentadien-1-yl,
2,5-cyclohexadien-1-yl and the like. Examples of the aryl group for R ¹ include a C _6-14 aryl group (eg, phenyl, naphthyl, anthranyl, phenanthryl, acenaphthylenyl, etc.). R
Examples of the ¹ aralkyl group include a C _7-14 aralkyl group (for example, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 2-naphthylmethyl, and the like).

Examples of the substituent which the hydrocarbon group of R ¹ may have include a halogen atom, a nitro group, a cyano group, an imino group, an amino group which may have a substituent, and a substituent. Optionally substituted hydroxy group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, cycloalkyl group, cycloalkenyl group ,
Examples include a heterocyclic group which may have a substituent. In the “hydrocarbon group”, regarding the group containing an aromatic ring, in addition to the above substituent, an alkyl group, a halogenoalkyl group, and an aryl group which may have a substituent are included. It may be. These substituents have 1 to 5 (preferably 1 to 3) on the “hydrocarbon group”.
It may be substituted. Examples of the “halogen atom” which is a substituent of the “hydrocarbon group” of R ¹ include, for example, fluorine, chlorine, bromine, iodine and the like. Examples of the “hydrocarbon group” of R ^{1 and} the “optionally substituted amino group” that is a substituent of D and G include (1) (i) 1 to 5 of the “halogen atoms” Or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl and the like), a C _6-14 aryl group (eg a phenyl group and the like) ), A C _7-14 aralkyl group (such as a benzyl group), (ii) a formyl group, a C _1-6 alkyl-carbonyl group (such as acetyl, propionyl, butyryl, etc.),
_6-14 aryl-carbonyl groups (e.g., phenylcarbonyl, naphthylcarbonyl, anthranylcarbonyl,
Phenanthrylcarbonyl, acenaphthylenylcarbonyl, etc.), C _6-14 aryl-carbonyl group (eg, benzoyl group), (iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl) , Sec-propoxycarbonyl, butoxycarbonyl, etc.), a C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, etc.), (iv)
Sulfo group, C _1-6 alkyl-sulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec-propylsulfonyl, butylsulfonyl, t-
Butylsulfonyl and the like) C _6-14 aryl-sulfonyl group (for example, phenylsulfonyl, naphthylsulfonyl,
Anthranylsulfonyl, phenanthrylsulfonyl,
One selected from the group consisting of acenaphthylenylsulfonyl, etc.) and (v) a C _1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, dimethylaminocarbonyl, etc.) or An amino group optionally having two substituents, and (2) a pyrrolidinyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group,
And 5- or 6-membered optionally substituted cyclic amino groups such as -methylpiperidyl group and 4-phenylpiperidyl group.

The "hydrocarbon group" for R ^{1 and} the "hydroxy group optionally having substituent (s)" which are substituents of D and G
Examples of the substituent which may have: (i) a C _1-6 alkyl group which may have a substituent, (ii) a C _6-10 aryl group which may have a substituent And (iii) an optionally substituted C _7-14 aralkyl group and (iv) an acyl group. Examples of the “C _1-6 alkyl group” of the “ _optionally substituted C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like. The “C _1-6 alkyl group”
Is, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxy group, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), a formyl group, a C _1-6 alkyl- A carbonyl group (eg, acetyl, propionyl, butyryl, etc.),
Carboxyl group, C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl, etc.), amino group, mono- or di-C
_1-6 alkylamino group (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), pyrrolidyl group, piperidyl group, morpholinyl group, thiomorpholinyl group, 4-methylpiperidyl group, 4-phenylpiperidyl group, carbamoyl group, thiol Carbamoyl group, mono-
Or a di-C _1-6 alkyl-carbamoyl group (for example,
N-methylcarbamoyl, N-ethylcarbamoyl,
N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc.), mono- or di-C _1-6 alkyl-thiocarbamoyl group (for example, N-methylthiocarbamoyl, N-ethylthiocarbamoyl, N, N-dimethylthio) Carbamoyl, N, N-diethylthiocarbamoyl, etc.), phenoxy group, mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N, N-
Dimethylcarbamoyloxy, N, N-diethylcarbamoyloxy, etc.), mono- or di-C _1-6 alkyl-
Thiocarbamoyloxy groups (for example, N-methylthiocarbamoyloxy, N-ethylthiocarbamoyloxy, N, N-dimethylthiocarbamoyloxy, N, N
-Diethylthiocarbamoyloxy, etc.), formylamino group, C _1-6 alkyl-carbonylamino group (for example,
Acetylamino, propionylamino, butyrylamino, etc.), formyloxy group and C _1-6 alkyl-carbonyloxy group (eg, acetoxy etc.) and may have 1 to 3 substituents. As the "C _6-10 aryl group" of the "optionally substituted C _6-10 aryl group", for example, phenyl, naphthyl and the like. The “C _6-10 aryl group” includes, for example, the aforementioned “C 6
_1-6 alkyl group "may have a substituent
_1-6 alkyl groups (eg, methyl, ethyl, propyl,
Isopropyl and the like and a halogeno-C _1-6 alkyl group (for example, a C _1-6 alkyl group substituted with 1 to 5 such “halogen atoms” such as trifluoromethyl and the like) May have a substituent. As the "C _7-14 aralkyl group" of the "optionally C _7-14 aralkyl group optionally having a substituent", for example, benzyl, phenethyl, and the like. Examples of the substituent that the “C _7-14 aralkyl group” may have include the same substituents as those that the “C _6-10 aryl group” may have, and the like. The radix is 1 to 5. Examples of the “acyl group” include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, t-butylcarbonyl, etc.), a benzoyl group,
_1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
sec-propoxycarbonyl, butoxycarbonyl, t-
Butoxycarbonyl), a benzyloxycarbonyl group, a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec
- propylsulfonyl, butylsulfonyl, t- butyl sulfonyl, etc.), a carbamoyl group, thiocarbamoyl group, mono- - or di -C _1-6 alkyl - carbamoyl group (e.g., N- methylcarbamoyl, N- ethylcarbamoyl, N, N - dimethylcarbamoyl, N, N- diethylcarbamoyl, etc.), mono - or di -C _1-6 alkyl - thiocarbamoyl group (e.g., N- methyl-thiocarbamoyl, N- ethyl thiocarbamoyl, N, N- dimethylthiocarbamoyl, N , N-diethylthiocarbamoyl, etc.), and further include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxy group, a C _1-6 alkoxy group (eg, methoxy,
Ethoxy, propoxy, isopropoxy, etc.), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), carboxy group, C
_1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
sec-propoxycarbonyl, butoxycarbonyl, etc.), amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), pyrrolidinyl group, piperidyl group, morpholinyl group, Thiomorpholinyl group, 4-methylpiperidyl group, 4-phenylpiperidyl group, 4-benzyloxycarbonylpiperidyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group (for example, methylcarbamoyl,
Ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), mono- or di-C _1-6 alkyl-
A thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), a phenoxy group, a mono- or di-C _1-6 alkyl-carbamoyloxy group (eg, methylcarbamoyloxy, ethylcarbamoyloxy) , dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), mono - or di -C _1-6 alkyl - thio carbamoyloxy group (e.g., methylthio carbamoyloxy, ethylthiomethyl carbamoyloxy, dimethylthiocarbamoyl oxy, diethyl thiocarbamoyl-oxy and the like), Formylamino group, C _1-6 alkyl-
Carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), formyloxy group and C _1-6 alkyl-carbonyloxy group (eg,
Acetoxy, etc.) and may have 1 to 3 substituents selected from the group.

Examples of the “optionally esterified carboxyl group” which is a substituent of the “hydrocarbon group” of R ¹ include, for example, a compound of the formula —COOR ^e (where R ^e is a hydrogen atom, C
_1-6 alkyl groups (eg, methyl, ethyl, propyl,
Isopropyl, butyl, t-butyl, etc.), benzyl group and the like. And the like. Examples of the substituent which may be possessed by the “hydrocarbon group” of R ^{1 and} the “carbamoyl group optionally having substituent (s)” which are the substituents of D and G include, for example, a C _1-6 alkyl group (Eg, methyl, ethyl, propyl, isopropyl, butyl, t-
Butyl, etc.), a benzyl group, an optionally substituted phenyl group (eg, an “optionally substituted aryl group” which is a substituent of the “hydrocarbon group” of R ¹ ) A phenyl group which may have the same substituent as the substituent which may be substituted), a heterocyclic group which may have a substituent (eg,
And the same as the “heterocyclic group which may have a substituent” which is a substituent of the “hydrocarbon group” for R ¹ ) and the like. The “hydrocarbon group” for R ^{1, and} the “optionally substituted thiocarbamoyl group” that is a substituent of D and G
Examples of the substituent which may have the same one as the above-mentioned "carbamoyl group which may have a substituent". Examples of the “cycloalkyl group” which is a substituent of the “hydrocarbon group” of R ¹ include C _3-6 such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
And cycloalkyl groups. Examples of the “cycloalkenyl group” which is a substituent of the “hydrocarbon group” for R ¹ include 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl,
-Cyclopenten-1-yl, 2-cyclohexene-1
- yl, and the like C _3-6 cycloalkenyl groups such as 3-cyclohexen-1-yl. R ¹ "hydrocarbon group"
As the "heterocyclic group" of the "heterocyclic group optionally having substituent (s)" which is a substituent of, for example, 1 to 4 carbon atoms other than a nitrogen atom, an oxygen atom and a sulfur atom 5- or 6-membered monocyclic heterocyclic group having a hetero atom (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, furzanil,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,
Pyridyl, pyridazinyl, pyrimidinyl, triazinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.) and the aforementioned “5- or 6-membered monocyclic heterocycle” Or a 2- or 3-cyclic fused heterocyclic group formed by condensing a benzene ring with a 2- or 3-cyclic fused heterocyclic group formed by condensing Heterocyclic group (preferably a bicyclic or tricyclic fused heterocyclic group containing a benzene ring) (for example, benzofuryl, isobenzofuryl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl) Le, 1, - benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] Pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-a] pyridazinyl, imidazo [1,2-a]
Pyrimidinyl, 1,2,4-triazolo [4,3-a]
Pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl and the like. Examples of the substituent that the “heterocyclic group” may have include, for example, those similar to the substituents that the “cyclic hydrocarbon group” as the ring B may have, an oxy group, And pyrrolidinyl groups. The “heterocyclic group” may have 1 to 5 substituents selected from these substituents.

The "alkyl group" which is a substituent of the "hydrocarbon group" for R ¹ includes, for example, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. And an alkyl group. R
^{As the} “halogenoalkyl group” which is a substituent of the “hydrocarbon group”, C 1 substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
_{And a 1-6} alkyl group (eg, trifluoromethyl, trichloromethyl, etc.). R ¹ "hydrocarbon group"
Examples of the “aryl group” of the “aryl group optionally having substituent (s)” which are the substituents of the above include, for example, phenyl, naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, anthranyl, phenanthryl, acenaphthylenyl and the like C _6-14 aryl group and the like. The “aryl group” is, for example, a halogen atom (eg, fluorine, chlorine,
Bromine, iodine, etc.), C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), halogeno-C _1-6 alkyl group (eg, 1 to 5 of the “halogen” A C _1-6 alkyl group substituted with an atom; for example, trifluoromethyl and the like; a C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy and the like), C _7-14 aralkyloxy Groups (eg, benzyloxy, etc.), hydroxy groups,
Amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl) Etc.), C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, sec-propoxycarbonyl,
Butoxycarbonyl), 1 to 5 substituents selected from a nitro group and a cyano group. R
^{As the} `` heterocyclic group optionally having a substituent '' represented by <sup>1</sup> , the `` optionally having a substituent '' exemplified as a substituent on the `` hydrocarbon group '' represented by R ¹ The same ones as the "good heterocyclic group" are used. The acyl group of R ^1, the illustrated "hydroxy group optionally having a substituent" as a substituent on "optionally may hydrocarbon group having a substituent" represented by R ¹ is The same as the acyl group which may be possessed are exemplified. R ¹ includes, for example, a hydrogen atom, (1) halogen, (2) nitro, (3) C _1-6 alkyl optionally substituted by C _1-6 alkyl-carbonyl, benzoyloxycarbonyl and C _1-6 Amino optionally having one or two substituents selected from alkylsulfonyl, (4) (i) hydroxy, _C1-6alkyl- carbonyl, carboxyl or _C1-6alkoxy-
C _1-6 alkyl optionally substituted with carbonyl, (i
i) phenyl optionally substituted with hydroxy, (iii)
Benzoyl or (iv) hydroxy optionally substituted with mono- or di-C _1-6 alkylamino-carbonyl, (5) C _3-6 cycloalkyl, (6) hydroxy or halogeno-C _1-6 alkyl. Optionally substituted phenyl and (7) a C _1-6 alkyl group optionally substituted by a substituent selected from thienyl, furyl, thiazolyl, indanyl, indolyl or benzyloxycarbonylpiperidyl, C _2-6 alkenyl group, C _6-14 aryl group or C _7-14 aralkyl group and the like are preferable, hydroxy, phenyl and C _1-6 alkyl - selected from amino optionally substituted sulfonyl - carbonyl or C _1-6 alkyl And a C _1-6 alkyl group or a C _7-14 aralkyl group which may be respectively substituted with a substituted substituent. The substitution position of the substituent in the aralkyl group represented by R ¹ is preferably the para position.

In the above formula, R^TwoIs an optionally substituted
Shows a mino group. The "optionally substituted amino group"
For example, (i) an unsubstituted amino group, (ii) a substituent
May have a hydrocarbon group, may have a substituent
One or two selected from good heterocyclic groups and acyl groups
And (iii) an amino group having a substituent of
And a nitrogen-containing heterocyclic group which may be substituted. R^Twoof
Examples of the “optionally substituted hydrocarbon group” include R
¹The "optionally substituted hydrocarbon represented by the formula:
And the like. R^TwoWith a substituent
A heterocyclic group which may be¹The represented by
Same as "heterocyclic group optionally having substituent (s)", etc.
Is used. R^TwoExamples of the “acyl group” include
Lumil group, C_1-6An alkyl-carbonyl group (e.g.,
Cetyl, propionyl, butyryl, etc.), benzoyl group,
C_1-6An alkoxy-carbonyl group (e.g., methoxy
Rubonyl, ethoxycarbonyl, propoxycarbonyl
, Sec-propoxycarbonyl, butoxycarboni
, T-butoxycarbonyl, etc.), C_7-14Aralquilo
Xy-carbonyl group (for example, benzyloxycarbonyl
Etc.), piperidin-4-ylcarbonyl group, C_1-6Al
Killsulfonyl group (for example, methylsulfonyl, ethyl
Sulfonyl, propylsulfonyl, sec-propylsul
Honyl, butylsulfonyl, t-butylsulfonyl
Etc.), carbamoyl group, thiocarbamoyl group, mono-
Or Di-C_1-6Alkyl-carbamoyl groups (e.g.,
Tylcarbamoyl, ethylcarbamoyl, dimethylcarb
Bamoyl, diethylcarbamoyl, etc.), mono- or di-
-C_1-6Alkyl-thiocarbamoyl group (for example, methyl
Luthiocarbamoyl, ethylthiocarbamoyl, dimethi
Ruthiocarbamoyl, diethylthiocarbamoyl, etc.)
And further include, for example, a halogen atom (eg,
For example, fluorine, chlorine, bromine, iodine, etc.), hydroxy
Group, C_1-6Alkoxy groups (eg, methoxy, ethoxy,
, Propoxy, isopropoxy, etc.), formyl group, C
_1-6Alkyl-carbonyl groups (e.g., acetyl, pro
Pionyl, butyryl, etc.), carboxyl group, C_1-6Al
A oxy-carbonyl group (e.g., methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, sec-p
Ropoxycarbonyl, butoxycarbonyl, etc.), amino
Group, mono- or di-C_1-6Alkylamino group (for example,
For example, methylamino, ethylamino, dimethylamino,
Ethylamino, etc.), pyrrolidinyl group, piperidyl group,
Rufolinyl group, thiomorpholinyl group, 4-methylpiperi
A jyl group, a 4-phenylpiperidyl group, a carbamoyl group,
Thiocarbamoyl group, mono- or di-C _1-6Alkyl
A carbamoyl group (e.g., methylcarbamoyl,
Rucarbamoyl, dimethylcarbamoyl, diethylcarb
Bamoyl etc.), mono- or di-C_1-6Alkyl-thio
Carbamoyl groups (eg, methylthiocarbamoyl,
Tylthiocarbamoyl, dimethylthiocarbamoyl, di
Ethylthiocarbamoyl, etc.), phenoxy group, mono-
Or Di-C_1-6Alkyl-carbamoyloxy group (eg,
For example, methyl carbamoyloxy, ethyl carbamoyl
Xy, dimethylcarbamoyloxy, diethylcarbamo
Iloxy, etc.), mono- or di-C_1-6Alkyl-thio
Ocarbamoyloxy group (for example, methylthiocarbamo
Yloxy, ethylthiocarbamoyloxy, dimethyl
Thiocarbamoyloxy, diethylthiocarbamoylo
Xy, etc.), formylamino group, C_1-6Alkyl-carbo
Nylamino group (for example, acetylamino, propionyl
Amino, butyrylamino, etc.), formyloxy group and
C_1-6Alkyl-carbonyloxy group (for example, aceto
Having 1 to 3 substituents selected from
May be.

The "nitrogen-containing heterocyclic group" of the "nitrogen-containing heterocyclic group optionally having substituent (s)" for R ² includes, for example, a nitrogen atom, an oxygen atom and a sulfur atom other than the nitrogen atom having a bond. And a 5- to 7-membered nitrogen-containing heterocyclic group optionally having 1 to 4 heteroatoms selected from
-Imidazolyl, 1-pyrazolyl, 1-pyrrolyl, 1-
A pyrrolidinyl, 1-piperidyl, morpholinyl, thiomorpholinyl, etc.) or a ring in which benzene, pyridine, etc. are condensed with this 5- to 7-membered nitrogen-containing heterocyclic group (for example, 1
-Benzimidazolyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1-indolyl and the like. As the substituent that the “nitrogen-containing heterocyclic group” of R ² may have, for example, the same substituents as those that the “cyclic hydrocarbon” in the ring B may have, and the like are preferably used. Represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl group (eg, methyl,
Ethyl, propyl, butyl, sec-butyl, t-butyl,
Isopropyl, etc.) and a C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, t-butoxy, isopropoxy, etc.), and the number of substituents is 1 to 5. R ² includes, for example, (1) an unsubstituted amino group, (2) piperidyl group or (3) (i)
Benzyl, (ii) C _1-6 alkyl optionally substituted with amino or phenyl, (iii) mono- or di-C _1-6 alkyl-carbamoyl, (iv) mono- or di-C _1-6 alkyl - thiocarbamoyl, (v) C _1-6 alkoxy - carbonyl, (vi) C _1-6 alkyl - sulfonyl, (vii) piperidylcarbonyl and (viii) halogen or C _1-6 alkyl optionally substituted by amino An amino group which may have one or two substituents selected from -carbonyl is preferable, and an unsubstituted amino group is particularly preferable.

E is a bond, -CO-, -CON (R ^a )-, -COO-, -N
(R ^a ) CON (R ^b )-,-N (R ^a ) COO-,-N (R ^a ) SO ₂ -,-N (R ^a )-,-O-,-S
-, - SO- or -SO ₂ - shows the (R ^a and R ^b represents an independently hydrogen atom or an optionally substituted hydrocarbon group). Preferably, -CON (R ^a )-and -N (R ^a ) CON (R ^b )-are used, and R ^a and R ^b are preferably hydrogen atoms. Among them, -CONH- is preferable. Examples of the “optionally substituted hydrocarbon group” for R ^a or R ^b include, for example, those similar to the aforementioned “optionally substituted hydrocarbon group” represented by R ^1. Used. In the above formula, L represents a bond or a divalent group. Examples of the divalent group include, for example, -O which may have a substituent.
And a divalent hydrocarbon group which may be via-or -S-. L is, for example, preferably a divalent hydrocarbon group which may have a substituent, and particularly preferably a C _1-6 alkylene group which may have a substituent. As the “divalent hydrocarbon group optionally having substituent (s)” for L, for example, those similar to the aforementioned “divalent group” represented by D and the like are used. As the “C _1-6 alkylene group” of the “ _optionally substituted C _1-6 alkylene group”, for example, methylene, ethylene, propylene, butylene and the like can be mentioned. The “C _1-6 alkylene group” is, for example, 1 to 5
C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.) and the like.
L is preferably, for example, a C _1-6 alkylene group which may be intervened with —O— or may be substituted with a C _1-6 alkyl, among which a C _1-6 alkylene group (preferably methylene or the like) is preferred. Is preferred. X and Y each represent a hydrogen atom or an independent substituent. Examples of the independent substituent of X and Y include the same as the “substituent” represented by A above.

Examples of the compound represented by the formula (I) include, for example, X and Y independently represent halogen, hydroxy, C _1-6 alkoxy, halogeno-C _1-6 alkoxy, C _7-14 aralkyloxy, benzoyl-C _1-6 alkoxy, hydroxy-C _1-6 alkoxy, C _1-6 alkoxy-carbonyl-
C _1-6 alkoxy, C _3-14 cycloalkyl-C _1-6 alkoxy, imidazol-1-yl-C _1-6 alkoxy, C
_7-14 aralkyloxy-carbonyl-C _1-6 alkoxy or hydroxyphenyl-C _1-6 alkoxy; a benzene ring in which ring B may be substituted by C _1-6 alkoxy,
A tetrahydroisoquinoline or isoindoline ring bonded to R ² ; Z is halogen, formyl, halogeno-C
_1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl - carbonyl, one to three substituents which may have respectively a C _6-14 aryl group selected from oxo and pyrrolidinyl, C _{3- 10} cycloalkyl group, piperidyl group, thienyl group, furyl group, pyridyl group, thiazolyl group, indanyl group, or indolyl group; A is a hydrogen atom; D is C
_1-6 alkylene group; C is a bond, or a C _1-6 alkylene group which may contain phenylene and may be substituted by phenyl; R ¹ is a hydrogen atom, (1) halogen,
Have a C _1-6 alkyl optionally substituted with carbonyl, 1 or 2 substituents selected from benzyloxycarbonyl and C _1-6 alkylsulfonyl - (2) nitro, (3) C _1-6 alkyl amino optionally be, (4) (i) hydroxy, C _1-6 alkyl - carbonyl, carboxy or C _1-6 alkoxy - C _1-6 alkyl optionally substituted with carbonyl, with (ii) hydroxy phenyl optionally substituted, (iii) benzoyl or (iv) mono- - or di -C _1-6 alkylamino - substituted carbonyl hydroxy, (5) C _3-6 cycloalkyl,
(6) phenyl optionally substituted with hydroxy or halogeno-C _1-6 alkyl and (7) thienyl, furyl,
A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkyl group, each of which may be substituted with a substituent selected from thiazolyl, indolyl and benzyloxycarbonylpiperidyl;
_{A 6-14} aryl group or a C _7-14 aralkyl group, wherein R ² is substituted with (1) an unsubstituted amino group, (2) piperidyl group or (3) (i) benzyl, (ii) amino or phenyl; also a C _1-6 alkyl, (iii) mono- - or di -C _1-6 alkyl - carbamoyl or mono - or di -C _1-6 alkyl - thiocarbamoyl, (iv) C _1-6 alkoxy - carbonyl, ( v) having one or two substituents selected from C _1-6 alkyl-sulfonyl, (vi) piperidylcarbonyl and (vii) C _1-6 alkyl-carbonyl optionally substituted with halogen or amino. An amino which may be a bond, E is a bond, -CON (R ^a )-, -N (R ^a ) CO-, -N
(R ^a ) CON (R ^b )-(R ^a and R ^b are each a hydrogen atom or a C _1-6 alkyl group); L may be via —O— and is substituted by C _1-6 alkyl. C _1-6 which may be
An alkylene group is preferred. In particular, X and Y are independently halogen, hydroxy or C _1-6 alkoxy; a ring B is bonded to a benzene ring or R ² to form a tetrahydroisoquinoline ring or an isoindoline ring; R is a C _1-6 alkylene group, G is a C _1-6 alkylene group; R ¹ is (1) hydroxy,
(2) phenyl and (3) C _1-6 alkyl - carbonyl or C _1-6 alkylsulfonyl which may be substituted with substituted respectively with substituents selected from even an amino optionally C _1-6 alkyl group Or a C _7-14 aralkyl group; R ² is preferably an unsubstituted amino group, E is —CONH—, and L is a C _1-6 alkylene group.

Of the compounds represented by the formula (I),
The compound represented by aa) or a salt thereof is, for example, as exemplified in Scheme 1 below, a compound represented by the formula (IIa), a reactive derivative thereof or a salt thereof as a production intermediate, To a compound represented by the formula (III) or a salt thereof.

Embedded image [In the scheme 1, R ^2a is a group which may have a protecting group (for example, t-butoxycarbonyl, benzyloxycarbonyl, trityl and the like) in the above R ² , and other symbols have the same meanings as described above. The compound represented by the formula (Ia-a) or a salt thereof is represented by the formula (II)
A compound represented by a), a reactive derivative thereof or a salt thereof, and a compound represented by the formula (III) or a salt thereof are produced by using a condensing agent in a solvent, if necessary, in the presence of a base. can do. Examples of the reactive derivative of the compound represented by the formula (IIa) include acid anhydride, acid halide (acid chloride, acid bromide), imidazolide or mixed acid anhydride (eg, anhydride with methyl carbonate, ethyl Specific examples thereof include, for example, COOH of the compound represented by the formula (IIa)
OQ [wherein Q is a leaving group: halogen atom ｛fluorine, chlorine,
And bromine, iodine, etc., methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and the like. And the like. Examples of the solvent used in the reaction of Scheme 1 include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.) and hydrocarbon solvents (eg,
Benzene, toluene, hexane, heptane, etc.), halogenated solvents (for example, dichloromethane, dichloroethane,
Chloroform, carbon tetrachloride, etc.), acetonitrile, dimethylformamide and the like. As the base to be used, triethylamine, 4-dimethylaminopyridine,
Triethylenediamine, tetramethylethylenediamine and the like can be mentioned. Examples of the condensing agent used include, for example, a condensing agent used for peptide synthesis, and specifically,
For example, dicyclohexylcarbodiimide, diethyl cyanophosphate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like are used. At this time, for 1 mol of the compound represented by the formula (IIa) or a salt thereof,
The compound represented by the formula (III) or a salt thereof is used in an amount of 0.5 to 2 molar equivalents, preferably 1 to 1.2 molar equivalents, and the condensing agent is used in an amount of 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents. Used in molar equivalents. The reaction temperature at this time is 0 to 100 ° C, preferably 20 to 50 ° C, and the reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.

The compound represented by the formula (IIa) in the above scheme 1 or a salt thereof can be produced by the method of the following scheme 2.

Embedded image [In Scheme 2, Le is a leaving group (eg, chlorine, bromine,
Iodine, methanesulfonyloxy, toluenesulfonyloxy, etc.); R ¹ ′ or R ¹ ″ is a group obtained by removing a methylene chain from an optionally substituted hydrocarbon group represented by R ¹ ; _{Represents a} C _1-6 alkyl, a C _7-14 aralkyl and a phenyl group which may be substituted with a halogen atom or C _1-6 alkoxy, respectively; other symbols are as defined above. The compound represented by the formula (IIa-3) or a salt thereof in the scheme 2 is obtained by reacting the compound represented by the formula (IIa-1) or a salt thereof with the compound represented by the formula (IIa-2). It can be manufactured by the following. This reaction is carried out, for example, without solvent or with an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), a halogen solvent (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), a hydrocarbon solvent (eg, Benzene, toluene, hexane, heptane, etc.), dimethylformamide, dimethylsulfoxide,
Performed in a solvent such as an ester solvent (ethyl acetate, methyl acetate, etc.) in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.) if necessary. be able to. The compound represented by the formula (IIa-2) is used in an amount of 0.5 to 5 molar equivalents, preferably 0.8 to 2 molar equivalents, per 1 mol of the compound represented by the formula (IIa-1) or a salt thereof. Can be The reaction temperature at this time is 0 ° C to 200 ° C, preferably 80 ° C to 150 ° C. The base used is 0.5 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, per 1 mol of the compound represented by the formula (IIa-2). The reaction time is between 0.5 and 48 hours. Preferably, it is 0.5 to 24 hours.

The reaction from the compound represented by the formula (IIa-3) or a salt thereof to the compound represented by the formula (IIa-4) or a salt thereof in the scheme 2 is carried out, for example, using an ether solvent (eg, diethyl ether). Hydrogen and palladium in solvents such as hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, etc.), acetone, dimethylformamide, etc. System catalyst (for example, metal palladium,
It can be produced by catalytic reduction using a metal catalyst such as palladium on carbon), Raney nickel, platinum or the like, or reduction reaction using a metal or metal salt such as iron chloride or tin chloride. The hydrogen pressure is 1 to 100 atm, preferably 1 to 10 atm, and the reaction temperature is 0 to 200 ° C, preferably 10 to 50 ° C. (The reaction time is 0.5 to 48 hours, preferably 0.5 to 12 hours.)

The reaction from the compound represented by the formula (IIa-4) or a salt thereof to the compound represented by the formula (IIa-5) or a salt thereof in the scheme 2 is represented by the formula (IIa-4) The compound can be produced by a nitrogen-carbon bond reaction between a compound or a salt thereof and a halogenated hydrocarbon, sulfonic acid ester, or the like, or a reductive alkylation reaction with an aldehyde or ketone. In the nitrogen-carbon bonding reaction, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), hydrocarbon solvents (eg,
Benzene, toluene, hexane, heptane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, butanol, etc.), solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, ester solvents (ethyl acetate, methyl acetate, etc.) and the like If necessary, a phase transfer catalyst (for example, quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride and 18-
crown ethers such as wn-6) or a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.), optionally in the presence of a phase transfer catalyst and a base. Can be done. The compound represented by the formula R ¹ -Le is used in an amount of 0.5 to 5 molar equivalents, preferably 0.1 mol, per 1 mol of the compound represented by the formula (IIa-4) or a salt thereof.
8 to 2 molar equivalents are used. The reaction temperature at this time is 0 ° C to 200 ° C, preferably 20 ° C to 80 ° C.
° C. The base used is 0.5 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, per 1 mol of the compound represented by the formula (IIa-4). The reaction time is between 0.5 and 48 hours. Preferably, it is 0.5 to 24 hours. In the reductive alkylation reaction, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran,
Dioxane), halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), and hydrocarbon-based solvents (eg, benzene, toluene,
Hexane, heptane, etc.), alcoholic solvents (for example,
In a solvent such as methanol, ethanol, propanol, butanol or the like or in a mixed solvent thereof, the compound represented by the formula (IIa-
4) or a salt thereof and a compound of the formula (R ¹ ′ -CH
O) or a compound represented by (R ¹ ′ —CO—R ¹ ″) or a salt thereof, for example, by catalytic reduction or a metal hydride complex compound (eg, sodium borohydride, sodium cyanoborohydride, etc.) ) Can be produced by reacting in the presence of At this time, the compound represented by the formula (R ¹ ′ -CHO) is added to 1 mol of the compound represented by the formula (IIa-4) or a salt thereof.
Or the compound represented by (R ¹ ′ —CO—R ¹ ″) or a salt thereof is 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, and the reducing agent is 0.3 to 5 molar equivalents, preferably Use 0.5 to 1.5 molar equivalents. The reaction temperature at this time is 0 to 100 ° C, preferably 10 to 7 ° C.
0 ° C. and the reaction time is 1 to 24 hours, preferably 3 to 15 hours.

The reaction from the compound represented by the formula (IIa-5) or a salt thereof to the compound represented by the formula (IIa-6) or a salt thereof in the scheme 2 is carried out, for example, using an ether solvent (eg, diethyl ether). , Tetrahydrofuran, dioxane, etc.), halogen-based solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), hydrocarbon-based solvents (eg, benzene, toluene,
Hexane, heptane, etc.), dimethylformamide, dimethylsulfoxide, ester solvents (ethyl acetate, methyl acetate, etc.), acetonitrile, water and other solvents are reacted with malonic acid monoester acid chloride (eg, ethyl malonyl chloride). It can be manufactured by the following. The acid temperature of the dicarboxylic acid monoester is 1 to 10 mole equivalent, preferably 1 to 2 mole equivalent, relative to 1 mole of the compound represented by the formula (IIa-5), and the reaction temperature is -2.
0-100 ° C, preferably 0-50 ° C,
The reaction time is 0.5 to 24 hours, preferably 1 to 3 hours. Formula (IIa-7) in the above Scheme 2
The method for producing the compound represented by the formula or a salt thereof is represented by the formula (IIa-
It can be produced by treating the compound represented by 6) or a salt thereof with an acid or a base. That is,
These compounds include compounds represented by the formula (IIa-6) or salts thereof, for example, mineral acids (eg, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or alkali metal hydroxides (eg, , Sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) at 0 to 150 ° C, preferably 0 to 20 ° C. At this time, the strength of the acid and the base is preferably 1 to 10 N, and more preferably 1 to 2 N. The reaction time at this time is 1 to 24 hours,
Preferably, it is 2 to 10 hours.

The compound represented by the formula (IIa-8) or a salt thereof in the scheme 2 can be prepared by converting the compound represented by the formula (IIa-7) or a salt thereof in a solvent, if necessary, in the presence of a base. It can be produced by using a condensing agent. Examples of the solvent to be used include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), and halogen solvents (eg, dichloromethane, dichloroethane, chloroform,
Carbon tetrachloride), acetonitrile, dimethylformamide and the like. Examples of the base used include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and the like.
Examples of the condensing agent used include condensing agents used for peptide synthesis, and specifically, for example, dicyclohexylcarbodiimide, diethyl cyanophosphate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like are used. Can be At this time, the condensing agent is added in an amount of 0.5 to 1 mol of the compound represented by the formula (IIa-7) or a salt thereof.
To 5 molar equivalents, preferably 1 to 2 molar equivalents. The reaction temperature at this time is 0 to 100 ° C, preferably 20 to 50 ° C, and the reaction time is 0.5
To 24 hours, preferably 1 to 5 hours. In the method for producing the compound represented by the formula (IIa-9) in the scheme 2, the compound represented by the formula (IIa-8) and the compound represented by the formula (Le
-D-COOR), for example, by reacting in the presence of sodium hydride, alkyllithium, or the like. For example, in a solvent such as dimethylformamide, acetonitrile, diethyl ether, tetrahydrofuran, or dioxane, the compound represented by the formula (Le-D-COO) is added to 1 mol of the compound represented by the formula (IIa-8).
R) is used in an amount of 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents, and sodium hydride,
The alkyllithium is used in 0.5 to 3 molar equivalents, preferably 1 to 5 molar equivalents. The reaction temperature is -20 ° C to 100 ° C, preferably 0 to 30 ° C, and the reaction time is 0.5 to 24 hours, preferably 1 to 3 hours. The method for producing the compound represented by the formula (IIa) or a salt thereof in the scheme 2 can be produced by treating the compound represented by the formula (IIa-9) or a salt thereof with an acid or a base. That is, these compounds are compounds represented by the formula (IIa-9) or a salt thereof:
For example, an aqueous solution of a mineral acid (eg, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) It can be produced at a medium temperature of 0 to 150 ° C, preferably 20 to 50 ° C. At this time, the strength of the acid and the base is preferably 1 to 10 N, and more preferably 4 to 10 N.
The reaction time at this time is 1 to 24 hours, preferably 2 to 10 hours.

The compound represented by the formula (IIa-8) in the above scheme 2 or a salt thereof is prepared by the following scheme 3,
It can also be produced by the method shown in Scheme 4.

Embedded image

Embedded image [The symbols in Schemes 3 and 4 are as defined above. That is, the compound represented by the formula (IIa-8) or a salt thereof in the above-mentioned scheme 3 can be obtained by converting the compound represented by the formula (IIa-5) or a salt thereof to an ether-based solvent (eg, diethyl ether, tetrahydrofuran, Dioxane), halogen-based solvent (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), hydrocarbon-based solvent (eg, benzene, toluene, hexane, heptane, etc.), dimethylformamide, dimethylsulfoxide, ester-based solvent (acetic acid) Ethyl, methyl acetate, etc.),
It can be produced by reacting malonyl dichloride in a solvent such as acetonitrile and water. Formula (IIa
1 to 10 mol equivalents, preferably 1 to 2 mol equivalents of malonyl dichloride to 1 mol of the compound represented by -5), and the reaction temperature is -20 to 100 ° C, preferably 0 to 100 mol.
To 70 ° C., and the reaction time is 0.5 to 24 hours, preferably 1 to 3 hours. In addition, the compound represented by the formula (IIa-8) or a salt thereof in Scheme 4 can be obtained by converting the compound represented by the formula (IIa-4) or a salt thereof by the same method as shown in Scheme 2 or Scheme 3. It can also be produced by reacting the compound represented by (IIa-10) or a salt thereof with the formula (Le-R ¹ ) as a production intermediate. The reaction between the formula (IIa-10) and the formula (R ¹ -Le) in the scheme 4 can be performed, for example, by an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), a halogen solvent (eg, dichloromethane, dichloroethane, chloroform) ,
Carbon tetrachloride, etc.), hydrocarbon solvents (for example, benzene,
Solvents such as toluene, hexane, heptane, etc., alcohol solvents (eg, methanol, ethanol, propanol, butanol, etc.), acetonitrile, dimethylformamide, dimethyl sulfoxide, ester solvents (ethyl acetate, methyl acetate, etc.) and mixtures thereof. In a solvent, if necessary, a phase transfer catalyst (for example, quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, and 18-Crown-6)
Etc.) or a base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.). The compound represented by the formula R ¹ -Le is added to 1 mol of the compound represented by the formula (IIa-4) or a salt thereof.
Is used in an amount of 0.5 to 5 molar equivalents, preferably 0.8 to 2 molar equivalents. The reaction temperature at this time is 0 ° C to 200 ° C, preferably 20 ° C to 80 ° C. The base used is 0.5 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, per 1 mol of the compound represented by the formula (IIa-4). The reaction time is 0.
5 to 24 hours.

Among the compounds represented by the formula (I) or salts thereof, the compounds represented by the formulas (Ia-b), (Ia-c), (Ia-d),
The compound represented by (Ia-e) or a salt thereof can be produced by the method exemplified in the following Scheme 5.

Embedded image [The symbols in the formula are as defined above. The compound represented by the formula (Ia-b) or a salt thereof in the scheme 5 is a compound represented by the formula (IV) or a salt thereof and a compound represented by the formula (III-1) or a salt thereof: It can be produced by reacting. This reaction is carried out by reacting a compound represented by the formula (IIa) or a salt thereof and a compound represented by the formula (III) in the production of the compound represented by the formula (Ia-a) or a salt thereof as illustrated in the above-mentioned scheme 1. The same conditions as in the condensation reaction with the compound or its salt are used. The compound represented by the formula (Ia-c) or a salt thereof in the scheme 5 is a compound represented by the formula (IV) or a salt thereof, a compound represented by the formula (III) and DSC (N, carbonate N,
Reagents such as N'-disuccinimidyl) or (III-
It can be produced by reacting the compound represented by 2) or a salt thereof. In this reaction, as a solvent used, for example, an ether solvent (for example,
Diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), acetonitrile, dimethylformamide, etc., and if necessary, bases (eg, triethylamine, 4-dimethylaminopyridine,
Triethylenediamine, tetramethylethylenediamine, etc.) are used. In this reaction, the compound represented by the formula (III) and a reagent such as N, N'-disuccinimidyl carbonate or the compound represented by the formula (III- The compound represented by 2) or a salt thereof is used in an amount of 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents. The reaction temperature at this time is 0 to 100
C., preferably 20 to 50 ° C., and the reaction time is:
It is 1 to 24 hours, preferably 3 to 10 hours.

The compound represented by the formula (Ia-d) or a salt thereof in the above-mentioned scheme 5 comprises a compound represented by the formula (IV) or a salt thereof and a compound represented by the formula (III-3) or a salt thereof Can be produced by reacting Examples of the solvent used in this reaction include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), acetonitrile, dimethylformamide, etc. With a base (eg, triethylamine, 4
-Dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, etc.). In this reaction, 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, of the compound represented by the formula (III-3) or the salt thereof is added to 1 mol of the compound represented by the formula (IV) or 1 mol thereof. Used. The reaction temperature at this time is 0 to 100
C., preferably 20 to 50 ° C., and the reaction time is:
It is 1 to 24 hours, preferably 3 to 10 hours. The compound represented by the formula (Ia-e) or a salt thereof in the scheme 5 is obtained by reacting the compound represented by the formula (IV) or a salt thereof with the compound represented by the formula (III-4) or a salt thereof It can be manufactured by doing. This reaction is carried out, for example, in a solvent such as an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), acetone, dimethylformamide, etc. , Sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, triethylamine, etc.). In this reaction, a compound represented by the formula (III-4) or a salt thereof is added to 1 mol of the compound represented by the formula (IV) or a salt thereof.
1 to 10 molar equivalents, preferably 1 to 2 molar equivalents are used. The reaction temperature at this time is 0 to 100 ° C.
It is preferably 20 to 50 ° C., and the reaction time is 1 to 24 hours, preferably 3 to 10 hours.

The compound represented by the formula (IV) in the above scheme 5 or a salt thereof can be produced by the method of the following scheme 6. After reacting the compound represented by the formula (IIa) or a salt thereof with diphenylphosphoryl azide or the like in a solvent in the presence of a base, the obtained acyl azide product is isocyanate is subjected to Curtius transfer reaction in a solvent. It can be produced by treating the acid derivative (V) as a production intermediate and treating it with an acid. Equation (I
The compound represented by V) or a salt thereof is obtained by converting the isocyanic acid derivative (V) into a carbamate derivative (VI) as shown in the following scheme 7, and then converting the compound represented by the formula (IV) or a salt thereof It can also be manufactured.

Embedded image

Embedded image [The symbols in Schemes 6 and 7 are as defined above. ]

Examples of the solvent used in the reaction of the compound represented by the formula (IIa) or a salt thereof with diphenylphosphoryl azide in the scheme 6 include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogens System solvent (for example,
Dichloromethane, dichloroethane, chloroform, etc.),
Dimethylformamide and the like. Examples of the base used at this time include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and the like. This reaction is performed based on 1 mol of the compound represented by the formula (IIa) or a salt thereof.
1 to 10 molar equivalents of diphenylphosphoryl azide,
Preferably, 1.5 to 3 molar equivalents are used. At this time, the reaction temperature is -20 to 50 ° C, preferably 0 to 20 ° C, and the reaction time is 0.5 to 5 hours, preferably 1 to 2 hours. When the product obtained by the above reaction is subjected to a Curtius rearrangement reaction, examples of the solvent to be used include hydrocarbon solvents (eg, benzene, toluene, xylene, etc.) and ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.). ), Halogenated solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), dimethylformamide and the like. The reaction temperature is 50-200 ° C., preferably 8
0 to 150 ° C. and the reaction time is 0.5 to 12
Hours, preferably 1 to 3 hours. When treating the product obtained by the above reaction with an acid, examples of the solvent to be used include water, dioxane, dimethylformamide and the like, and examples of the acid to be used include sulfuric acid, hydrochloric acid,
Mineral acids such as nitric acid and hydrobromic acid; At this time, the reaction temperature is 20 to 200 ° C, preferably 50 to 100 ° C, and the reaction time is 0.5 to 5 hours, preferably 1 to 2 hours.

The compound represented by the formula (Ia-c) or the formula (Ia-d) or a salt thereof in the above scheme 5 can be prepared by reacting the compound represented by the scheme 6
By reacting the compound represented by the formula (V) with the compound represented by the formula (III) or the formula (VII). In this case, the reaction between the compound represented by the formula (V) and the compound represented by the formula (III) or the formula (VII) is carried out by reacting the compound represented by the formula (IV) in the scheme 5 or a salt thereof with the compound represented by the formula The reaction can be carried out under the same conditions as when reacting with the compound represented by (III-2).

Embedded image [The symbols in Scheme 8 are as defined above. The compound represented by the formula (I) or a salt thereof,
The compound represented by af) or a salt thereof is prepared by a method exemplified in the following scheme 9 by a method represented by the following formula 9: Can be produced by reacting

Embedded image [The symbols in Scheme 9 are as defined above. ]

For example, a compound represented by the formula (IIa) or a salt thereof and a compound represented by the formula (VII) or a salt thereof are prepared by using a condensing agent in a solvent, if necessary, in the presence of a base. Can be. Examples of the solvent used include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), acetonitrile, dimethylformamide and the like. Examples of the base used include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine and the like. Examples of the condensing agent used include condensing agents used for peptide synthesis, and specific examples include dicyclohexylcarbodiimide, diethyl cyanophosphate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like. No. In this reaction, a compound represented by the formula (VII) or a salt thereof is added to 1 mol of the compound represented by the formula (II) or 1 mol thereof,
0.5 to 2 molar equivalents, preferably 1 to 1.2 molar equivalents, and the condensing agent are used in 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents. The reaction temperature at this time is 0 to 100 ° C, preferably 20 to 50 ° C, and the reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.

Of the compounds represented by the formula (I) or salts thereof, the compounds represented by the formula (Ia-g) or salts thereof are prepared by the method shown in the following Scheme 10 by the method shown in the following Scheme 10.
Or a salt thereof, and a compound represented by the formula (IX) or a salt thereof.

Embedded image [The symbols in Scheme 10 are as defined above. The compound represented by the formula (VIII) or a salt thereof is represented by the formula (II)
The compound represented by a) or a salt thereof is converted to a mixed acid anhydride by reaction with ethyl chlorocarbonate or the like, for example, a protic solvent (eg, methanol, ethanol, propanol, butanol, etc.) or an aprotic solvent (eg, , Ethyl ether, tetrahydrofuran, dioxane, etc.) in a solvent, for example, with a metal hydride complex compound (eg, lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, etc.). The metal hydride complex is used in an amount of 0.3 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, per 1 mol of the compound represented by the formula (IIa) or a salt thereof. The reaction temperature at this time is -20
To 100 ° C, preferably 0 to 20 ° C, and the reaction time is 0.5 to 10 hours, preferably 1 to 3 hours. In the reaction between the compound represented by the formula (VIII) or a salt thereof and the compound represented by the formula (IX) or a salt thereof, the solvent used includes, for example, an aprotic solvent (eg, ethyl ether, tetrahydrofuran,
Dioxane, acetonitrile, dimethylformamide, etc.), and if necessary, for example, an inorganic base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.), an organic base (eg, triethylamine, 4-dimethylamino) For example, pyridine, triethylenediamine, tetramethylethylenediamine, sodium hydride, cesium fluoride, or the like may be used. This reaction is carried out by reacting the compound represented by the formula (VIII) or a salt thereof 1
The compound represented by the formula (IX) or a salt thereof is used in 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol. The reaction temperature at this time is 0 to 200
C., preferably 20 to 100 ° C., and the reaction time is 10 minutes to 5 hours, preferably 30 minutes to 2 hours.

Among the compounds represented by the formula (I) or salts thereof, the compounds represented by the formulas (Ia-h) or (Ia-i) or the salts thereof are prepared by the method shown in the following scheme 11, etc. By reacting the compound represented by the formula (X) or a salt thereof with the compound represented by the formula (VII) or the formula (XI) or a salt thereof.

Embedded image [In Scheme 11, Le ² is a halogen (eg, chlorine, bromine, iodine, etc.), and other symbols are as defined above. The compound represented by the formula (X) or a salt thereof is obtained by converting the compound represented by the formula (IV) or a salt thereof into a compound represented by the formula (IV) in, for example, hydrochloric acid, hydrobromic acid or hydroiodic acid. The compound or its salt is subjected to diazotization using 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents of sodium nitrite, followed by heating. At this time, the reaction temperature is 20 to 200 ° C, preferably 50 to 100 ° C, and the reaction time is 5 minutes to 2 minutes.
Time, preferably 15 to 30 minutes. The compound represented by the formula (X) or a salt thereof is combined with the compound represented by the formula (VII) or the formula (X
The reaction with the compound represented by the formula (I) or a salt thereof is carried out according to the formula (Ia)
-G) when producing a compound or a salt thereof, a compound represented by the formula (VIII) or a salt thereof and a compound of the formula (I
The reaction can be carried out under the same conditions as in the reaction with the compound represented by X) or a salt thereof.

Of the compounds of the formula (I) or salts thereof, the compounds of the formula (Ia-j) or salts thereof
As shown in the following Scheme 12, it can be produced by oxidizing the compound represented by the formula (Ia-i) or a salt thereof.

Embedded image [The symbols in the formula are as defined above. In this reaction, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane,
In a solvent such as heptane, a halogen-based solvent (eg, dichloromethane, dichloroethane, chloroform, etc.), acetonitrile, dimethylformamide, etc., metachloroperbenzoic acid is added to 1 mol of the compound represented by the formula (Ia-i) or 1 mol of a salt thereof. 1 to 5 molar equivalents, preferably 2 to 3 molar equivalents. At this time, the reaction temperature is 0 to 100 ° C, preferably 0 to 30 ° C, and the reaction time is 1 to 10 hours, preferably 1 to 2 hours.

The compound represented by the formula (I) or a salt thereof and the compound represented by the formula (Ib) or a salt thereof may be a compound represented by the formula (Ia) It can be produced by removing the protecting group of the salt by a method known per se. Further, the compound represented by the formula (I) or a salt thereof is the compound represented by the formula (Ib) or a salt thereof, and a compound represented by the formula (XII) or the formula (X
It can be produced by reacting the compound represented by III) or a salt thereof.

Embedded image [In the formula, R ^2b is a deprotected R ^2a , R ^2c and R ^2d is a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a hydrogen atom or The acyl group and other symbols have the same meanings as described above. In the removal of the protecting group, when the protecting group is a t-butoxycarbonyl group, a trityl group, or a benzyloxycarbonyl group, for example, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), an alcohol solvent (eg, methanol, Treatment with a solvent such as ethanol, propanol, etc.) or a halogen-based solvent (eg, dichloromethane, dichloroethane, chloroform, etc.) with an acid such as hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, trifluoroacetic acid, etc. Thus, the protecting group can be removed. When the protecting group is a benzyloxycarbonyl group, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, propanol, etc.), dimethylformamide, ethyl acetate, acetic acid The protective group can be removed by hydrolysis in a solvent such as a palladium-based catalyst (for example, palladium metal, palladium / carbon catalyst, etc.). In this reaction, when an acid treatment is performed, the reaction temperature is -20 to 100 ° C, preferably 0 to 30 ° C.
The reaction time is about 0.1 to 5 hours, preferably about 0.5 to 1 hour. In this reaction, when hydrolyzing, the reaction temperature is -20 to 150 ° C,
It is preferably 0 to 50 ° C, and the reaction time is 0.1
For 10 to 10 hours, preferably 0.5 to 3 hours, and the hydrogen pressure is 1 to 100 atm, preferably 1 to 3 atm. The catalyst used at this time is 0.001 to 0.5 mole equivalent, preferably 0.01 to 0.1 mole equivalent to 1 mole of the compound represented by the formula (Ia) or a salt thereof.
It is a molar equivalent.

The reaction between the compound represented by the formula (Ib) or a salt thereof and the compound represented by the formula (XII) or the salt thereof is carried out by reacting the compound represented by the formula (IIa-4) or The reaction can be carried out under the same conditions as in the reaction of the salt with the compound represented by the formula R ¹ -Le or the salt thereof. Further, a compound represented by the formula (Ib) or a salt thereof and a compound of the formula (XII)
The reaction with the compound represented by the formula (I) or a salt thereof is carried out by reacting the compound represented by the formula (IV) or the salt thereof with the compound represented by the formula (III-2) or the salt thereof in the above scheme 5. Then, the reaction can be carried out under the same conditions as those for producing the compound represented by the formula (Ia-c) or a salt thereof. The compound represented by the formula (IIa-2) in the scheme 2 or a salt thereof is represented by the formula:
A compound represented by the formula (IIb-1) or a salt thereof is produced by attaching a protecting group by a method known in the field of organic synthesis, or a compound represented by the formula (IIb-4) or a salt thereof substituents X ^a in the methods known in the art of organic synthesis can be prepared by converting the substituent NH _2. The formula or a salt thereof (IIb-1) is the formula (IIb-2) a compound represented by or a salt thereof a substituent X ^a by methods known in the art of organic synthesis substituent NH ₂ It can be manufactured by conversion. Formula (IIb-2)
The compound represented by the formula (IIb-3) or a salt thereof is produced from the compound represented by the formula (IIb-3) or a salt thereof by converting a substituent R ^2e into a substituent R ^2b by a method known in the field of organic synthesis. Can be. The compound represented by the formula (IIb-4) or a salt thereof is obtained by converting the substituent R ^2e to a substituent R ^2a from the compound represented by the formula (IIb-3) or a salt thereof by a method known in the field of organic synthesis. Can be manufactured.

Embedded image [Wherein, R ^2b is a deprotected R ^2a , R ^2e is a substituent convertible to R ^2a or R ^2b , X ^a is a substituent convertible to NH ₂ , and other symbols are as defined above. Show. ]

The starting compound and the production intermediate of the present invention may form a salt, and are not particularly limited as long as the reaction proceeds. Salts of these compounds include, for example, inorganic acid salts (eg, hydrochloride, sulfate,
Hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, maleate,
Fumarate, propionate, citrate, tartrate, malate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc., alkali metal salts (eg, sodium salt, potassium salt) Etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), organic base salts (eg, trimethylamine salts, triethylamine salts, pyridine salts, piperidine salts, ethanolamine salts, etc.), aluminum salts, ammonium salts and the like. Used. In addition, the starting compound and the production intermediate of the present invention can be isolated according to a conventional method, but can also be used as they are in the next reaction step without isolation. In each of the reactions of the present invention, when the compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, even if a protecting group generally used in peptide chemistry or the like is introduced into these groups, The desired compound can be obtained by removing the protecting group if necessary after the reaction.

Examples of the amino-protecting group include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), a benzyl group, a t-butyloxycarbonyl group, a benzyloxycarbonyl group, and a 9-amino group.
Fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, phenylcarbonyl group, C _1-6 alkyloxy-carbonyl group (for example, methoxycarbonyl,
Ethoxycarbonyl, etc.), C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.), trityl group,
A phthaloyl group, an N, N-dimethylaminomethylene group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, etc.), nitro group and the like. As the protecting group for the carboxyl group,
For example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), a phenyl group, a silyl group, a benzyl group, an allyl group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, etc.), nitro group and the like. As the protecting group for the hydroxy group,
For example, a methoxymethyl group, an allyl group, a t-butyl group, a C _7-10 aralkyl group (eg, benzyl etc.), a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, ethyl carbonyl etc.), Benzoyl group, C _7-10
An aralkyl-carbonyl group (e.g., benzylcarbonyl), a pyranyl group, a furanyl group, a trialkylsilyl group, and the like are used. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.), a phenyl group , C _7-10
It may be substituted with an aralkyl group (for example, benzyl and the like), a nitro group and the like.

As a method for removing these protecting groups, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium A method using fluoride, palladium acetate or the like is used. When a compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, converted to a free form or another salt according to a conventional method. You can also. The compound (I) of the present invention or a salt thereof thus obtained may be isolated and purified from the reaction solvent by a known means, for example, phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like. Can be. Compound (I) of the present invention or a salt thereof is a diastereomer,
When present as a conformer or the like, each can be isolated by a usual separation and purification means, if desired. When the compound (I) or a salt thereof of the present invention is in a racemic form, it can be separated into d-form and l-form by a usual optical resolution means. The compound having a somatostatin receptor function regulating action or a prodrug thereof used in the present invention may be itself or a pharmacologically acceptable salt. Examples of such salts include inorganic bases (eg, alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium) when the compound having a somatostatin receptor function regulating action has an acidic group such as a carboxyl group. , Zinc, iron,
Transition metals such as copper) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N'-dibenzylethylenediamine, arginine, lysine And basic amino acids such as ornithine). When the compound having a somatostatin receptor function regulating action has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, triionic acid) Fluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,
Salts with acidic amino acids such as succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid, and glutamic acid.

The prodrug of a compound having a somatostatin receptor function regulating action used in the present invention is a compound which is converted into a compound having a somatostatin receptor function regulating action by a reaction with an enzyme or gastric acid under physiological conditions in a living body. That is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. to change into a compound having a somatostatin receptor function regulating action, and a compound which is hydrolyzed, such as by gastric acid, etc. to be converted into a compound having a somatostatin receptor function regulating action, Say. As a prodrug of a compound having a somatostatin receptor function regulating action, a compound in which the amino group of a compound having a somatostatin receptor function regulating action is acylated, alkylated or phosphorylated (eg, having a somatostatin receptor function regulating action) When the amino group of the compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds and the like); compounds having a somatostatin receptor function regulating action. Hydroxyl groups are acylated, alkylated, phosphorylated,
Borated compounds (eg, compounds in which the hydroxyl group of a compound having a somatostatin receptor function regulating action is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.) ); A compound having a somatostatin receptor function-modifying action in which the carboxyl group is esterified or amidated (eg, a compound having a somatostatin receptor function-modulating action) in which the carboxyl group is ethylesterified, phenylesterified, or carboxymethyl. Esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound and the like). These compounds can be produced from compounds having a somatostatin receptor function regulating action by a method known per se.

Further, prodrugs of compounds having a somatostatin receptor function regulating activity are described in “Development of Pharmaceuticals”, Hirokawa Shoten, 1990, Vol. 7, Molecular Design, pp. 163 to 198.
It may be a compound which changes into a compound having a somatostatin receptor function regulating action under physiological conditions as described on page. The compound having a somatostatin receptor function regulating action may be either a hydrate or a non-hydrate. In addition, compounds having a somatostatin receptor function-modulating effect include isotopes (eg, ³ H, ¹⁴ C,
³⁵ S, ¹²⁵ I etc.). The above-mentioned somatostatin receptor function modulation indicates activation or suppression of the function of the somatostatin receptor, and activation of the function of the somatostatin receptor indicates activation of the somatostatin receptor transmission system. The substance having an action can be applied as a somatostatin receptor ligand, a somatostatin receptor ligand agonist, a somatostatin receptor agonist, a somatostatin receptor co-activator, and the like. Any substance can be used as long as it can provide a response similar to the response produced by the action of the ligand. In addition, suppression of somatostatin receptor function refers to suppression of the somatostatin receptor transmission system, and a substance having such an action can be applied as a somatostatin receptor antagonist or the like. Any substance can be used as long as it can suppress the response caused by the action of. Among the above-mentioned somatostatin receptor function regulating actions, preferably, somatostatin receptor action action (agonist action)
It is.

The compound (I) or a salt thereof of the present invention has low toxicity and side effects, and is useful in mammals (for example, human,
It can be used as a variety of prophylactic, diagnostic, or therapeutic agents for cattle, horses, dogs, cats, monkeys, mice, rats, etc., and especially humans). The compound (I) of the present invention or a salt thereof suppresses or regulates the production or secretion of various hormones, growth factors, physiologically active substances and the like. As hormones, for example, growth hormone (GH),
Thyroid stimulating hormone (TSH), prolactin, insulin, glucagon and the like. As growth factors,
For example, IGF-1 and the like can be mentioned. Examples of the physiologically active substance include bathoactive intestinal polypeptide (VIP), gastrin, and glucagon-like peptide.
1, amylin, substance-P, CGRP, CCK
(Cholecystokinin), amylase and the like. The "bioactive substance" includes interleukins and T
Cytokines such as NF-α. These compounds also act via various intracellular signaling systems involving somatostatin. These intracellular signaling systems include adenylate cyclase, K ⁺ channel, Ca ²⁺
Channel, protein dephosphorylation, phospholipase C / inositol 3-phosphate producing system, MAP kinase, Na ⁺ /
H ⁺ exchange system, intracellular signal transduction system involving transcription factors such as phospholipase A2, NF-κB and the like are included. Also,
These compounds and salts thereof regulate the direct or indirect cytostatic or apoptotic action involving somatostatin. Therefore, the compound (I) of the present invention or a salt thereof may be used for these hormones, growth factors,
Diseases associated with abnormal production or secretion of physiologically active substances,
It is useful for these abnormalities in the intracellular signal transduction system (for example, diseases accompanied by excessive enhancement or suppression) or diseases accompanied by abnormal cell growth control. Specifically, for example, (1) acromegaly, TSH producing tumor, non-secreting (non-functional) pituitary tumor, ectopic ACTH (adrenocorticotropin) producing tumor, medullary thyroid cancer, VIP producing tumor, Remedies for tumors such as glucagon producing tumor, gastrin producing tumor, insulinoma, carcinoid, (2) insulin dependent or independent diabetes or various diseases related to these diabetes, for example, diabetic retinopathy, diabetic nephropathy Drugs for diabetic neuropathy, Dawn syndrome, orthostatic hypotension, etc., (3) drugs for obesity, bulimia, etc. due to improvement of hyperinsulinemia or suppression of appetite, (4) exocrine secretion in the digestive tract From suppressing or regulating, for example, acute pancreatitis, chronic pancreatitis, pancreatic / intestinal fistula, hemorrhagic ulcer,
Remedies for peptic ulcer, gastritis, hyperacidity, etc., (5) agents for improving various symptoms associated with Helicobacter pylori infection,
For example, gastrin secretion inhibitor, (6) an amylase secretion inhibitor associated with endoscopic cholangiopancreatography, and a prognostic agent for pancreatic surgery, (7) reduced intestinal absorption capacity, increased secretion or digestive tract Diarrhea caused by abnormal motor function (eg, short bowel syndrome), diarrhea caused by drugs such as cancer chemotherapy, diarrhea caused by congenital small bowel atrophy, diarrhea caused by neuroendocrine tumors such as VIP-producing tumors, AIDS For diarrhea due to stomach, diarrhea due to graft reaction against host accompanying bone marrow transplantation, diarrhea due to diabetes, diarrhea due to blockade of celiac plexus, diarrhea due to systemic sclerosis and eosinophilia Remedy for diarrhea caused by the disease, (8) therapeutic drug for dumping syndrome, irritable colitis, Crohn's disease, inflammatory bowel disease, etc .; Tumors or cancers caused by various types of cancers having cell viability or abnormal cell growth suppression due to other reasons (for example, thyroid cancer, colon cancer, breast cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, Gastric cancer, bile duct cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, melanoma, osteosarcoma, chondrosarcoma, malignant pheochromocytoma, neuroblastoma, brain tumor, thymoma, kidney cancer, etc.), leukemia (for example, Therapeutic agents such as basic leukocyte leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, etc. (therapeutic agents used for these cancers can be used alone or with other anticancer agents such as tamoxifen, LHRH Agonist,
LHRH antagonists, interferon-α, interferon-β and inderferon-γ, can be used in combination with interleukin-2, etc.), (1
0) Hypertrophic cardiomyopathy, arteriosclerosis, valvular heart disease, myocardial infarction (especially myocardial infarction after percutaneous transluminal coronary angioplasty), prophylactic / therapeutic agent for revascularization, (11) esophageal varices hemorrhage, cirrhosis A therapeutic agent for peripheral vascular disease, (12) inhibiting or regulating secretion of a physiologically active substance (eg, substance P, tahikinin, cytokine, etc.) acting on the immune system, and thus accompanying, for example, systemic or local inflammation. Diseases, for example,
Polyarteritis, rheumatoid arthritis, psoriasis, sunburn,
Eczema, allergies (eg asthma, atopic dermatitis,
(13) Since it affects the production and secretion of neuromodulating factors, for example, dementia (eg, Alzheimer's disease, Alzheimer's senile dementia, vascular / multiple dementia, etc.) Remedies for headache, migraine, schizophrenia, epilepsy, depression, general anxiety disorder, sleep disorder, multiple sclerosis, (14) analgesics, (15) acute bacterial meningitis, acute viral encephalitis, Adult respiratory distress syndrome, bacterial pneumonia, severe systemic fungal infection, tuberculosis,
Spinal cord injury, fracture, liver failure, pneumonia, alcoholic hepatitis, A
Hepatitis B, hepatitis B, hepatitis C, AIDS infection, human papillomavirus infection, influenza infection, cancer metastasis, multiple myeloma, osteomalacia, osteoporosis, bone Petchet disease, reflux esophagitis, nephritis, kidney Insufficiency, sepsis, septic shock, hypercalcemia, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, systemic lupus erythematosus,
Remedies for transient cerebral ischemia attacks, alcoholic hepatitis, etc. (1
6) healing of organ transplants, burns, wounds, alopecia, etc. (17)
Ocular diseases (eg, glaucoma), (18) radioactive substances (eg, ¹²⁵ °, ¹¹¹ °, etc.) introduced into the present compound directly or via an appropriate spacer, and imaging of a tumor having a somatostatin receptor; and 19) An anticancer agent can be introduced into the present compound directly or via an appropriate spacer, and used for targeting a tumor having a somatostatin receptor.

The compound (I) of the present invention or a salt thereof can be used as it is, but is usually formulated with an appropriate amount of a carrier for pharmaceutical preparations according to a conventional method. Examples of the “carrier for pharmaceutical preparations” include excipients (eg, calcium carbonate, kaolin, sodium bicarbonate, lactose, D-mannitol, starches, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binding Agents (eg, dextrin, gums, pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid derivatives, etc.), disintegrants (eg, , Carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, etc.), solvent (eg, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.), dispersion Agent For example, Tween 80, HCO 60, polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), solubilizing agents (e.g.,
Polyethylene glycol, propylene glycol, D-
Mannitol, benzyl benzoate, ethanol, trisaminomethane, triethanolamine, sodium carbonate, sodium citrate, etc., suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, benzalkonium chloride, polyvinyl alcohol, polyvinyl alcohol) Pyrrolidone, hydroxymethylcellulose, etc.), soothing agents (eg, benzyl alcohol, etc.), tonicity agents (eg, sodium chloride, glycerin, etc.), buffers (eg, phosphate, acetate, carbonate, citrate) ), Lubricants (eg, magnesium stearate, calcium stearate, talc, starch, sodium benzoate, etc.), coloring agents (eg, tar dye, caramel, iron sesquioxide, titanium oxide, riboflavins, etc.), flavoring agents (Eg, sweets, flavors, etc.) Stabilizers (e.g., sodium sulfite, ascorbic acid, etc.) and preservatives (e.g.,
Parabens, sorbic acid, etc.). The medical prophylaxis and / or medical treatment of the present invention which may contain the carrier for pharmaceutical preparations.
The therapeutic agent contains the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an amount necessary for preventing or treating various diseases. The content of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in the preparation of the present invention is usually 0.1 to 100% by weight of the whole preparation. Specific examples of the dosage form include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, drops, syrups, emulsions, emulsions, Suspensions, injections, inhalants, ointments, suppositories, troches, cataplasms and the like are used. These preparations are prepared according to a conventional method (for example, the method described in Japanese Pharmacopoeia 12th Edition).

The production methods of the main preparations in the present invention are shown below, but are not limited thereto. (1) Tablets The compound of the present invention as it is, or a mixture obtained by adding an excipient, a binder, a disintegrant or other suitable additives and mixing uniformly, is granulated by an appropriate method, and then lubricated. Add the agent and compression molding. Then, if necessary, the skin may be coated with a suitable coating agent for the purpose of taste masking, enteric coating or persistence. (2) Injection A certain amount of the compound of the present invention is added to a stabilizer, a solubilizer, a suspending agent, an emulsifier, a buffer, a preservative, and the like, if necessary.
Dissolve, suspend or emulsify in water for injection to make a fixed dose. (3) Suppository Based on an oily base, water-soluble base, or other appropriate substance, add an emulsifier, a suspending agent, and the like, if necessary, add the compound of the present invention, and mix. After equalizing, it is made into an appropriate shape. (4) Capsules The compound of the present invention and additives such as suitable excipients are mixed evenly, or granulated by an appropriate method, or the granules are coated with an appropriate coating agent. The capsules are filled as they are or lightly.

The pharmaceutical preparation of the present invention has low toxicity, high safety and excellent somatostatin receptor agonism, and thus is useful as a preventive / therapeutic agent for the above-mentioned diseases. The amount of the compound of the present invention used in the pharmaceutical preparation varies depending on the compound selected, the species of the animal to be administered, the number of times of administration, and the like, but it is effective over a wide range.
For example, for an adult patient with acromegaly, diabetic complications, intractable laxatives, diabetes or obesity, the daily dose when the pharmaceutical preparation of the present invention is orally administered is the same as that of the compound (I) of the present invention. As an effective amount, usually 0.001 to 20
mg / kg body weight, preferably 0.2-3 mg / k
Although it is g body weight, in the case of parenteral administration, it will generally be smaller than these dosages when it is used in combination with other active ingredients or in combination with other pharmaceutical preparations. However, the amount of the compound actually administered depends on the selection of the compound, various formulation forms,
It is determined by the patient's age, weight, sex, degree of disease, administration route, period and interval of administration, and can be changed at any time by the judgment of a doctor. The administration route of the pharmaceutical preparation is not particularly limited by various circumstances, and for example, can be administered by an oral or parenteral route. "Parenteral" as used herein includes:
Intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal and intraperitoneal administration are included. The administration period and interval of the pharmaceutical preparation are changed according to various situations and are determined at any time by a doctor's judgment, but divided administration, daily administration, intermittent administration, short-term large-volume administration, repeated administration There are methods such as administration. For example, in the case of oral administration, it is preferable to administer the drug in one to several times a day (particularly one to three times a day). It is also possible to perform intravenous infusion over a long period of time.

[0048]

DETAILED DESCRIPTION OF THE INVENTION The present invention further includes the following examples,
Although described in detail with experimental examples, these examples are merely implementations and do not limit the present invention, and may be changed without departing from the scope of the present invention. The abbreviations in Reference Examples and Examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, d
t: double triplet, m: multiplet, bs:
Broad singlet, J: coupling constant, room temperature: 0
~ 30 ° C

EXAMPLES Example 1 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) (4-aminobenzyl) carbamic acid tert-butyl ester 4-aminobenzylamine (24.3 g, 199 mmol) in tetrahydrofuran (400 ml) ice Add di-t-carbonate to the cooled stirring solution.
ert-Butyl (43.9 g, 199 mmol) was added dropwise. The resulting reaction mixture was stirred at 0 C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was crystallized from hexane and collected by filtration. (4-aminobenzyl) carbamic acid tert-butyl ester (41.9 g,
94.8%). Mp 69-70 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.62 (2H, bs), 4.19 (2
H, d, J = 5.8Hz), 4.73 (1H, bs), 6.65 (2H, d, J = 8.6H
z), 7.08 (2H, d, J = 8.6Hz). (2) [4- (2-nitrophenylamino) benzyl] carbamic acid tert-butyl ester (4-aminobenzyl) carbamic acid tert-butyl ester
(89.2 g, 401 mmol), o-fluoronitrobenzene (56.7
g, 401 mmol) and potassium carbonate (55.4 g, 401 mmol) were stirred at 140 ° C. for 2 hours under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give [4- (2-
Crystals of nitrophenylamino) benzyl] carbamic acid tert-butyl ester (36 g, 26%) were obtained. Mp 121-123 ° C. Elemental analysis C ₁₈ H ₂₁ N ₃ O ₄ as a theory:. C, 62.96; H, 6.16; N, 12.24 Found:. C, 62.71; H, 6.05; N, 12.12 1 H- NMR (CDCl ₃ ) δ: 1.49 (9H, s), 4.34 (2H, d, J = 6 Hz), 4.9
2 (1H, bs), 6.78 (1H, t, J = 7.2Hz), 7.18-7.37 (6H, m), 8.
21 (1H, d, J = 8.6Hz), 9.47 (1H, bs).

(3) [4- (2-aminophenylamino) benzyl] carbamic acid tert-butyl ester [4- (2-nitrophenylamino) benzyl] carbamic acid t
To a solution of ert-butyl ester (36 g, 105 mmol) in ethanol was added 10% palladium on carbon (4 g). The resulting mixture was hydrogenated under normal temperature and normal pressure conditions for 4 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The remaining solid was recrystallized from hexane-ethyl acetate to give [4- (2-aminophenylamino) benzyl] carbamic acid tert-butyl ester (29.
(5 g, 89.9%). Melting point 117-119 ° C Elemental analysis: C ₁₈ H ₂₃ N ₃ O ₂ Theoretical: C, 68.88; H, 7.40; N, 13.41. Found: C, 69.09; H, 7.55; N, 13.48. ¹ H- NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.78 (2H, bs), 4.21 (2
(H, d, J = 5.4Hz), 4.73 (1H, bs), 5.19 (1H, bs), 6.69-7.15
(4H) [4- [2- (4-biphenylmethylamino) phenylamino] benzyl] carbamic acid tert-butyl ester [4- (2-aminophenylamino) benzyl] carbamic acid t
Acetic acid (5.4 m) was added to an ethanol solution (500 ml) of ert-butyl ester (29.5 g, 94.1 mmol) and 4-phenylbenzaldehyde.
1, 94 mmol) was added. After stirring the resulting mixture at 0 ° C. for 30 minutes, sodium cyanoborohydride (7.1 g, 117
mmol) was added. Thereafter, the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give [4- [2- (4-biphenylmethylamino) phenylamino] benzyl] carbamic acid tert-butyl ester (4
(0.5 g, 90%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9 H, s), 4.21 (2 H, d, J = 5.4 Hz),
4.39 (2H, s), 4.75 (1H, bs), 5.12 (1H, bs), 6.68-7.59
(16H, m).

(5) 5- (4-biphenylmethyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine [4- [2- (4-biphenylmethylamino) phenylamino] benzyl] carbamic acid tert-butyl ester (40.5 g, 8
Potassium carbonate (14.0 g, 101 mmol) was added to an ice-cooled stirred solution of 4.4 mmol) of tetrahydrofuran (500 ml).
Then, a tetrahydrofuran solution (50 ml) of malonyl dichloride (14.1 g, 101 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3, Crystals of 4,5-tetrahydro-1H-1,5-benzodiazepine (5.9 g, 13%) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.54 (2H, s), 4.32 (2H,
d, J = 5.8Hz), 4.95 (1H, bs), 6.89-7.34 (8H, m), 9.27 (1
H, bs). (6) 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4, 5-tetrahydro-1H-1,5-benzodiazepine (5.9 g, 10.8 mmo
l) to a stirred solution of N, N-dimethylformamide (120 ml)
% Oily sodium hydride (1.3 g, 32.4 mmol) was added. After stirring at room temperature for 5 minutes, methyl bromoacetate (2.0 ml, 21.
6 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then added in small portions over 2 hours in 60% oily sodium hydride (1.
3 g, 32.4 mmol) and methyl bromoacetate (3.1 ml, 32.4 mmo
l) was added. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure,
The residue was purified by silica gel column chromatography to give 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5
A non-crystalline solid of -tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (5.6 g, 84%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.18 (2H, dd, J = 1.6 Hz,
7Hz), 3.71 (3H, s), 3.96 (1H, t, J = 7Hz), 4.22 (2H, d, J
= 5.6Hz), 4.74 (1H, bs), 4.78 (1H, d, J = 14.8Hz), 5.84
(1H, d, J = 14.8Hz), 6.60-7.59 (17H, m).

(7) 5- (4-biphenylmethyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
Acetic acid 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3- To a stirred solution of acetic acid methyl ester (5.6 g, 9.0 mmol) in tetrahydrofuran (50 ml) and methanol (150 ml) was added a 1N aqueous sodium hydroxide solution (40 ml, 40 mmol). The resulting mixture was stirred at 60 C for 2 hours. After cooling the reaction solution, water and potassium hydrogen sulfate (5.4 g, 40 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 5- (4-biphenylmethyl) -1- (4-te
(rt-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (3.5 g, 64%) was obtained as an amorphous solid. Was. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9 H, s), 3.21 (2 H, d, J = 7 Hz),
3.92 (2H, t, J = 7Hz), 4.21 (2H, d, J = 5.6Hz), 4.76 (1H,
bs), 4.78 (1H, d, J = 14.6Hz), 5.82 (1H, d, J = 14.6H
z), 6.60-7.59 (17H, m). (8) N- (2-fluorobenzyl) -5- (4-biphenylmethyl)
-1- (4-tert-butoxycarbonylaminomethylphenyl)
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzophenazine
-3-acetamide 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine -3-acetic acid (0.13 g, 0.
22 mmol) of N, N-dimethylformamide (1 ml) was added to an ice-cooled stirred solution of 2-fluorobenzylamine (0.028 ml, 0.2
4 mmol), diethyl cyanophosphate (0.04 ml, 0.26 mmol),
Triethylamine (0.037 ml, 0.26 mmol) was added.
The resulting mixture was stirred at room temperature for 48 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-
(2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (4-t
(ert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (135 mg, 86%) was obtained as an amorphous solid. Was. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.03 (2H, d, J = 7.0Hz),
4.07 (2H, d, J = 7.0Hz), 4.22 (2H, d, J = 5.8Hz), 4.40-
4.61 (2H, m), 4.71 (1H, bs), 4.77 (1H, d, J = 14.6Hz),
5.82 (1H, d, J = 14.6Hz), 6.31 (1H, t, J = 5.8Hz), 6.59-
7.59 (21H, m). (9) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4, Five-
Tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (4
-tert-butoxycarbonylaminomethylphenyl) -2,4-
Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (165 mg, 0.23 mmol) in ethyl acetate
(1 ml) to a stirred solution of 4N hydrogen chloride in ethyl acetate (1 m
l) was added. After the obtained mixture was stirred at room temperature for 30 minutes, it was concentrated under reduced pressure. N- (2-fluorobenzyl) -5- (4-
(Biphenylmethyl) -1- (4-aminomethylphenyl) -2,4-
A non-crystalline solid of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (140 mg, 93%) was obtained. Elemental analysis: C ₃₈ H ₃₄ N ₄ O ₃ ClF.2H ₂ O Theoretical: C, 66.61; H, 5.59; N, 8.18. Found: C, 66.37; H, 5.66; N, 7.93. ¹ H- NMR (DMSO-d ₆ ) δ: 2.914 (2H, t, J = 7.0Hz), 3.92-3.9
9 (3H, m), 4.30 (2H, d, J = 5.4Hz), 5.04 (1H, d, J = 15.2H
z), 5.66 (1H, d, J = 15.2Hz), 6.78-7.86 (21H, m), 8.41
(3H, bs), 8.63 (1H, t, J = 6.2 Hz). Examples 2 and 3 were synthesized in the same manner as in Example 1 (7).

Example 2 N- (2-chlorobenzyl) -5- (4-biphenylmethyl) -1- (4-
(Aminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- (2-chlorobenzyl) -5- (4 -Biphenylmethyl) -1
-(4-tert-butoxycarbonylaminomethylphenyl)-
2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl)- 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.2 g, 0.33
mmol) of N, N-dimethylformamide (2 ml) was added to an ice-cooled stirred solution of o-chlorobenzylamine (51 mg, 0.36 mmo).
l), diethyl cyanophosphate (0.060 ml, 0.4 mmol) and triethylamine (0.055 ml, 0.4 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-chlorobenzyl) -5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3 , 4,5-tetrahydro-
1H-1,5-benzodiazepine-3-acetamide (150 mg, 65
%) Of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.04 (2H, d, J = 6.6 Hz),
4.07 (1H, t, J = 6.6Hz), 4.21 (2H, d, J = 5.8Hz), 4.45-
4.56 (2H, m), 4.73 (1H, bs), 4.77 (1H, d, J = 14.6Hz),
5.81 (1H, d, J = 14.6Hz), 6.41 (1H, t, J = 5Hz), 6.57 (2
H, d, J = 8.4Hz), 6.80 (1H, d, J = 8.4Hz), 7.04-7.55 (18
(2) N- (2-chlorobenzyl) -1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5- Tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride N- (2-chlorobenzyl) -5- (4-biphenylmethyl) -1- (4-t
(ert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (160 mg, 0.22 mmol) in ethyl acetate (1
4N solution of hydrogen chloride in ethyl acetate (1 ml)
Was added. After stirring the resulting mixture at room temperature for 1 hour,
It was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N- (2-chlorobenzyl) -1- (4-aminomethylphenyl)
Non-crystallinity of -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (140 mg, 97%) A solid was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.65-2.84 (2H, m), 3.71-3.80 (2H,
m), 4.11 (2H, d, J = 5.8Hz), 4.84 (1H, d, J = 15.4Hz),
5.44 (1H, d, J = 15.4Hz), 6.56-7.44 (20H, m), 7.62 (1H,
d, J = 7.8Hz), 8.14 (3H, bs), 8.47 (1H, t, J = 6.2Hz).

Example 3 N- (2-methoxybenzyl) -5- (4-biphenylmethyl) -2,4-
Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- (2-methoxybenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-biphenylmethyl)
-1- (4-tert-butoxycarbonylaminomethylphenyl)
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2.3,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.2 g, 0.33 m
mol) of N, N-dimethylformamide (2 ml) was added to an ice-cooled stirred solution of o-methoxybenzylamine (50 mg, 0.36 mmo).
l), diethyl cyanophosphate (0.060 ml, 0.4 mmol) and triethylamine (0.055 ml, 0.4 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-methoxybenzyl) -5-
(4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2.3,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (145 m
g, 61%). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9 H, s), 2.99 (2 H, d, J = 6.6 Hz),
3.86 (3H, s), 4.06 (1H, t, J = 6.6Hz), 4.21 (2H, d, J =
6.6Hz), 4.39-4.47 (2H, m), 4.71 (1H, bs), 4.74 (1H,
d, J = 15.2Hz), 5.82 (1H, d, J = 15.2Hz), 6.41 (1H, t, J
= 5Hz), 6.56 (2H, d, J = 8.4Hz), 6.77-7.40 (19H, m). (2) N- (2-methoxybenzyl) -1- (4-aminomethylphenyl) -5- ( 4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride N- (2-methoxybenzyl) -5- (4-biphenylmethyl) -1- (4
-tert-butoxycarbonylaminomethylphenyl) -2,4-
Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (145 mg, 0.21 mmol) in ethyl acetate
(1 ml) into a 4 N solution of hydrogen chloride in ethyl acetate
(1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N- (2-methoxybenzyl) -5- (4-biphenylmethyl) -1- (4-aminomethylphenyl) -2,4-dioxo-2,3,4,
An amorphous solid of 5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (130 mg, 98%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.89-2.96 (2H, m), 3.81 (3H, s),
3.96-4.06 (3H, m), 4.13-4.31 (3H, m), 5.05 (1H, d, J =
15Hz), 5.67 (1H, d, J = 15Hz), 6.77-7.68 (20H, m), 7.8
5 (1H, d, J = 8.4Hz), 8.30 (3H, bs), 8.46 (1H, t, J = 5.0
Hz).

Example 4 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (phenylcarbamoylmethyl) -2,4-dioxo-2,3,4,
5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- [2- [4- (tert-butoxycarbonylaminomethyl)
Phenylamino] phenyl] malonamic acid ethyl ester [4- (2-aminophenylamino) benzyl] carbamic acid t
Triethylamine (2.45 ml, 17.6 mmol) and ethyl malonyl chloride were added to an ice-cooled stirred solution of ert-butyl ester (5.00 g, 16.0 mmol) in tetrahydrofuran (100 ml).
(2.25 ml, 17.6 mmol) in tetrahydrofuran (5 ml) was added. After stirring the resulting mixture at 0 ° C. for 1 hour,
A solution of triethylamine (0.446 ml, 3.20 mmol) and ethylmalonyl chloride (0.410 ml, 3.20 mmol) in tetrahydrofuran (1 ml) was added. After the reaction solution was stirred at 0 ° C. for 10 minutes, it was poured into water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and N- [2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid ethyl ester (3.70 g, 98.0%) was obtained. An oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 6.8 Hz), 1.46 (9H,
s), 3.45 (2H, s), 4.17 (2H, q, J = 6.8Hz), 4.21 (2H, d,
J = 4.4Hz), 4.75 (1H, bs), 5.84 (1H, bs), 6.81 (2H, d,
J = 8.4Hz), 7.05-7.31 (5H, m), 7.77 (1H, d, J = 7.0Hz),
9,20 (1H, bs). (2) N- [2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid N- [2- (4-tert-butoxycarbonylaminomethyl) Phenylamino] phenylmalonamic acid ethyl ester (6.60
g, 15.4 mmol) of tetrahydrofuran (30 ml) and methanol (90 ml) was added to an ice-cooled stirred solution of a 1 N aqueous sodium hydroxide solution (33 ml, 33 mmol). The resulting mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 3 hours. Water was added to the reaction solution, which was washed with diisopropyl ether. Potassium hydrogen sulfate (4.49 g, 33 mmol) was added and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure to obtain an oily substance of N- [2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid (5.98 g, 97.2%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.36 (2H, s), 4.16 (2
H, d, J = 5.8Hz), 5.03 (1H, bs), 6.60 (1H, bs), 6.70 (2
H, d, J = 8.4Hz), 7.01-7.25 (5H, m), 7.78 (1H, d, J = 7.4
Hz), 9.04 (1H, bs).

(3) 1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepine of N- [2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid (5.88 g, 14.7 mmol)
4-dimethylaminopyridine (1.80 g, 14.7 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.47 g, 44.2) were added to an ice-cooled stirred solution of N, N-dimethylformamide (250 ml). mmol) was added. The resulting mixture
The mixture was stirred at 0 ° C for 15 minutes and at room temperature for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (6.
11 g, 58.2%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.54 (2H, s), 4.33 (2
H, d, J = 6.2Hz), 4.93 (1H, t, J = 6.2Hz), 6.90-7.52 (8
H, m), 8.93 (1H, bs). (4) 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine 1- (4-tert-butoxycarbonylaminomethylphenyl)-
2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (2.0 g, 5.2 mmol) in acetonitrile (100 ml)
Benzyltriethylammonium chloride (0.56 g, 2.4 mmol), powdered potassium carbonate (1.8 g, 1
3 mmol) and methyl bromoacetate (0.83 ml, 8.7 mmol) were added. After stirring the reaction mixture at 90 ° C. for 1.5 hours, the reaction solution was cooled and insolubles were filtered off. The filtrate was concentrated under reduced pressure, the residue was added to water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.4
g, 62%). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.53 (1H, d, J = 12.0H
z), 3.61 (1H, d, J = 12.0Hz), 3.78 (3H, s), 4.32 (2H,
d, J = 6.0Hz), 4.61 (1H, d, J = 17.2Hz), 4.80 (1H, d, J =
17.2Hz), 4.86 (1H, bs), 6.95 (1H, d, J = 8.2Hz), 7.11-
7.36 (7H, m).

(5) 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl)-
2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid benzyl ester 1- (4-tert-butoxycarbonylaminomethylphenyl)-
5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine (2.0 g, 4.7 mm
ol) in a stirred solution of N, N-dimethylformamide (20 ml).
% Oily sodium hydride (410 mg, 10 mmol) was added.
After stirring at room temperature for 10 minutes, benzyl bromoacetate (0.89 ml, 5.
6 mmol) was added. After stirring the obtained mixture at room temperature for 10 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-
An oil of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid benzyl ester (1.3 g, 46%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.05-3.33 (2H, m), 3.
74 (3H, s), 3.99 (1H, t, J = 7.4Hz), 4.32 (1H, d, J = 5.8H
z), 4.53 (2H, d, J = 17.6Hz), 4.84 (1H, bs), 4.88 (1H,
d, J = 17.6Hz), 5.09 (1H, d, J = 12.6Hz), 5.16 (1H, d, J
= 12.6Hz), 6.97 (1H, d, J = 8.0Hz), 7.11-7.33 (12H, m). (6) 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid 1- (4-tert-butoxycarbonylaminomethylphenyl)-
5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,4,5-
To a stirred suspension of tetrahydro-1H-1,5-benzodiazepine-3-acetic acid benzyl ester (1.3 g, 2.1 mmol) in methanol (30 ml) was added 5% palladium on carbon (0.13 g).
The obtained mixture was hydrogenated under normal temperature and normal pressure conditions for 1 hour.
The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. 1- (4-tert-
Butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (1.1 g, 98%) An oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.01-3.32 (2H, m), 3.
74 (3H, s), 3.93 (1H, t, J = 7.0Hz), 4.31 (2H, bs), 4.56
(1H, d, J = 17.2Hz), 4.88 (1H, d, J = 17.2Hz), 4.93 (1H,
bs), 6.99 (1H, d, J = 8.0Hz), 7.13-7.36 (7H, m).

(7) N- (2-fluorobenzyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-acetamide 1- (4-tert-butoxycarbonylamino Methylphenyl)-
5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (1.1 g,
2.11 mmol) of N, N-dimethylformamide (20 ml) was added to an ice-cooled stirred solution of 2-fluorobenzylamine (0.29 ml,
2.5 mmol), diethyl cyanophosphate (0.41 ml, 2.7 mmo
l), triethylamine (0.382 ml, 2.74 mmol) was added.
The resulting mixture was stirred at 0 ° C. for 1 hour and at room temperature for 12 hours.
The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-
(Fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4
A non-crystalline solid of -dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (960 mg, 73.3%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.86-3.11 (2H, m), 3.
73 (3H, s), 4.07 (1H, t, J = 7.0Hz), 4.32 (2H, d, J = 5.6H
z), 4.74 (2H, t, J = 5.2Hz), 4.72 (1H, d, J = 17.2Hz),
4.87 (1H, bs), 4.90 (1H, d, J = 17.2Hz), 6.29 (1H, bs),
6.94-7.33 (12H, m). (8) N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (carbonoxymethyl)
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (methoxycarbonylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (0.71 g, 1.15 mmol) in tetrahydrofuran (10 ml) 1N aqueous sodium hydroxide solution (2.3 ml, 2.3 mmo) was added to a stirred solution of methanol (10 ml).
l) was added. The resulting mixture was stirred at 60 C for 2 hours.
After cooling the reaction solution, water and potassium hydrogen sulfate (0.313 g, 2.3
0 mmol) was added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure
N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (carboxymethyl) -2,4-
An oil of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (0.69 g, 99.3%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.84 (1H, dd, J = 5.8,1
5.0Hz), 3.05 (1H, dd, J = 7.6,15.0Hz), 4.04 (2H, dd, J
= 5.8,7.6Hz), 4.18 (2H, bs), 4.31-4.57 (3H, m), 4.97 (1
H, d, J = 17.2Hz), 5.39 (1H, bs), 6.55 (1H, bs), 6.74-
7.42 (17H, m).

(9) N- (2-fluorobenzyl) -5- (phenylcarbamoylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5 -Tetrahydro-1H-1,5-benzodiazepine-3-acetamide N- (2-fluorobenzyl) -5- (carboxymethyl) -1- (4-t
ert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (200 mg, 0.331 mmol) N, N-dimethylformamide (2 ml) to a stirred solution of aniline (0.0603
ml, 0.662 mmol), 4-dimethylaminopyridine (4.0 mg,
0.0331 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (95.2 mg, 0.497 mmol) were added. The resulting mixture was stirred at room temperature for 24 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was solidified from diethyl ether to give N- (2-fluorobenzyl) -1
-(4-tert-butoxycarbonylaminomethylphenyl) -5
-(Phenylcarbamoylmethyl) -2,4-dioxo-2,3,4,5
A non-crystalline solid of -tetrahydro-1H-1,5-benzodiazepine-3-acetamide (168 mg, 74.7%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, bs), 2.93-3.19 (2H, m),
4.12 (1H, t, J = 7.2Hz), 4.23 (2H, d, J = 5.8Hz), 4.37 (1
H, d, J = 15.4Hz), 4.41-4.58 (2H, m), 4.75 (1H, bs),
4.85 (1H, d, J = 15.4Hz), 6.35 (1H, t, J = 6.6Hz), 6.92-
7.55 (17H, m). (10) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (phenylcarbamoylmethyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (phenyl (Carbamoylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (128 mg, 0.29 mmol) in a stirred solution of ethyl acetate (1 ml). A 4N solution of hydrogen chloride in ethyl acetate (1 ml) was added. The resulting mixture is heated at room temperature for 1 hour.
After stirring for an hour, the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (phenylcarbamoylmethyl)
Crystals of -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (110 mg, 94%) were obtained. Melting point: 212-215 ° C Elemental analysis: as C ₃₃ H ₃₁ N ₅ O ₄ ClF.2H ₂ O Theoretical: C, 60.78; H, 5.41; N, 10.74. Found: C, 60.73; H, 5.48; N, ^{. 10.79 1 H-NMR (DMSO} -d 6) δ: 2.86 (2H, d, J = 6.8Hz), 3.94 (1H,
t, J = 6.8Hz), 4.07 (2H, bs), 4.28 (2H, d, J = 5.2Hz), 4.
72 (1H, d, J = 16.2Hz), 5.07 (1H, d, J = 16.2Hz), 6.90 (1
H, d, J = 8.0Hz), 7.02-7.68 (16H, m), 8.39 (3H, bs),
8.60 (1H, t, J = 5.2Hz).

Example 5 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-benzoylaminobenzyl) -2,4-dioxo-2,3,4,
5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) 5- (4-nitrobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2 , 3,4,5-tetrahydro-1H-1,5-benzodiazepine 1- (4-tert-butoxycarbonylaminomethylphenyl)-
2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.8 g, 4.7 mmol) in acetonitrile (100 ml)
Benzyltriethylammonium chloride (0.5 g, 2.2 mmol), powdered potassium carbonate (1.6 g, 1
1.8 mmol) and 4-nitrobenzyl chloride (1.4 g, 7.9 mmo
l) was added. After stirring the reaction mixture at 90 ° C. for 2 hours, the reaction solution was cooled and insolubles were filtered off. The filtrate was concentrated under reduced pressure, the residue was added to water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-nitrobenzyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.9
g, 79%). ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.60 (2H, s), 4.30 (2
H, d, J = 6.2Hz), 4.89 (1H, bs), 4.93 (1H, d, J = 15.4H
z), 5.77 (1H, d, J = 15.4Hz), 6.82 (2H, d, J = 8.4Hz),
6.89 (2H, d, J = 8.2Hz), 7.08-7.42 (7H, m), 8.14 (2H,
(2) 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine 1- (4-tert-butoxycarbonylaminomethylphenyl)-
5- (4-Nitrobenzyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.7 g, 3.2 mmol) in methanol (50 ml) with stirring To the solution was added 5% palladium on carbon (0.2 g). The obtained mixture was hydrogenated under normal temperature and normal pressure conditions for 1 hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine (1.2 g, 79
%) Oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.50 (2H, d, J = 5.6H
z), 3.70 (2H, bs), 4.26 (2H, d, J = 5.8Hz), 4.53 (1H,
d, J = 14.6Hz), 4.83 (1H, bs), 5.75 (1H, d, J = 14.6Hz),
6.51 (2H, d, J = 8.4Hz), 6.67 (2H, d, J = 8.4Hz), 6.81
(1H, d, J = 8.0Hz), 6.94 (2H, d, J = 8.4Hz), 7.06 (1H,
t, J = 8.0Hz), 7.17-7.28 (3H, m), 7.48 (1H, d, J = 8.2H
z).

(3) 5- [4- (benzylideneamino) benzyl]
-1- (4-tert-butoxycarbonylaminomethylphenyl)
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4 To a stirred solution of -dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.1 g, 2.3 mmol) in methanol (20 ml) was added benzaldehyde (0.46
ml, 4.5 mmol) and acetic acid (0.013 ml, 0.23 mmol). The resulting mixture was stirred at room temperature for 1 hour. Diethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. Five-
[4- (benzylideneamino) benzyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,
3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.1 g,
81%) of a solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 3.57 (2H, s), 4.25 (2
H, d, J = 6.2Hz), 4.76 (1H, d, J = 15.2Hz), 4.79 (1H, b
s), 5.82 (1H, d, J = 15.2Hz), 6.77-7.92 (17H, m), 8.41
(1H, bs). (4) 5- [4- (benzylideneamino) benzyl] -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
Acetic acid methyl ester 5- [4- (benzylideneamino) benzyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.1
g, 1.8 mmol) in dimethylformamide (10 ml) was added 60% oily sodium hydride (160 mg, 4.0 mmol). After stirring at room temperature for 10 minutes, methyl bromoacetate (0.21 m
1, 2.2 mmol) was added. After stirring the obtained mixture at room temperature for 10 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate.
After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was solidified from ethyl acetate-diethyl ether-diisopropyl ether to give 5- [4- (benzylideneamino) benzyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4- Dioxo-2,3,4,5-
A non-crystalline solid of tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.57 g, 48%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s);
17 (2H, d, J = 7.2 Hz), 3.70
(3H, s), 3.96 (1H, t, J = 7.
2 Hz), 4.24 (2H, d, J = 5.8H)
z), 4.79 (1H, d, J = 14.6H)
z), 4.83 (1H, bs), 5.78 (1
H, d, J = 14.6 Hz), 6.73 (2H,
d, J = 8.4 Hz), 6.85 (1H, d,
J = 8.0 Hz), 7.07-7.91 (14H,
m), 8.40 (1H, bs).

(5) 5- (4-aminobenzyl) -1- (4-tert
-Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetic acid methyl ester 5- [4- (benzylideneamino) benzyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-
Methanol of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.46 g, 0.71 mmol)
(8 ml) was added to 1N hydrochloric acid (0.71 ml, 0.71 mmol). After stirring at room temperature for 1 hour, 1N aqueous sodium hydroxide solution (0.71 ml, 0.71 mmol) was added. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was solidified from diisopropyl ether to give 5- (4-aminobenzyl)-
1- (4-tert-butoxycarbonylaminomethylphenyl)-
A non-crystalline solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.34 g, 86%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.14 (2H, d, J = 7.0H
z), 3.64 (2H, bs), 3.69 (3H, s), 3.91 (1H, t, J = 7.0H
z), 4.26 (2H, d, J = 5.4Hz), 4.56 (1H, d, J = 14.4Hz),
4.83 (1H, bs), 5.74 (1H, d, J = 14.4Hz), 6.50 (2H, d, J
= 8.4Hz), 6.62 (1H, d, J = 8.4Hz), 6.84 (1H, d, J = 6.6H
z), 6.91 (2H, d, J = 8.4Hz), 7.06-7.31 (4H, m), 7.52 (1
(H, d, J = 8.4Hz). (6) 5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4- Triethylamine (0.049 ml, 0.35 mmol) in a stirred solution of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.15 mg, 0.27 mmol) in tetrahydrofuran (3 ml) And benzoyl chloride (0.041 ml, 0.35 mmol) were added.
After stirring the reaction mixture at room temperature for 30 minutes, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diisopropyl ether to give 5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepine-3-acetic acid methyl ester (170m
g, 96%) of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 3.15 (2H, d, J = 6.6H
z), 3.69 (3H, s), 3.95 (1H, t, J = 6.6Hz), 4.20 (2H, d,
J = 5.6Hz), 4.73 (1H, d, J = 15.0Hz), 4.93 (1H, bs), 5.
75 (1H, d, J = 15.0Hz), 6.69 (2H, d, J = 8.4Hz), 6.86 (1
H, d, J = 8.2Hz), 7.08-7.52 (12H, m), 7.89 (2H, d, J =
6.2Hz), 8.07 (1H, bs).

(7) 5- (4-benzoylaminobenzyl) -1-
(4-tert-butoxycarbonylaminomethylphenyl) -2,
4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid 5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2 , 4-dioxo-2,3,
To a stirred solution of 4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (170 mg, 0.26 mmol) in tetrahydrofuran (3 ml) and methanol (3 ml) was added a 1N aqueous sodium hydroxide solution (0.51 ml, 0.51 mmol) was added. The resulting mixture was stirred at 60 C for 2.5 hours. After cooling the reaction solution, water and potassium hydrogen sulfate (70 mg, 0.51 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure, 5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1, An amorphous solid of 5-benzodiazepine-3-acetic acid (160 mg, 96%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.10 (1H, dd, J = 7.8,1
7.4Hz), 3.28 (1H, dd, J = 7.8,17.4Hz), 3.97 (1H, t, J =
7.8Hz), 4.24 (1H, bs), 4.86 (1H, d, J = 15.4Hz), 5.02 (1
H, bs), 5.39 (1H, d, J = 15.4Hz), 6.78 (2H, d, J = 8.4H
z), 6.89 (1H, d, J = 8.2Hz), 7.03-7.54 (12H, m), 7.87 (2
(H, d, J = 6.6Hz), 8.42 (1H, bs). (8) N- (2-fluorobenzyl) -5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethyl (Phenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-
Benzodiazepine-3-acetamide 5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (16
0 mg, 0.25 mmol) of N, N-dimethylformamide (2 ml) was added to an ice-cooled stirred solution of 2-fluorobenzylamine (0.044
ml, 0.30 mmol), diethyl cyanophosphate (0.48 ml, 0.3
2 mmol) and triethylamine (0.045 ml, 0.32 mmol) were added. The resulting mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-fluorobenzyl) -5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2, An amorphous solid of 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (133 mg, 71%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 2.97 (2H, d, J = 7.0H
z), 4.04 (1H, t, J = 7.0Hz), 4.21 (2H, bs), 4.40-4.59
(2H, m), 4.68 (1H, d, J = 14.0Hz), 4.97 (1H, bs), 5.75
(1H, d, J = 14.0Hz), 6.42 (1H, bs), 6.61 (2H, d, J = 7.8
Hz), 6.82 (1H, d, J = 8,2Hz), 7.00-7.58 (16H, m), 7.87
(2H, d, J = 7.8Hz), 8.11 (1H, bs). (9) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-benzoylaminobenzyl)- 2,4-dioxo-2,
3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-benzoylaminobenzyl) -1- (4-tert-butoxycarbonylamino (Methylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (130 mg, 0.17 mmol) in a stirred solution of ethyl acetate (1 ml). A 4N solution of hydrogen chloride in ethyl acetate (1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-benzoylaminobenzyl)-
An amorphous solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (110 mg, 97%) was obtained. Elemental analysis _{C 39 H 35 N 5 O 4} ClF · H 2 O theoretically:. C, 65.96; H, 5.25; N, 9.86 Found:. C, 65.71; H, 5.36; N, 9.66 1 H- NMR (DMSO-d ₆ ) δ: 2.78-3.02 (2H, m), 3.93 (1H, t, J
= 6.8Hz), 3.99 (2H, d, J = 5.6Hz), 4.30 (2H, d, J = 5.8H
z), 4.94 (1H, d, J = 15.4Hz), 5.59 (1H, d, J = 15.4Hz),
6.78-7.80 (19H, m), 7.98 (2H, d, J = 6.2Hz), 8.37 (3H,
bs), 8.62 (1H, t, J = 5.8Hz), 10.34 (1H, bs).

Example 6 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetic acid methyl ester 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5- To a stirred solution of benzodiazepine-3-acetic acid methyl ester (0.15 mg, 0.27 mmol) in tetrahydrofuran (3 ml) was added triethylamine (0.049 ml, 0.35 mmol) and methanesulfonyl chloride (0.027 ml, 0.35 mmol). After stirring the reaction mixture at room temperature for 1 hour, dimethylaminopyridine (43 mg, 0.35 mmol), triethylamine (0.04
9 ml, 0.35 mmol) and methanesulfonyl chloride (0.027 m
1,0.35 mmol) was added. The resulting mixture is further added at room temperature
Stir for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5- Tetrahydro-1H
-1,5-benzodiazepine-3-acetic acid methyl ester (75 mg,
44%) of an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.91 (3H, s), 3.19 (2H,
d, J = 7.0Hz), 3.69 (3H, s), 3.94 (1H, t, J = 7.0Hz), 4.
22 (2H, d, J = 5.8Hz), 4.65 (1H, d, J = 14.8Hz), 5.38 (1H,
bs), 5.75 (1H, d, J = 14.8Hz), 6.57 (2H, d, J = 8.2Hz),
6.85-7.34 (9H, m), 7.52 (1H, d, J = 8.2Hz), 7.61 (1H, b
s). (2) 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1 , 5-benzodiazepine-
3-acetic acid 1- (4-tert-butoxycarbonylaminomethylphenyl)-
5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-
2N, 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (75 mg, 0.12 mmol) in 1 mL of a stirred solution of tetrahydrofuran (2 ml) and methanol (2 ml) An aqueous sodium solution (0.47 ml, 0.47 mmol) was added.
The resulting mixture was stirred at 60 C for 2 hours. After cooling the reaction solution, water and potassium hydrogen sulfate (64 mg, 0.47 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure, 1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1 , 5-benzodiazepine-3-acetic acid (63 mg, 98
%). ¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 2.77-2.89 (2H, m), 2.
94 (3H, s), 3.78 (1H, t, J = 7.0Hz), 4.10 (2H, d, J = 6.0H
z), 4.92 (1H, d, J = 15.0Hz), 5.52 (1H, d, J = 15.0Hz),
6.65-7.38 (11H, m), 7.75 (1H, d, J = 8.2Hz), 9.65 (1H,
bs), 9.74 (1H, bs).

(3) N- (2-fluorobenzyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetamide 1- (4-tert-butoxycarbonylaminomethylphenyl)-
5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (60 mg, 0.096 mmol) in N, N-dimethylformamide (2
ml) of 2-fluorobenzylamine
(0.013 ml, 0.12 mmol), diethyl cyanophosphate (0.019
ml, 0.13 mmol), triethylamine (0.017 ml, 0.13 mmo
l) was added. The resulting mixture is allowed to stand at 0 ° C for 1 hour and at room temperature for 12 hours.
Stirred for hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2 , 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (38 m
g, 54%) of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.82 (3H, s), 2.98-3.
11 (2H, m), 4.10 (1H, t, J = 6.6Hz), 4.27 (2H, bs), 4.38
-4.54 (4H, m), 5.71 (1H, bs), 5.83 (1H, d, J = 14.4Hz),
5.71 (1H, bs), 5.83 (1H, d, J = 14.4Hz), 6.3 (2H, d, J
= 7.0Hz), 6.78-7.35 (13H, m), 7.54 (2H, d, J = 7.4Hz),
7.84 (1H, bs). (4) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3, 4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetamide hydrochloride N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4 , 5-tetrahydro-1H-
1,5-benzodiazepine-3-acetamide (38 mg, 0.06 mm
ol) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate (1 ml). After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N- (2-fluorobenzyl) -1- (4
-Aminomethylphenyl) -5- (4-methanesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5
-Benzodiazepine-3-acetamide hydrochloride (30 mg, 76
%) Of an amorphous solid. ¹ H-NMR (DMSO-d ₆ ) δ: 2.85-2.9
2 (2H, m), 2.96 (3H, s), 3.92 (1H, t, J = 7.2Hz), 4.04
(2H, d, J = 7.2Hz), 4.29 (1H, d, J = 6.0Hz), 4.93 (1H,
d, J = 14.8Hz), 5.54 (1H, d, J = 14.8Hz), 6.75-7.48 (15
H, m), 7.77 (1H, d, J = 7.8Hz), 8.30 (3H, bs), 8.61 (1
(H, t, J = 6.0Hz), 9.77 (1H, bs).

Example 7 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [2- (4-biphenyl) ethyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride (1) N, O-dimethylhydroxyamine hydrochloride in N, N-dimethylformamide (140 ml) solution of N-methyl-N-methoxy-4-biphenylacetamide 4-biphenylacetic acid (4.9 g, 15.6 mmol) (6.2 g, 64 mmol), triethylamine (8.9 ml,
64 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.5 g, 70 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. Pour the reaction into water,
Extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was solidified from diisopropyl ether to give N-methyl-N-methoxy-4-
An amorphous solid of biphenylacetamide (7.6 g, 48%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.21 (3H, s), 3.65 (3H, s), 3.82 (2
H, s), 7.26-7.61 (9H, m). (2) 4-Biphenylacetaldehyde N-methyl-N-methoxy-4-biphenylacetamide (5.0
g, 20.5 mmol) in tetrahydrofuran (100 ml).
At -60 ° C, a 1M toluene solution of diisopropylaluminum hydride (25.5 ml, 25.5 mmol) was added dropwise. After stirring at that temperature for 30 minutes, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed sequentially with 1N hydrochloric acid and water, and then dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave an oil of 4-biphenylacetaldehyde (4 g, 100%). ¹ H-NMR (CDCl ₃ ) δ: 3.74 (2H, d, J = 2.2 Hz), 7.12-7.62 (9
H, m), 9.80 (1H, t, J = 2.2Hz).

(3) [4- [2- [2- (4-biphenyl) ethylamino] phenylamino] benzyl] carbamic acid tert-butyl ester [4- (2-aminophenylamino) benzyl] carbamic acid t
Acetic acid (1.8 g) was added to a methanol solution (125 ml) of ert-butyl ester (4.9 g, 15.6 mmol) and 4-biphenylacetaldehyde.
ml, 31 mmol) and sodium cyanoborohydride (1.2 g,
19.5 mmol) was added. Thereafter, the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Solidification of the residue from diisopropyl ether
[4- [2- [2- (4-biphenyl) ethylamino] phenylamino] benzyl] carbamic acid tert-butyl ester (3.2
g, 42%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.92 (2H, t, J = 7.0 Hz),
3.43 (2H, t, J = 7.0Hz), 4.17 (2H, d, J = 5.6Hz), 4.19 (1H,
s), 4.77 (1H, bs), 4.99 (1H, bs), 6.60-7.58 (17H,
m). (4) N- [2- (4-biphenyl) ethyl] -N- [2- [4- (tert-butoxycarbonylaminomethyl) phenylamino] phenyl] malonamic acid ethyl ester [3- [2- [2- (4-biphenyl) ethylamino] phenylamino] benzyl] carbamic acid tert-butyl ester (3.0
g, 6.1 mmol) in ice-cold stirred solution of tetrahydrofuran (50 ml) was added triethylamine (0.93 ml, 6.7 mmol) and ethylmalonyl chloride (0.86 ml, 6.7 mmol). After the obtained mixture was stirred at 0 ° C. for 1 hour, triethylamine (0.47 ml, 3.3 mmol) and ethylmalonyl chloride (0.43 ml, 3.3 mmol) were added. Reaction mixture at 0 ° C for 1
After stirring for 0 minutes, the mixture was poured into water and extracted with ethyl acetate.
After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and N- [2- (4-biphenyl) ethyl] -N
-[2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid ethyl ester (3.4
g, 92%). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.46 (9H,
s), 2.91-3.14 (2H, m), 3.22 (1H, d, J = 15.8Hz), 3.34
(1H, d, J = 15.8Hz), 3.66-3.80 (2H, m), 4.13 (2H, q, J
= 7.2Hz), 4.24 (2H, d, J = 5.8Hz), 4.76 (1H, bs), 6.03
(1H, bs), 6.84-7.56 (17H, m).

(5) N- [2- (4-biphenyl) ethyl] -N- [2- (4
-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid N- [2- (4-biphenyl) ethyl] -N- [2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonami A 1N aqueous sodium hydroxide solution (11 ml, 11 mmol) was added to an ice-cooled stirred solution of ethyl dodecate ester (3.3 g, 5.4 mmol) in tetrahydrofuran (10 ml) and methanol (30 ml). The resulting mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 3 hours. Water was added to the reaction solution, which was washed with diisopropyl ether. Potassium hydrogen sulfate (1.5 g, 11 mmol) was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give N- [2
An oil of-(4-biphenyl) ethyl] -N- [2- (3-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid (2.3 g, 74%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.84-3.18 (2H, m), 3.
23 (2H, d, J = 2.2Hz), 3.88-4.02 (2H, m), 4.22 (2H, d,
J = 6.2Hz), 4.82 (1H, bs), 5.48 (1H, bs), 6.88-7.58 (17
H, m). (6) 5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine N- [2- (4-biphenyl) ethyl] -N- [2- (3-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid ( 2.25 g, 3.9 mmol) N, N-dimethylformamide
(50 ml) of an ice-cooled stirred solution was added 4-dimethylaminopyridine (47 mg, 0.39 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.82 g, 4.3 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography.
[2- (4-biphenyl) ethyl] -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.0 g, 47%). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.59 (2H, s), 2.98-3.
08 (2H, m), 3.51 (2H, s), 3.85-3.99 (1H, m), 4.24 (2H,
d, J = 6.0Hz), 4.27-4.87 (2H, m), 6.89-7.55 (17H, m).

(7) 5- [2- (4-biphenyl) ethyl] -1- (4-t
ert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester 5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine (0.95 g, 1.7 m
mol) of N, N-dimethylformamide (10 ml) in a stirred solution.
0% oily sodium hydride (0.15 g, 3.7 mmol) was added. After stirring at room temperature for 10 minutes, methyl bromoacetate (0.19 ml,
2.0 mmol) was added. After stirring the obtained mixture at room temperature for 10 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 5- [2- (4-biphenyl) ethyl] -1- (4-
(tert-butoxycarbonylaminomethylphenyl) -2,4-
An oil of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.61 g, 57%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.00 (2H, t, J = 7.6Hz),
3.90-4.01 (1H, m), 3.15 (2H, d, J = 7.2Hz), 3.70 (3H,
s), 3.89 (1H, t, J = 7.2Hz), 4.24 (2H, d, J = 5.8Hz), 4.
69-4.79 (2H, m), 6.89-7.55 (17H, m). (8) 5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2, 4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid 5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo- 2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.5 g, 0.79 mmol) in tetrahydrofuran (5
1N aqueous sodium hydroxide solution (1.6 ml, 1.6 mmol) was added to a stirred solution of methanol (5 ml) and methanol (5 ml). The resulting mixture was stirred at 60 C for 2 hours. After cooling the reaction solution, water and potassium hydrogen sulfate (5.4 g, 40 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H An amorphous solid of -1,5-benzodiazepine-3-acetic acid (0.43 g, 89%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.00 (2H, t, J = 7.6Hz),
3.13-3.23 (2H, m), 3.84 (2H, m), 3.84 (1H, t, J = 6.6H
z), 3.91-4.03 (1H, m), 4.24 (2H, d, J = 5.8Hz), 4.68-4.
82 (2H, m), 6.88-7.55 (17H, m).

(9) N- (2-fluorobenzyl) -5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2, 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- [2- (4-biphenyl) ethyl] -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4- Dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.25
g, 0.40 mmol) of N, N-dimethylformamide (3 ml) was added to an ice-cooled stirred solution of 2-fluorobenzylamine (0.055 m
l, 0.48 mmol), diethyl cyanophosphate (0.078 ml, 0.52
mmol) and triethylamine (0.073 ml, 0.52 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.
N- (2-fluorobenzyl) -5- [2- (4-biphenyl) ethyl]
-1- (4-tert-butoxycarbonylaminomethylphenyl)
A non-crystalline solid of -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (200 mg, 68%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.00 (2H, d, J = 7.4H
z), 3.78-4.02 (2H, m), 4.24 (2H, d, J = 6.2Hz), 4.49 (2H
(H, t, J = 5.0Hz), 4.66-4.78 (2H, m), 6.37 (1H, bs), 5.
94 (1H, d, J = 14.8Hz), 6.84-7.54 (21H, m). (10) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [2- (4 -Biphenyl) ethyl] -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -5- [2- (4-biphenyl) ethyl]-
1- (4-tert-butoxycarbonylaminomethylphenyl)-
To a stirred solution of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (158 mg, 0.22 mmol) in ethyl acetate (1 ml) was added 4N chloride. Ethyl hydrogen acetate solution (1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [2- (4-biphenyl) ethyl] -2,4-dioxo-2,3 , 4,5-tetrahydro-1H-1,5-benzodiazepine-
Crystals of 3-acetamide hydrochloride (140 mg, 94%) were obtained. Melting point 165-167 ° C Elemental analysis value as C ₃₉ H ₃₆ N ₄ O ₃ ClF ・ H ₂ O Theoretical value: C, 68.76; H, 5.62; N, 8.22. Found value: C, 68.72; H, 5.53; N, 8.02. ¹ H-NMR (DMSO-d ₆ ) δ: 2.79-2.94 (4H, m), 3.87 (1H, t, J
= 6.8Hz), 3.96-4.12 (3H, m), 4.29 (2H, d, J = 5.4Hz), 4.
46-4.68 (1H, m), 6.88 (1H, d, J = 8.2Hz), 7.05-7.65 (19
H, m), 7.79 (1H, d, J = 8.0Hz), 8.32 (3H, bs), 8.60 (1
(H, t, J = 5.8Hz).

Example 8 N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1-
(Isoindoline-5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) 5-amino-2-tert-butoxy While heating carbonylisoindoline 4-nitroorthoxylene (25.5 g) to 120-130 ° C, bromine (18.2 ml) was slowly added dropwise. After completion of the dropwise addition, the reaction solution was cooled and diluted with ethyl acetate (200 ml).
The obtained mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was ethanol (500
ml). Potassium carbonate (70 g) and α-aminodiphenylmethane (31 g) were added thereto, and the mixture was stirred under reflux for 3 hours. After cooling the reaction solution, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), and washed sequentially with 1N aqueous sodium hydroxide solution and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was crystallized from diisopropyl ether. The crystals were collected by filtration to give 2-diphenylmethyl-5-nitroisoindoline (12.9 g). [Mp 154-155 ° C. ¹ H-NMR (CDCl ₃ )
δ: 3.91 (4H, s), 4.67 (1H, s), 7.18-7.38 (7H, m), 7.5
0-7.58 (4H, m), 7.95-8.15 (2H, m).] Then, 2-diphenylmethyl-5-nitroisoindoline
(12.8 g) was dissolved in methanol (200 ml), and 4N hydrogen chloride in ethyl acetate (20 ml) and 10% palladium on carbon were added. The resulting mixture was hydrogenated under normal temperature and normal pressure conditions. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was mixed with water and tetrahydrofuran (1/1 = v
/ v) (200 ml) and 1N aqueous sodium hydroxide solution (120 ml) was added. Di-tert dicarbonate is added to the resulting mixture.
-Butyl (9.3 g) was added and the mixture was stirred at room temperature for 2 hours. After the reaction solution was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 5-amino-2-tert-butoxycarbonylisoindoline (7.7 g)
Oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 3.65 (2H, bs), 4.50-
4.63 (4H, m), 6.52-6.64 (2H, m), 6.95-7.08 (1H, m). (2) 2-tert-butoxycarbonyl-5- (2-nitrophenylamino) isoindoline 5-amino- 2-tert-butoxycarbonylisoindoline (5.3 g, 22.6 mmol), o-fluoronitrobenzene (7.15 ml, 22.6 mmol) and potassium carbonate
(3.12 g, 22.6 mmol) in dimethylformamide (10 ml) was stirred under a nitrogen atmosphere at 145 ° C. for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-ter
An oil (4.9 g, 61%) of t-butoxycarbonyl-5- (2-nitrophenylamino) isoindoline was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 4.67 (2H, s), 4.70 (2
H, s), 6.76 (1H, t, J = 6.8Hz), 7.15-7.41 (5H, m), 8.2
0 (1H, d, J = 8.8Hz), 9.47 (1H, bs).

(3) 5- (2-aminophenylamino) -2-tert-
Butoxycarbonylisoindoline 2-tert-butoxycarbonyl-5- (2-nitrophenylamino) isoindoline (4.8 g, 13.5 mmol) in methanol (200
ml) solution was added 5% palladium on carbon (0.5 g).
The resulting mixture was hydrogenated under normal temperature and normal pressure conditions for 2 hours.
The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. An oil of 5- (2-aminophenylamino) -2-tert-butoxycarbonylisoindoline (4.2 g, 95%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 3.48 (2H, bs), 4.55 (2
H, s), 4.58 (2H, s), 5.22 (1H, bs), 6.56-7.11 (7H,
m). (4) 5- [2- (4-biphenylmethylamino) phenylamino]
-2-tert-butoxycarbonylisoindoline 5- (2-aminophenylamino) -2-tert-butoxycarbonylisoindoline (4.1 g, 12.5 mmol), methanol solution of 4-phenylbenzaldehyde (3.0 g, 16.4 mmol) ( 125 m
Acetic acid (1.4 ml, 25 mmol) and sodium cyanoborohydride (1 g, 16.4 mmol) were added to l). Thereafter, the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was poured into water, and the precipitated solid was collected by filtration. 5- [2- (4-biphenylmethylamino) phenylamino]
-2-tert-butoxycarbonylisoindoline (6 g, 98
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 4.39 (2H, s), 4.56 (2
H, s), 4.60 (2H, s), 4.75 (1H, bs), 6.57-7.59 (16H,
m).

(5) N- (4-biphenylmethyl) -N- [2- (2-ter
t-butoxycarbonylisoindoline-5-ylamino) phenyl] malonamic acid ethyl ester 5- [2- (4-biphenylmethylamino) phenylamino] -2-t
ert-butoxycarbonylisoindoline (4.6 g, 9.3 mm
ol) in ethyl acetate (500 ml) was added triethylamine (1.4 ml, 10.2 mmol) and ethylmalonyl chloride (1.3 ml, 10.2 mmol). After the obtained mixture was stirred at 0 ° C. for 1 hour, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and ethyl N- (4-biphenylmethyl) -N- [2- (2-tert-butoxycarbonylisoindoline-5-ylamino) phenyl] malonamidate was used. An oil of the ester (3.8 g, 71%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 6.8 Hz), 1.52 (9H,
s), 3.25 (1H, d, J = 15.8Hz), 3.34 (1H, d, J = 15.8Hz),
4.09 (2H, q, J = 6.8Hz), 4.43-4.77 (5H, m), 5.08-5.27
(1H, m), 5.60 (0.5H, s), 5.70 (0.5H, s), 6.52-7.51 (1
6H, m). (6) N- (4-biphenylmethyl) -N- [2- (2-tert-butoxycarbonylisoindoline-5-ylamino) phenyl] malonamic acid N- (4-biphenylmethyl) -N -[2- (2-tert-butoxycarbonylisoindolin-5-ylamino) phenyl] malonamic acid ethyl ester (3.7 g, 6.1 mmol) in tetrahydrofuran (10 ml) and methanol (30 ml) in an ice-cooled stirred solution
A 1N aqueous sodium hydroxide solution (12 ml, 12 mmol) was added. The resulting mixture was stirred at 0 ° C. for 20 minutes and at room temperature for 2 hours. Water was added to the reaction solution, which was washed with diisopropyl ether. Potassium hydrogen sulfate (1.6 g, 12 mmol) was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give N- (4
-Biphenylmethyl) -N- [2- (2-tert-butoxycarbonylisoindoline-5-ylamino) phenyl] malonamic acid
(2.5 g, 70%) of an oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 3.26 (2H, s), 4.27-4.
54 (5H, m), 5.54 (0.5H, d, J = 13.6Hz), 5.65 (0.5H, d, J
= 13.2Hz), 6.31 (0.5H, bs), 6.51 (0.5H, bs), 6.91-7.5
9 (16H, m).

(7) 5- (4-biphenylmethyl) -1- (2-tert-
(Butoxycarbonylisoindoline-5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine N- (4-biphenylmethyl) -N- [2- (2- tert-Butoxycarbonylisoindoline-5-ylamino) phenyl] malonamic acid (2.4 g, 4.12 mmol) in N, N-dimethylformamide (5
(0 ml) in an ice-cooled stirred solution.
(50 mg, 0.41 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.87 g, 4.5 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. Extract to water,
After washing with saturated aqueous sodium bicarbonate solution and water,
It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography,
5- (4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline-5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine ( 1.2 g, 51%) of an amorphous solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (4.5 H, s), 1.49 (4.5 H, s), 3.5
8 (2H, s), 4.47-4.59 (4H, m), 4.74 (0.5H, d, J = 14.6H
z), 4.80 (0.5H, d, J = 12.4Hz), 5.80 (0.5H, d, J = 12.4H
z), 5.88 (0.5H, d, J = 14.6Hz), 6.32 (0.5H, d, J = 7.8H
z), 6.45 (0.5H, d, J = 9.2Hz), 6.79-7.55 (15H, m). (8) 5- (4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline-5 -Il) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester 5- (4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline-5-yl) -2,4-dioxo-2,3 Of 4,4,5-tetrahydro-1H-1,5-benzodiazepine (1.1 g, 1.9 mmol)
To a stirred solution of N, N-dimethylformamide (10 ml) was added 60% oily sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 15 minutes, methyl bromoacetate (0.22 ml, 2.3 mmo
l) was added. After stirring the resulting mixture at room temperature for 15 minutes,
The reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were recrystallized from ethyl acetate to give 5-
(4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline-5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3- Acetic acid methyl ester (0.56 g, 46%) was obtained as an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (4.5 H, s), 1.50 (4.5 H, s), 3.1
9 (2H, d, J = 7.0Hz), 3.71 (3H, s), 3.97 (1H, t, J = 7.0H
z), 4.46 (1H, bs), 4.56 (1H, bs), 4.58 (2H, bs), 4.77
(0.5H, d, J = 14.8Hz), 4.84 (0.5H, d, J = 13.4Hz), 5.78
(0.5H, d, J = 13.4Hz), 5.84 (0.5H, d, J = 14.8Hz), 6.24
(0.5H, d, J = 10Hz), 6.39 (0.5H, d, J = 8.2Hz), 6.84-7.
59 (15H, m).

(9) 5- (4-biphenylmethyl) -1- (2-tert-
(Butoxycarbonylisoindoline-5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetic acid 5- (4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline-5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5 -Benzodiazepine-3-acetic acid methyl ester (0.5 g, 0.8 mmol) in tetrahydrofuran (15 ml)
To a stirred solution of methanol and methanol (15 ml) was added a 1 N aqueous solution of sodium hydroxide (1.6 ml, 1.6 mmol). The resulting mixture was stirred at 60 C for 2 hours. After cooling the reaction solution, water and potassium hydrogen sulfate (0.32 g, 2.4 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 5- (4-biphenylmethyl) -1-
(2-tert-butoxycarbonylisoindoline-5-yl)-
An oil of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.46 g, 94%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (4.5 H, s), 1.49 (4.5 H, s), 3.2
2 (2H, d, J = 7.0Hz), 3.93 (2H, t, J = 7.0Hz), 4.46 (1H,
bs), 4.55 (1H, bs), 4.58 (2H, bs), 4.79 (0.5H, d, J = 1
4.2Hz), 4.85 (0.5H, d, J = 13Hz), 5.76 (0.5H, d, J = 13H
z), 5.83 (0.5H, d, J = 14.2Hz), 6.24 (0.5H, d, J = 9.6H
z), 6.40 (0.5H, d, J = 9.2Hz), 6.69-7.61 (15H, m). (10) N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (2 -tert-butoxycarbonylisoindoline-5-
Yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline -5-yl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.25 g, 0.
4 mmol) of N, N-dimethylformamide (3 ml) was added to an ice-cooled stirred solution of 2-fluorobenzylamine (0.055 ml, 0.4 ml).
8 mmol), diethyl cyanophosphate (0.078 ml, 0.52 mmo
l), triethylamine (0.073 ml, 0.52 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (2-tert-butoxycarbonylisoindoline-5-yl) -2,4-dioxo -
An amorphous solid of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (180 mg, 62%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (4.5 H, s), 1.49 (4.5 H, s), 3.0
4 (2H, d, J = 7.0Hz), 4.08 (2H, d, J = 7.0Hz), 4.41-4.58
(6H, m), 4.77 (0.5H, d, J = 15Hz), 4.82 (0.5H, d, J = 1
4.4Hz), 5.76 (0.5H, d, J = 14.4Hz), 5.83 (0.5H, d, J = 1
5.0Hz), 6.21 (0.5H, d, J = 8.2Hz), 6.35-6.41 (1.5H,
m), 6.69-7.73 (19H, m). (11) N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (isoindoline-5-yl) -2,4-dioxo- 2,3,4,5
-Tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (2
-tert-butoxycarbonylisoindoline-5-yl) -2,4
-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (140 mg, 0.19 mmol) in ethyl acetate
(1 ml) into a 4 N solution of hydrogen chloride in ethyl acetate
(1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (isoindoline-5-yl) -2,4-dioxo-2,3,4, Five
Crystals of -tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (140 mg, 86%) were obtained. Melting point: 190-192 ° C Elemental analysis: C ₃₉ H ₃₄ N ₄ O ₃ ClF ・ 2H ₂ O Theoretical: C, 67.19; H, 5.49; N, 8.04. Found: C, 67.35; H, 5.20; N, ^{. 7.87 1 H-NMR (DMSO} -d 6) δ: 2.68-3.03 (2H, m), 3.95 (1H, t, J
= 7.2Hz), 4.30 (2H, d, J = 5.8Hz), 4.35 (2H, s), 4.45 (2
H, s), 5.02 (1H, d, J = 15Hz), 5.64 (1H, d, J = 15Hz),
6.60 (1H, d, J = 8.0Hz), 6.80-7.67 (18H, m), 7.83 (1H,
d, J = 8.4Hz), 8.61 (1H, t, J = 5.8Hz), 9.68 (2H, bs).

Example 9 N- (2-fluorobenzyl) -1- (3-aminomethylphenyl)-
5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) (3-aminobenzyl) carbamic acid tert -Butyl ester A solution of 3-aminobenzylamine (30 g, 246 mmol) in tetrahydrofuran (500 ml) was added to an ice-cooled stirred solution.
t-Butyl (56.5 ml, 246 mmol) was added dropwise. The resulting reaction mixture was stirred at 0 C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
-Aminobenzyl) carbamic acid tert-butyl ester (5
4 g, 99%) of an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 3.67 (2H, bs), 4.21 (2
(H, d, J = 6Hz), 4.83 (1H, bs), 6.56-6.67 (3H, m), 7.10
(1H, t, J = 7.4Hz). (2) [3- (2-Nitrophenylamino) benzyl] carbamic acid tert-butyl ester (3-aminobenzyl) carbamic acid tert-butyl ester
(54 g, 243 mmol), o-fluoronitrobenzene (51.3 g,
243 mmol) and potassium carbonate (38.6 g, 243 mmol) were stirred at 140 ° C. for 2 hours under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give an oil of [3- (2-nitrophenylamino) benzyl] carbamic acid tert-butyl ester (34.3 g, 41%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.25-4.34 (2H, m), 4.
93 (1H, bs), 6.78 (1H, t, J = 8.4Hz), 7.11-7.41 (5H, m),
8.19 (1H, d, J = 8.4Hz), 9.47 (1H, bs).

(3) [3- (2-aminophenylamino) benzyl] carbamic acid tert-butyl ester [3- (2-nitrophenylamino) benzyl] carbamic acid t
To a solution of ert-butyl ester (34.3 g, 99.8 mmol) in ethanol (500 ml) was added 5% palladium on carbon (3.5 g). The resulting mixture was hydrogenated under normal temperature and normal pressure conditions for 2 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give [3- (2
-Aminophenylamino) benzyl] carbamic acid tert-
An oil of butyl ester (27 g, 86%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.74 (2H, bs), 4.24 (2
H, dd, J = 6.2Hz, 9.2Hz), 4.83 (1H, bs), 5.21 (1H, bs),
6.51-7.33 (8H, m). (4) [3- [2- (4-biphenylmethylamino) phenylamino] benzyl] carbamic acid tert-butyl ester [3- (2-aminophenylamino) benzyl] carbamic acid t
ert-butyl ester (26.3 g, 83.9 mmol), methanol solution of 4-phenylbenzaldehyde (15.3 g, 83.9 mmol)
Acetic acid (4.8 ml, 83.9 mmol) was added to (500 ml). After the resulting mixture was stirred at 0 ° C. for 30 minutes, sodium cyanoborohydride (6.4 g, 105 mmol) was added. Then 0
The mixture was stirred at C for 1 hour and at room temperature for 30 minutes. Pour the reaction into water,
Extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [3- [2- (4-biphenylmethylamino) phenylamino] benzyl] carbamic acid tert-butyl ester (22.7 g, 57%) as an amorphous solid. . Elemental analysis: C ₃₁ H ₃₃ N ₃ O ₂ .0.5H ₂ O Theoretical: C, 76.20; H, 7.01; N, 8.60. Found: C, 76.01; H, 7.15; N, 8.72. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.22-4.40 (4H, m), 4.
63 (1H, bs), 4.80 (1H, bs), 5.16 (1H, bs), 6.49-7.60 (1
7H, m).

(5) 5- (4-biphenylmethyl) -1- (3-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine [3- [2- (4-biphenylmethylamino) phenylamino] benzyl] carbamic acid tert-butyl ester (10 g, 20.8
potassium carbonate (3.45 g, 25 mmol) was added to an ice-cooled stirred solution of tetrahydrofuran (500 ml). Then, a tetrahydrofuran solution (10 ml) of malonyl dichloride (2.43 ml, 25 mmol) was added dropwise. The resulting mixture is
After stirring at 30 ° C for 30 minutes, potassium carbonate (3.45 g, 25 mmol)
Was further added. Then malonyl dichloride (2.43 ml,
25 mmol) in tetrahydrofuran solution (10 ml) was added dropwise.
Stir for 1 hour. Thereafter, the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and 5- (4-biphenylmethyl) -1- (3-tert-
-Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
(1.1 g, 10%) of an amorphous solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 3.58 (2H, s), 4.12 (2
H, d, J = 7.4Hz), 4.73 (1H, bs), 4.77 (1H, d, J = 14.8H
z), 5.84 (1H, d, J = 14.8Hz), 6.38 (1H, bs), 6.80-7.57
(16H, m). (6) 5- (4-biphenylmethyl) -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester 5- (4-biphenylmethyl) -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4, 5-tetrahydro-1H-1,5-benzodiazepine (1 g, 1.83 mmol)
To a stirred solution of N, N-dimethylformamide (20 ml) was added 60% oily sodium hydride (0.22 g, 5.5 mmol).
After stirring at room temperature for 10 minutes, methyl bromoacetate (0.35 ml, 3.66 mm
ol) and stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 5- (4
-Biphenylmethyl) -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid ethyl ester (0.7 g, 62%) of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s);
15-3.20 (2H, m), 3.71 (3H,
3.s), 3.97 (1H, t, J = 7 Hz),
12 (2H, d, J = 7 Hz), 4.74 (1
H, bs), 4.81 (1H, d, J = 14.
8 Hz), 5.84 (1H, d, J = 14.8H)
z), 6.32 (1H, d, J = 6.8 Hz),
6.84-7.58 (16H, m).

(7) 5- (4-biphenylmethyl) -1- (3-te
(rt-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid 5- (4-biphenylmethyl) -1- (3- (tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.65 g, 1 mmol) in tetrahydrofuran (6 ml ) And methanol (18 ml) were added with 1N aqueous sodium hydroxide solution (4.5 ml, 4.5 mmol). The resulting mixture was stirred at 40 C for 1 hour. After cooling the reaction solution, water and potassium hydrogen sulfate (0.61 g, 4.5 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 5- (4-biphenylmethyl) -1- (3-
(tert-butoxycarbonylaminomethylphenyl) -2,4-
An amorphous solid of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.63 g, 99%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.20 (2H, d, J = 7.4H
z), 3.93 (1H, t, J = 7.4Hz), 4.12 (2H, d, J = 7Hz), 4.78
(1H, bs), 4.81 (1H, d, J = 15Hz), 5.81 (1H, d, J = 15H
z), 6.29 (1H, d, J = 6.8Hz), 6.83-7.58 (16H, m). (8) N- (2-fluorobenzyl) -5- (4-biphenylmethyl)
-1- (3-tert-butoxycarbonylaminomethylphenyl)
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.1 g, 0.17
mmol) of N, N-dimethylformamide (1 ml) was added to an ice-cooled stirred solution of o-fluorobenzylamine (0.021 ml, 0.18
mmol), diethyl cyanophosphate (0.06 ml, 0.2 mmol) and triethylamine (0.028 ml, 0.2 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-fluorobenzyl)-
5- (4-biphenylmethyl) -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (68
mg, 58%) of an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 3.02 (2H, d, J = 7 Hz),
4.08 (1H, t, J = 7Hz), 4.09-4.18 (2H, m), 4.50 (2H, dd,
J = 3.2Hz, 5.8Hz), 4.72 (1H, bs), 4.80 (1H, d, J = 15H
z), 5.79 (1H, d, J = 15Hz), 6.28-6.39 (2H, m), 6.79-7.
56 (20H, m). (9) N- (2-Fluorobenzyl) -1- (3-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4, Five-
Tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- (3
-tert-butoxycarbonylaminomethylphenyl) -2,4-
Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (68 mg, 0.095 mmol) in ethyl acetate
(1 ml) was added to a stirred solution of 4N hydrogen chloride in ethyl acetate (1 ml). After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N- (2-fluorobenzyl) -1- (3-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,
An amorphous solid of 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (50 mg, 81%) was obtained. ^{1 H-NMR (DMSO-d} 6) δ: 2.66-2.73 (2H, m), 3.73-3.79 (3H,
m), 4.07-4.12 (2H, m), 4.86 (1H, d, J = 15.8Hz), 5.38
(1H, d, J = 15.8Hz), 6.16 (1H, d, J = 8Hz), 6.66 (1H, d,
J = 6.6Hz), 6.89-7.44 (18H, m), 7.58 (1H, d, J = 7.8H
z), 8.02 (3H, bs), 8.40 (1H, t, J = 5.4Hz).

Example 10 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-methoxybenzoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-amino Benzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 4-methoxy From benzoyl chloride, Example 6 (6),
(7), (8), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-methoxybenzoylamino) benzyl]-by the same method as in (9). An amorphous solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis: C ₄₀ H ₃₇ N ₅ O ₅ ClF.H ₂ O Theoretical: C, 64.90; H, 5.31; N, 9.46. Found: C, 65.07; H, 5.44; N, 9.27. ¹ H- NMR (DMSO-d ₆ ) δ: 2.38-2.52 (2H, m), 3.84 (3H, s),
3.93-4.01 (2H, m), 4.30 (2H, d, J = 5.6Hz), 4.93 (1H,
d, J = 15.2Hz), 5.56 (1H, d, J = 15.2Hz), 6.77-7.47 (15
H, m), 7.66 (2H, d, J = 8.6Hz), 7.79 (1H, d, J = 8.4Hz),
7.98 (2H, d, J = 8.8Hz), 8.31 (3H, bs), 8.62 (1H, t, J
= 5.8Hz), 10.15 (1H, bs) .Example 11 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-chlorobenzoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5- Benzodiazepine-3-acetic acid methyl ester and 4-chlorobenzoyl chloride from Example 5 (6),
(7), (8), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-chlorobenzoylamino) benzyl]-by a method similar to (9). An amorphous solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis: C ₃₉ H ₃₄ N ₅ O ₄ Cl ₂ F.H ₂ O Theoretical: C, 62.91; H, 4.87; N, 9.41. Found: C, 62.81; H, 4.87; N, 9.14. ¹ H-NMR (DMSO-d ₆ ) δ: 2.76-3.03 (2H, m), 3.88-4.00 (3H,
m), 4.30 (2H, d, J = 5.6Hz), 4.96 (1H, d, J = 15.7Hz),
5.58 (1H, d, J = 15.7Hz), 6.78-7.81 (18H, m), 8.02 (2H,
d, J = 8.6Hz), 8.37 (3H, bs), 8.62 (1H, t, J = 5.6Hz),
10.42 (1H, bs).

Example 12 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-trifluoromethylbenzoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4 -Aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 4 -N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-from trifluoromethylbenzoyl chloride in the same manner as in (6), (7), (8), (9) of Example 5 5- [4- (4-
Trifluoromethylbenzoylamino) benzyl] -2,4-
An amorphous solid of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis: C ₄₀ H ₃₄ N ₅ O ₄ ClF ₄ .H ₂ O Theoretical: C, 61.88; H, 4.65; N, 9.02. Found: C, 62.10; H, 4.95; N, 8.82. ¹ H -NMR (DMSO-d ₆ ) δ: 2.78-3.03 (2H, m), 3.90-4.01 (3H,
m), 4.30 (2H, d, J = 5.8Hz), 4.98 (1H, d, J = 15.2Hz),
5.58 (1H, d, J = 15.2Hz), 6.77-7.47 (13H, m), 7.68 (2H,
d, J = 8.6Hz), 7.78 (1H, d, J = 8.4Hz), 7.91 (2H, d, J =
8.4Hz), 8.18 (2H, d, J = 8.0Hz), 8.32 (3H, bs), 8.61 (1
(H, t, J = 5.8Hz), 10.55 (1H, bs) .Example 13 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (2-furoylamino) benzyl] -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2, 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 2-furoyl chloride from Example 5 (6), (7), (8),
N- (2-fluorobenzyl) -1- (4-
Amorphous aminomethylphenyl) -5- [4- (2-furoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride A crystalline solid was obtained. Elemental analysis: C ₃₇ H ₃₃ N ₅ O ₅ ClF · 1.5H ₂ O Theoretical: C, 62.66; H, 5.12; N, 9.88. Found: C, 62.75; H, 4.97; N, 9.58. ¹ H -NMR (DMSO-d ₆ ) δ: 2.71-3.03 (2H, m), 3.89-4.02 (3H,
m), 4.30 (2H, d, J = 5.6Hz), 4.94 (1H, d, J = 15.8Hz),
5.58 (1H, d, J = 15.8Hz), 6.68-7.47 (15H, m), 7.66 (2H,
d, J = 8.6Hz), 7.79 (1H, d, J = 7.4Hz), 7.93 (1H, s),
8.32 (3H, bs), 8.62 (1H, t, J = 5.6Hz), 10.25 (1H, bs).

Example 14 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (2-thenoylamino) benzyl] -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2, 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 2-thenoyl chloride from Example 5 (6), (7), (8),
N- (2-fluorobenzyl) -1- (4-
Aminomethylphenyl) -5- [4- (2-thenoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride A crystalline solid was obtained. Elemental analysis: C ₃₇ H ₃₃ N ₅ O ₄ ClFS · 2H ₂ O Theoretical: C, 60.52; H, 5.08; N, 9.54. Found: C, 60.81; H, 4.92; N, 9.42. ¹ H- _{NMR (DMSO-d 6) δ} : 2.76-3.03 (2H, m), 3.89-4.00 (3H,
m), 4.30 (2H, d, J = 5.2Hz), 4.94 (1H, d, J = 15.0Hz),
5.59 (1H, d, J = 15.0Hz), 6.78-7.87 (18H, m), 8.16 (2H,
d, J = 2.8Hz), 8.38 (3H, bs), 8.62 (1H, t, J = 5.2Hz),
10.39 (1H, bs) .Example 15 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (cyclohexylcarbonylamino) benzyl] -2,4
-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2 Of Example 5 from 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and cyclohexanecarbonyl chloride
(6), (7), (8), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (cyclohexylcarbonylamino) benzyl by the same method as in (9) ] -2,4-dioxo-2,
An amorphous solid of 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis: C ₃₉ H ₄₁ N ₅ O ₄ ClF.H ₂ O Theoretical: C, 65.40; H, 6.05; N, 9.78. Found: C, 65.32; H, 5.78; N, 9.50. ¹ H- NMR (DMSO-d ₆ ) δ: 1.18-2.43 (11H, m), 2.76-3.01 (2
H, m), 3.90 (1H, t, J = 7.0Hz), 4.01 (2H, bs), 4.29 (2
H, d, J = 5.4Hz), 4.90 (1H, d, J = 15.0Hz), 5.54 (1H, d,
J = 15.0Hz), 6.71-7.51 (15H, m), 7.76 (1H, d, J = 8.0H
z), 8.35 (3H, bs), 8.61 (1H, t, J = 5.4Hz), 9.91 (1H, b
s).

Example 16 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (pivaloylamino) benzyl] -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2, 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and pivaloyl chloride from Example 5 (6), (7), (8),
N- (2-fluorobenzyl) -1- (4-
Aminomethylphenyl) -5- [4- (pivaloylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride non-crystalline solid I got Elemental analysis: C ₃₇ H ₃₉ N ₅ O ₄ ClF · 1.5H ₂ O Theoretical: C, 63.56; H, 6.05; N, 10.02. Found: C, 63.58; H, 6.05; N, 9.79. ¹ H -NMR (DMSO-d ₆ ) δ: 1.28 (9H, s), 2.73-3.01 (2H, m),
3.91 (1H, t, J = 7.0Hz), 3.98 (2H, bs), 4.29 (2H, d, J =
5.8Hz), 4.90 (1H, d, J = 15.0Hz), 5.55 (1H, d, J = 15.0H
z), 6.73-7.43 (13H, m), 7.53 (2H, d, J = 8.4Hz), 7.76
(1H, d, J = 8.4Hz), 8.36 (3H, bs), 8.60 (1H, t, J = 5.8H
z), 9.27 (1H, bs) .Example 17 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (benzyloxycarbonylamino) benzyl] -2,4
-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2 , 4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and benzyl chloroformate from Example 5 (6), (7), (8),
N- (2-fluorobenzyl) -1- (4-
Aminomethylphenyl) -5- [4- (benzyloxycarbonylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride A crystalline solid was obtained. Elemental analysis: C ₄₀ H ₃₇ N ₅ O ₅ ClF · 1.5H ₂ O Theoretical: C, 64.12; H, 5.38; N, 9.35. Found: C, 63.96; H, 5.39; N, 9.49. ¹ H -NMR (DMSO-d ₆ ) δ: 2.75-3.02 (2H, m), 3.91 (1H, t, J
= 7.2Hz), 3.98-4.15 (2H, m), 4.29 (2H, d, J = 5.6Hz), 4.
91 (1H, d, J = 14.6Hz), 5.15 (2H, s), 5.52 (1H, d, J = 14.
6Hz), 6.75-7.78 (21H, m), 8.38 (3H, bs), 8.62 (1H, t,
J = 5.6Hz), 9.80 (1H, bs).

Example 18 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-fluorobenzoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-amino Benzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 4-fluoro From benzoyl chloride, Example 6 (6),
(7), (8), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-fluorobenzoylamino) benzyl]-by the same method as in (9). An amorphous solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis _{C 39 H 34 N 5 O 4} ClF 2 · 2H 2 O theoretically:. C, 62.77; H, 5.13; N, 9.39 Found:. C, 62.94; H, 5.04; N, 9.20 1 H -NMR (DMSO-d ₆ ) δ: 2.78-3.03 (2H,
m), 3.93 (1H, t, J = 7.8 Hz),
4.02 (2H, bs), 4.29 (2H, d,
J = 5.2 Hz), 4.96 (1H, d, J =
15.8 Hz), 5.58 (1H, d, J = 1)
5.8Hz), 6.77-8.10 (20H,
m), 8.32 (3H, bs), 8.61 (1
H, t, J = 5.2 Hz), 10.33 (1H,
bs). Example 19 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (3-chlorobenzoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5- Benzodiazepine-3-acetic acid methyl ester and 3-chlorobenzoyl chloride from Example 5 (6),
(7), (8), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (3-chlorobenzoylamino) benzyl]-by a method similar to (9). An amorphous solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis: C ₃₉ H ₃₄ N ₅ O ₄ Cl ₂ F1.5 H ₂ O Theoretical: C, 62.15; H, 4.95; N, 9.29. Found: C, 62.23; H, 4.75; N, 9.06. ¹ H-NMR (DMSO-d ₆ ) δ: 2.78-3.03 (2H, m), 3.90-4.01 (3H,
m), 4.29 (2H, d, J = 5.4Hz), 4.97 (1H, d, J = 14.6Hz),
5.58 (1H, d, J = 14.6Hz), 6.77-7.81 (18H, m), 7.94 (1H,
d, J = 7.4Hz), 8.03 (1H, s), 8.33 (3H, bs), 8.62 (1H,
t, J = 5.4Hz), 10.43 (1H, bs).

Example 20 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (2-chlorobenzoylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5- Benzodiazepine-3-acetic acid methyl ester and 2-chlorobenzoyl chloride from Example 5 (6),
(7), (8), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (2-chlorobenzoylamino) benzyl]-by a method similar to (9). An amorphous solid of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis: C ₃₉ H ₃₄ N ₅ O ₄ Cl ₂ F.H ₂ O Theoretical: C, 62.91; H, 4.87; N, 9.41. Found: C, 63.18; H, 4.90; N, 9.23. ¹ H-NMR (DMSO-d ₆ ) δ: 2.74-3.03 (2H, m), 3.89-4.02 (3H,
m), 4.29 (2H, d, J = 6.2Hz), 4.95 (1H, d, J = 15.2Hz),
5.56 (1H, d, J = 15.2Hz), 6.76-7.80 (20H, m), 8.37 (3H,
bs), 8.62 (1H, t, J = 6.2Hz), 10.56 (1H, bs) .Example 21 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (benzenesulfonylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5- Example 6 (1) from benzodiazepine-3-acetic acid methyl ester and benzenesulfonyl chloride,
(2), (3), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (benzenesulfonylamino) benzyl] -2, An amorphous solid of 4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis _{C 38 H 35 N 5 O 5} ClFS · 1.5H 2 O theoretically:. C, 60.43; H, 5.07; N, 9.27 Found:. C, 60.45; H, 5.09; N, 8.98 1 H -NMR (DMSO-d ₆ ) δ: 2.76-2.99 (2H, m), 3.97 (1H, t, J
= 7.7Hz), 4.07 (2H, bs), 4.28 (2H, d, J = 5.6Hz), 4.90 (1
H, d, J = 15.8Hz), 5.43 (1H, d, J = 15.8Hz), 6.74-7.72
(21H, m), 8.32 (3H, bs), 8.60 (1H, t, J = 5.6Hz), 10.3
2 (1H, bs).

Example 22 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-fluorobenzenesulfonylamino) benzyl]
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethyl Example from phenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 4-fluorobenzenesulfonyl chloride
6- (1), (2), (3), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-fluoro Benzenesulfonylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
A non-crystalline solid of 3-acetamide hydrochloride was obtained. Elemental analysis: C ₃₈ H ₃₄ N ₅ O ₅ ClF ₂ S.2H ₂ O Theoretical: C, 58.35; H, 4,90; N, 8.95. Found: C, 58.57; H, 4,57; N ^{, 8.83 1 H-NMR (DMSO} -d 6) δ:. 2.78-2.94 (2H, m), 3.89 (1H, t, J
= 6.8Hz), 4.03 (2H, d, J = 7.4Hz), 4.28 (2H, d, J = 5.0H
z), 4.90 (1H, d, J = 15.4Hz), 5.44 (1H, d, J = 15.4Hz),
6.77-7.79 (20H, m), 8.36 (3H, bs), 8.59 (1H, t, J = 5.0
Hz), 10.35 (1H, bs) .Example 23 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-methylbenzenesulfonylamino) benzyl]-
2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl Example 6 from methyl 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid and 4-methylbenzenesulfonyl chloride.
(1), (2), (3), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-methylbenzene Sulfonylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
An amorphous solid of acetamide hydrochloride was obtained. Elemental analysis: C ₃₉ H ₃₇ N ₅ O ₅ ClFS ・ 2H ₂ O Theoretical: C, 60.19; H, 5.31; N, 9.00. Found: C, 60.38; H, 5.01; N, 8.93. ¹ H- _{NMR (DMSO-d 6) δ} : 2.83-2.89 (2H,
m), 3.89 (1H, t, J = 7.4 Hz),
4.08-4.15 (2H, m), 4.28 (2
H, d, J = 6.0 Hz), 4.89 (1H,
d, J = 15.0 Hz), 5.42 (1H, d,
J = 15.0 Hz), 6.75-7.67 (20H,
m), 8.36 (3H, bs), 8.60 (1
H, t, J = 6.0 Hz), 10.24 (1H,
bs).

Example 24 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-trifluoromethyloxybenzenesulfonylamino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro
-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5 -Tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 4-trifluoromethyloxybenzenesulfonyl chloride from Example 6 in the same manner as (1), (2), (3), (4) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-trifluoromethyloxybenzenesulfonylamino) benzyl] -2,4-dioxo-2,3,4 A non-crystalline solid of 1,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was obtained. Elemental analysis _{C 39 H 34 N 5 O 5} ClF 4 S · 2H 2 O theoretically:. C, 56.28; H, 4.60; N, 8.41 Found:. C, 56.21; H, 4.37; N, 8.17 1 H-NMR (DMSO-d ₆ ) δ: 2.83-2.89 (2H, m), 3.89 (1H, t, J
= 6.6Hz), 4.03 (2H, d, J = 5.2Hz), 4.28 (2H, d, J = 4.4H
z), 4.92 (1H, d, J = 15.0Hz), 5.43 (1H, d, J = 15.0Hz),
6.75-7.53 (17H, m), 7.65 (1H, d, J = 8.4Hz), 7.83 (2H,
d, J = 8.8Hz), 8.34 (3H, bs), 8.60 (1H, t, J = 4.4Hz), 1
0.48 (1H, bs) .Example 25 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (4-nitrobenzenesulfonylamino) benzyl]-
2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride 5- (4-aminobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl ) -2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester and 4-nitrobenzenesulfonyl chloride Example 6
(1), (2), (3), N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (4-nitrobenzenesulfonyl) in the same manner as in (4). Amino) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
An amorphous solid of acetamide hydrochloride was obtained. Elemental analysis _{C 38 H 34 N 6 O 7} ClFS · 1.5H 2 O theoretically:. C, 57.03; H, 4.66; N, 10.50 Found:. C, 56.97; H, 4.46; N, 10.23 1 H -NMR (DMSO-d ₆ ) δ: 2.83-2.90 (2H, m), 3.89 (1H, t, J
= 6.6Hz), 4.01-4.05 (2H, m), 4.27 (2H, d, J = 5.4Hz), 4.
92 (1H, d, J = 15.4Hz), 5.44 (1H, d, J = 15.4Hz), 6.75-7.
97 (18H, m), 8.27-8.34 (5H, m), 8.60 (1H, t, J = 5.4H
z), 10.68 (1H, bs).

Example 26 N- (2-Fluorobenzyl) -5- [4- (4-aminobenzenesulfonylamino) benzyl] -1- (4-aminomethylphenyl)-
2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide dihydrochloride (1) N- (2-fluorobenzyl) -1- (4-tert-butoxy Carbonylaminomethylphenyl) -5- [4- (4-nitrobenzenesulfonylaminobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
(0.4 g, 0.48 mmol) in ethanol (8 ml) was added 5% palladium on carbon (0.04 g). The resulting mixture was hydrogenated at normal temperature and normal pressure for 7 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. N- (2-fluorobenzyl) -5- [4- (4
-Aminobenzenesulfonylaminobenzyl) -1- (4-tert
-Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
An oil of 3-acetamide (0.33 g, 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.88-3.15 (2H, m), 4.
05-4.46 (7H, m), 5.77 (1H, d, J = 14.4Hz), 5.79 (1H, b
s), 6.25 (1H, bs), 6.42-7.53 (20H, m), 8.10 (1H, bs). (2) N- (2-fluorobenzyl) -5- [4- (4-aminobenzenesulfonylamino Benzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide from Example 6 N- (2-fluorobenzyl) -5- [4- (4-aminobenzenesulfonylamino) by the same method as (3)
[Benzyl] -1- (4-aminomethylphenyl) -2,4-dioxo-
2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine-3-acetamide dihydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ ) δ: 2.80-2.98 (2H, m), 3.91-4.22 (3H,
m), 4.31 (2H, bs), 4.93 (1H, bs), 5.42 (1H, bs), 6.5
2-7.75 (20H, m), 8.48 (4H, bs), 8.61 (3H, bs), 9.93 (1
H, bs).

Example 27 N- (2-Fluorobenzyl) -5- [4- (4-acetamidobenzenesulfonylamino) benzyl] -1- (4-aminomethylphenyl) -2,4-dioxo-2,3 , 4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- (2-fluorobenzyl) -5- [4- (4-aminobenzenesulfonylaminobenzyl) -1- ( 4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
(0.24 g, 0.30 mmol) in tetrahydrofuran (4 ml) solution of 4-dimethylaminopyridine (3.6 mg, 0.03 mmol), triethylamine (0.054 ml, 0.39 mmol), acetic anhydride (0.03
6 g, 0.39 mmol) and stirred at room temperature for 1 hour. Triethylamine (0.054 ml, 0.39 mmol) and acetic anhydride (0.036 g, 0.39 mmol) were added to the reaction solution, and the mixture was further stirred at room temperature for 24 hours. The reaction solution was poured into water and extracted with ethyl acetate.
After washing the extract with water and drying over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue was solidified from diisopropyl ether to give N- (2-fluorobenzyl) -5- [4- (4-acetamidobenzenesulfonylaminobenzyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
A solid of acetamide (0.22 g, 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 2.21 (1.5H, s), 2.32
(1.5H, s), 3.04 (2H, d, J = 7.0Hz), 4.10 (1H, t, J = 7.0H
z), 4.24 (2H, bs), 4.47-4.53 (2H, m), 4.91 (1H, d, J = 1
5.2Hz), 4.95 (1H, bs), 5.72 (1H, d, J = 15.2Hz), 6.34
(1H, bs), 6.74-7.47 (18H, m), 7.62 (2H, d, J = 8.4Hz),
7.98 (2H, d, J = 8.4 Hz). (2) N- (2-fluorobenzyl) -5- [4- (4-acetamidobenzenesulfonylaminobenzyl) -1- (4-tert-butoxycarbonylaminomethyl (Phenyl) -2,4-dioxo-2,3,
From 4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide, N- (2-fluorobenzyl) -5- [4- (4-acetamidobenzene) was obtained in the same manner as in Example 6, (3). Sulfonylamino) benzyl] -1- (4-aminomethylphenyl) -2,
4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ ) δ: 2.12 (1.5H, s), 2.41 (1.5H, s),
2.83-2.95 (2H, m), 3.89-4.00 (3H, m), 4.31 (2H, bs),
5.14 (1H, d, J = 15.6Hz), 5.63 (1H, d, J = 15.6Hz), 6.77-
8.00 (22H, m), 8.40 (3H, bs), 8.64 (1H, bs).

Example 28 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- [4- (phenylcarbamoylamino) benzyl] -2,4-
Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- (2-fluorobenzyl) -5- (4-aminobenzyl) -1-
(4-tert-butoxycarbonylaminomethylphenyl) -2,
4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.25 g, 0.45 mmol) in tetrahydrofuran (5 ml) solution of phenyl isocyanate
(0.058 ml, 0.54 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diisopropyl ether to give N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- [4- [4- (phenylcarbamoyl) amino] benzyl]- 2,4-dioxo-2,3,4,5-
A solid of tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.27 g, 90%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 3.18 (2H, d, J = 7.0H
z), 3.66 (3H, s), 3.92 (1H, t, J = 7.0Hz), 4.11 (2H, d,
J = 4.0Hz), 4.45 (1H, d, J = 14.0Hz), 5.33 (1H, bs), 5.
90 (1H, d, J = 14.0Hz), 6.33 (2H, d, J = 8.4Hz), 6.78-7.
61 (16H, m), 7.92 (1H, bs). (2) N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- [4- [4- (phenyl Carbamoyl) amino] benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester from Example 6 (2), (3), By the same method as (4)
N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- [4- (phenylcarbamoylamino) benzyl] -2,4-
Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride was synthesized. Elemental analysis: C ₃₉ H ₃₆ N ₆ O ₄ ClF · 1.5H ₂ O Theoretical: C, 63.80; H, 5.35; N, 11.45. Found: C, 63.97; H, 5.44; N, 11.24. ¹ H -NMR (DMSO-d ₆ ) δ: 2.71-3.01 (2H, m), 3.90 (1H, t, J
= 7.0Hz), 3.98 (2H, bs), 4.29 (2H, d, J = 5.4Hz), 4.84 (1
H, d, J = 14.8Hz), 5.61 (1H, d, J = 15.0Hz), 6.66 (2H,
d, J = 8.0Hz), 6.77 (1H, d, J = 8.0Hz), 6.91-7.48 (17H,
m), 7.82 (1H, d, J = 7.4Hz), 8.30 (3H, bs), 8.61 (1H, t,
J = 5.4Hz), 9.77 (1H, bs), 9.20 (1H, s).

Example 29 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-bromobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) [4- [2- (4- Bromobenzylamino) phenylamino]
Benzyl] carbamic acid tert-butyl ester [4- (2-aminophenylamino) benzyl] carbamic acid t
A solution of ert-butyl ester (10.0 g, 32.0 mmol) and 4-bromobenzaldehyde (5.92 ml, 32 mmol) in methanol (250
Acetic acid (3.66 ml, 64 mmol) was added to the mixture. After stirring the resulting mixture at 0 ° C. for 30 minutes, sodium cyanoborohydride (2.44 g, 40 mmol) was added. Thereafter, the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. After washing the extract with water, drying over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain crystals of [4- [2- (4-bromobenzylamino) phenylamino] benzyl] carbamic acid tert-butyl ester (15 g, 97%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.21 (2H, d, J = 5.6Hz),
4.30 (2H, s), 4.75 (2H, bs), 5.12 (1H, bs), 6.59-7.26
(10H, m), 7.42 (2H, d, J = 8.4Hz). (2) N- (4-bromobenzyl) -N- [2- [4- (tert-butoxycarbonylaminomethyl) phenylamino] phenyl ] Malonamic acid ethyl ester [3- [2- (4-bromobenzylamino) phenylamino] benzyl] carbamic acid tert-butyl ester (15.0 g, 31.1
mmol) of tetrahydrofuran (250 ml) was added a solution of triethylamine (4.77 ml, 34.2 mmol) and ethylmalonyl chloride (4.38 ml, 34.2 mmol) in tetrahydrofuran (10 ml). The resulting mixture is 0 ° C
After stirring for 1 hour with triethylamine (2.17 ml, 15.6
mmol) and ethylmalonyl chloride (2.0 ml, 15.6 mmo
A solution of l) in tetrahydrofuran (3 ml) was added. After the reaction solution was stirred at 0 ° C. for 10 minutes, it was poured into water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and N- (4-bromobenzyl) -N
-[2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid ethyl ester (14.9
g, 81%). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.47 (9H,
s), 3.23 (1H, d, J = 16.2Hz), 3.34 (1H, d, J = 16.2Hz),
4.08 (2H, q, J = 7.0Hz), 4.26 (2H, d, J = 5.6Hz), 4.71 (1
H, d, J = 13.8Hz), 4.82 (1H, bs), 4.91 (1H, d, J = 13.8H
z), 5.83 (1H, s), 6.75-7.27 (10H, m), 7.37 (2H, d, J =
6.2Hz).

(3) N- (4-bromobenzyl) -N- [2- (4-tert-
Butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid N- (4-bromobenzyl) -N- [2- (4-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid ethyl ester (14.3 g, A 1N aqueous sodium hydroxide solution (48 ml, 48 mmol) was added to an ice-cooled stirred solution of 24.0 mmol) of tetrahydrofuran (52 ml) and methanol (154 ml). The resulting mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 3 hours. Water was added to the reaction solution, which was washed with diisopropyl ether. Potassium hydrogen sulfate (6.54 g, 48 mmol) was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give N- (4
-Bromobenzyl) -N- [2- (3-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid (1
1.0 g, 81%). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.24 (2H, s), 4.23 (2
H, d, J = 5.8Hz), 4.63 (1H, d, J = 14.4Hz), 4.86 (1H, b
s), 5.03 (1H, d, J = 14.4Hz), 5.25 (1H, bs), 6.72 (2H,
d, J = 8.4Hz), 6.86-7.26 (8H, m), 7.42 (2H, d, J = 8.4H
z). (4) 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5 -Benzodiazepine N- (4-bromobenzyl) -N- [2- (3-tert-butoxycarbonylaminomethyl) phenylamino] phenylmalonamic acid
(10.8 g, 19 mmol) of N, N-dimethylformamide (500 m
l) 4-dimethylaminopyridine (2.3
2 g, 19 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (10.9 g, 57 mmol) were added.
The resulting mixture was stirred at room temperature for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and 5- (4-bromobenzyl) -1- (3-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3, 4,5-tetrahydro-1H
An oil of -1,5-benzodiazepine (6.11 g, 58%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.55 (2H, s), 4.30 (2
H, d, J = 5.8Hz), 4.64 (1H, d, J = 14.8Hz), 4.87 (1H, b
s), 5.79 (1H, d, J = 14.8Hz), 6.63 (2H, d, J = 8.4Hz),
6.84 (1H, d, J = 8.2Hz), 7.04-7.40 (8H, m), 7.47 (1H,
d, J = 8.2Hz).

(5) 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo
-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4 -Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (6.0 g, 10.9 mmol)
To a stirred solution of N, N-dimethylformamide (100 ml) was added 60% oily sodium hydride (0.959 g, 24.0 mmol).
After stirring at room temperature for 30 minutes, methyl bromoacetate (1.24 ml, 13.1
mmol) was added. After stirring the obtained mixture at room temperature for 10 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-
A solid of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (3.5 g, 52%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.13-3.17 (2H, m), 3.7
0 (3H, s), 3.93 (1H, t, J = 6.8Hz), 4.30 (2H, d, J = 6.2H
z), 4.69 (1H, d, J = 15.0Hz), 4.86 (1H, bs), 5.74 (1H,
d, J = 15.0Hz), 6.59 (2H, d, J = 8.2Hz), 6.87 (1H, d, J =
8.2Hz), 7.02-7.39 (8H, m), 7.50 (1H, d, J = 7.0Hz). (6) 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (3.40 g, 5.46 mmol) in tetrahydrofuran (100 ml)
1N aqueous sodium hydroxide solution (25 ml, 25 mmol) was added to a stirred solution of methanol and methanol (100 ml). The resulting mixture was stirred at 60 ° C. for 1 hour. After cooling the reaction solution, water and potassium hydrogen sulfate (3.40 g, 25 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 5- (4-bromobenzyl) -1- (4-
(tert-butoxycarbonylaminomethylphenyl) -2,4-
An amorphous solid of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (3.3 g, 98%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.16 (2H, t, J = 7.6Hz),
3.92 (1H, t, J = 6.8Hz), 4.29 (2H, d, J = 5.4Hz), 4.73 (1
H, d, J = 15.0Hz), 5.01 (1H, t, J = 5.4Hz), 5.68 (1H, d,
J = 15.0Hz), 6.62 (2H, d, J = 8.6Hz), 6.85 (1H, d, J = 8.
0Hz), 7.03-7.29 (6H, m), 7.36 (2H, d, J = 8.6Hz), 7.47
(1H, d, J = 8.0Hz).

(7) N- (2-fluorobenzyl) -5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4, 5-tetrahydro-1H-
1,5-benzodiazepine-3-acetamide 5- (4-bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine-3-acetic acid (2.5 g, 4.1 mm
ol) in N, N-dimethylformamide (25 ml) was stirred in an ice-cooled solution with 2-fluorobenzylamine (0.52 ml, 4.5 mmo).
l), diethyl cyanophosphate (0.74 ml, 4.9 mmol) and triethylamine (0.69 ml, 4.9 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-fluorobenzyl) -5-
(4-Bromobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (1.9 m
g, 65%). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.00 (2H, d, J = 6.6H
z), 4.04 (1H, t, J = 6.6Hz), 4.29 (2H, d, J = 6.0Hz),
4.39-4.59 (2H, m), 4.68 (1H, d, J = 15.0Hz), 4.85 (1H, m
bs), 5.71 (1H, d, J = 15.0Hz), 6.31 (1H, bs), 6.54 (2H,
d, J = 8.4Hz), 6.82 (1H, d, J = 8.0Hz), 7.00-7.37 (12H,
m), 7.46 (1H, d, J = 8.4Hz). (8) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-bromobenzyl) -2,4- Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-bromobenzyl) -1- (4-t
(ert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (200 mg, 0.28 mmol) in ethyl acetate (1
of 4N hydrogen chloride in ethyl acetate (1 ml).
ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-bromobenzyl) -2,4-dioxo-2,3,4,5 -
Crystals of tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (180 mg, 97%) were obtained. Mp 176-178 ° C. Elemental analysis _{C 32 H 29 N 4 O 3} BrClF · 1.5H 2 O theoretically:. C, 57.37; H, 4.66; N, 8.36 Found: C, 57.43; H, 4.60 ; N ^{, 8.10 1 H-NMR (DMSO} -d 6) δ:. 2.74-2.97 (2H, m), 3.91 (1H, t, J
= 4.8Hz), 4.04 (2H, d, J = 6.2Hz), 4.29 (2H, d, J = 5.4H
z), 4.97 (1H, d, J = 15.6Hz), 5.56 (1H, d, J = 15.6Hz),
6.72-7.49 (15H, m), 7.77 (1H, d, J = 7.4Hz), 8.23 (3H,
bs), 8.61 (1H, t, J = 5.4Hz).

Example 30 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (3-thienyl) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride (1) N- (2-fluorobenzyl) -5- (4-bromobenzyl) -1-
(4-tert-butoxycarbonylaminomethylphenyl) -2,
4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (0.36 g, 0.5 mmol), 3-thiophenboronic acid (0.077 g, 0.6 mmol), sodium carbonate (0.132
g, 1.25 mmol), a mixture of toluene (25 ml), ethanol (5 ml) and water (5 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium
After adding (0) (34.7 mg, 0.03 mmol), the mixture was heated under reflux for 15 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from ethyl acetate to give N- (2-fluorobenzyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -5- [4- (3-thienyl) benzyl)]-2,4-dioxo-2.3,5-tetrahydro-
1H-1,5-benzodiazepine-3-acetamide (0.17 g, 47
%) Solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.02 (2H, d, J = 7.0H
z), 4.05 (1H, t, J = 7.0Hz), 4.21 (2H, d, J = 5.8Hz),
4.38-4.58 (2H, m), 4.73 (1H, d, J = 15.0Hz), 4.77 (1H,
bs), 5.80 (1H, d, J = 15.0Hz), 6.31 (1H, bs), 6.55 (2H,
d, J = 8.4Hz), 6.81 (1H, d, J = 8.4Hz), 6.99-7.62 (16H,
m). (2) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (3-thienyl) benzyl] -2,4-dioxo-2,3,4,
5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- [4- (3-thienyl) (Benzyl)]-2,4-dioxo-2.3,5-tetrahydro-1H-1,5-benzoic acid acetyl-3-acetamide (168 mg, 0.23 mmol) in ethyl acetate (1
of 4N hydrogen chloride in ethyl acetate (1 ml).
ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (3-thienyl) benzyl] -2,4-dioxo-2,
Crystals of 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (142 mg, 93%) were obtained. Melting point: 188-189 ° C Elemental analysis: C ₃₆ H ₃₂ N ₄ O ₃ ClFS · 1.8H ₂ O Theoretical: C, 62.88; H, 5.22; N, 8.15. Found: C, 62.94; H, 5.12; N ^{, 8.06 1 H-NMR (DMSO} -d 6) δ:. 2.81-3.03 (2H, m), 3.91-4.05 (3H,
m), 4.31 (2H, d, J = 5.8Hz), 4.99 (1H, d, J = 15.2Hz),
5.63 (1H, d, J = 15.2Hz), 6.77-7.83 (19H, m), 8.28 (3H,
bs), 8.61 (1H, t, J = 6.2Hz).

Example 31 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- [4- (2-thienyl) benzyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride (1) N- (2-fluorobenzyl) -5- (4-bromobenzyl) -1-
(4-tert-butoxycarbonylaminomethylphenyl) -2,
4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (0.36 g, 0.5 mmol), 2-thiophenboronic acid (0.077 g, 0.6 mmol), sodium carbonate (0.132
g, 1.25 mmol), a mixture of toluene (25 ml), ethanol (5 ml) and water (5 ml) was stirred at room temperature for 30 minutes under an argon atmosphere. Tetrakis (triphenylphosphine) palladium
After adding (0) (34.7 mg, 0.03 mmol), the mixture was heated under reflux for 15 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from ethyl acetate to give N- (2-fluorobenzyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -5- [4- (2-thienyl) benzyl)]-2,4-dioxo-2.3,5-tetrahydro-
1H-1,5-benzodiazepine-3-acetamide (0.14 g, 39
%) Solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.02 (2H, d, J = 7.0H
z), 4.06 (1H, t, J = 7.0Hz), 4.21 (2H, d, J = 6.0Hz),
4.41-4.59 (2H, m), 4.72 (1H, d, J = 14.6Hz), 4.75 (1H,
bs), 5.80 (1H, d, J = 14.6Hz), 6.29 (1H, bs), 6.57 (2H,
d, J = 8.4Hz), 6.82 (1H, d, J = 7.2Hz), 6.99-7.54 (16H,
m). (2) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (2-thienyl) benzyl] -2,4-dioxo-2,3,4,
5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- [4- (2-thienyl) Benzyl)]-2,4-Dioxo-2.3,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (0.14 g, 0.2 mmol) in a stirred solution of ethyl acetate (1 ml) was treated with 4N chloride. Hydrogen ethyl acetate solution (1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- [4- (2-thienyl) benzyl] -2,4-dioxo-2,3 Crystals of 4,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (113 mg, 88%) were obtained. Melting point: 185-187 ° C Elemental analysis: C ₃₆ H ₃₂ N ₄ O ₃ ClFS · 1.5H ₂ O Theoretical: C, 63.38; H, 5.17; N, 8.21. Found: C, 63.64; H, 5.17; N ^{, 8.23 1 H-NMR (DMSO} -d 6) δ:. 2.82-2.94 (2H, m), 3.90-4.05 (3H,
m), 4.30 (2H, d, J = 6.4Hz), 5.00 (1H, d, J = 15.6Hz),
5.60 (1H, d, J = 15.6Hz), 6.75-7.57 (18H, m), 7.80 (1H,
d, J = 8.0Hz), 8.19 (3H, bs), 8.61 (1H, t, J = 5.4Hz).

Example 32 1- (4-Aminomethylphenyl) -5- (4-biphenylmethyl)-
3- (2-fluorobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (1) 5- (4-biphenylmethyl) -1- (4 -tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine (310 mg, 0.57 m
mol) of N, N-dimethylformamide (3 ml) in a stirred solution.
% Oily sodium hydride (50 mg, 1.25 mmol) was added. After stirring at room temperature for 20 minutes, 2-fluorobenzyl chloride
(0.081 ml, 0.68 mmol) was added. After stirring the obtained mixture at room temperature for 10 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -3- (2-fluorobenzyl) -2 , 4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (73 mg, 20%) was obtained as a solid. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.43-3.53 (2H, m), 3.7
2 (1H, t, J = 7.0Hz), 4.20 (2H, d, J = 5.8Hz), 4.71 (1H,
d, J = 14.6Hz), 4.75 (1H, bs), 5.85 (1H, d, J = 14.6Hz),
6.54 (2H, d, J = 8.0Hz), 6.80 (1H, d, J = 8.4Hz), 6.89-
7.55 (18H, m). (2) 1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -3- (2-fluorobenzyl) -2,4-dioxo-2,3,4, 5-tetrahydro-1H-1,5-benzodiazepine hydrochloride 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -3- (2-fluorobenzyl) -2,4
To a stirred solution of -dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (73 mg, 0.11 mmol) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate (1 ml). ) Was added.
After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give 1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -3- (2-fluorobenzyl) -2,4-dioxo-2,3,4,5 -Tetrahydro-
Crystals of 1H-1,5-benzodiazepine hydrochloride (61 mg, 93%) were obtained. Melting point: 172-174 ° C Elemental analysis: C ₃₆ H ₃₁ N ₃ O ₂ ClF · 1 / 2H ₂ O Theoretical: C, 71.93; H, 5.37; N, 6.99. Found: C, 71.55; H, 5.53; N, 6.83. ¹ H-NMR (DMSO-d ₆ ) δ: 3.14-3.36 (2H,
m), 3.86 (1H, t, J = 7.6 Hz),
3.96 (2H, s), 4.98 (1H, d,
J = 15.0 Hz), 5.65 (1H, d, J =
15.0 Hz), 6.74-7.64 (20H,
m), 7.82 (1H, d, J = 8.0 Hz),
8.32 (3H, bs).

Example 33 1- (4-Aminomethylphenyl) -5- (4-biphenylmethyl) -3- (3,4-dichlorobenzyl) -2,4-dioxo-2,3,4,
5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (1) 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4 ,Five-
Tetrahydro-1H-1,5-benzodiazepine (310 mg, 0.57 m
mol) of N, N-dimethylformamide (3 ml) in a stirred solution.
% Oily sodium hydride (50 mg, 1.25 mmol) was added. After stirring at room temperature for 20 minutes, 3,4-dichlorobenzyl chloride (0.094 ml, 0.68 mmol) was added. After stirring the obtained mixture at room temperature for 10 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -3- (3,4-dichlorobenzyl) -2,4-dioxo-2,3,4,
5-tetrahydro-1H-1,5-benzodiazepine (220 mg, 55
%) Solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.34-3.56 (3H, m), 4.2
1 (2H, d, J = 6.0Hz), 4.74 (1H, d, J = 14.8Hz), 4.78 (1H,
bs), 5.83 (1H, d, J = 14.8Hz), 6.54 (2H, d, J = 8.4Hz),
6.82 (1H, d, J = 8.0Hz), 7.05-7.56 (17H, m). (2) 1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -3- (3,4- Dichlorobenzyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine hydrochloride 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -3- (3,4-dichlorobenzyl)-
To a stirred solution of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (180 mg, 0.25 mmol) in ethyl acetate (1 ml), add 4N hydrogen chloride in ethyl acetate (1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue is crystallized from ethyl ether 1
-(4-aminomethylphenyl) -5- (4-biphenylmethyl) -3
-(3,4-Dichlorobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (162 mg, 98
%). Melting point: 175-176 ° C Elemental analysis: C ₃₆ H ₃₀ N ₃ O ₂ Cl ₃・ 0.6H ₂ O Theoretical: C, 66.13; H, 4.81; N, 6.43. Found: C, 66.00; H, 5.04; ^{. N, 6.35 1 H-NMR} (DMSO-d 6) δ: 3.17-3.35 (2H, m), 3.85 (1H, t, J
= 6.4Hz), 3.97 (2H, s), 5.00 (1H, d, J = 15.4Hz), 5.62 (1
H, d, J = 15.4Hz), 6.75-7.64 (19H, m), 7.77 (1H, d, J =
8.8Hz), 8.28 (3H, bs).

Example 34 N- (2-Fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (benzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H
-1,5-benzodiazepine-3-acetamide hydrochloride (4- (2-aminophenylamino) obtained in (3) of Example 1
Benzyl] carbamic acid N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (benzyl) -2,4-dioxo-from tert-butyl ester and benzaldehyde in a similar manner to Example 11. Crystals of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride were obtained. Mp 176-178 ° C. Elemental analysis _{C 32 H 30 N 4 O 3} ClF · 1.5H 2 O theoretically:. C, 64.05; H, 5.54; N, 9.34 Found: C, 63.98; H, 5.55 ; N , 9.16. ¹ H-NMR (DMSO-d ₆ ) δ: 2.78-3.02 (2H, m), 3.93 (1H, t, J
= 7.0Hz), 4.05 (2H, d, J = 7.0Hz), 4.31 (2H, d, J = 5.6H
z), 4.97 (1H, d, J = 15.0Hz), 5.67 (1H, d, J = 15.0Hz),
6.66 (2H, d, J = 8.4Hz), 6.89 (1H, dd, J = 1.4,8.2Hz),
7.13-7.45 (13H, m), 7.84 (1H, dd, J = 1.4,8.2Hz), 8.34
(3H, bs), 8.63 (1H, t, J = 6.0Hz) .Example 35 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-benzyloxybenzyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- (2-fluorobenzyl) -5- (4-benzyloxybenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-
Benzodiazepine-3-acetamide (4- (2-aminophenylamino) obtained in (3) of Example 1
[Benzyl] carbamic acid tert-butyl ester and 4-benzyloxybenzaldehyde using Example 11 (1),
N- (2-fluorobenzyl) -5- (4-
Non-crystallinity of (benzyloxybenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide A solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.01 (2H, d, J = 6.8H
z), 3.99 (1H, t, J = 6.8Hz), 4.24 (2H, d, J = 5.6Hz), 4.
48 (2H, t, J = 5.8Hz), 4.67 (1H, d, J = 15.0Hz), 4.79 (1H,
bs), 5.00 (2H, s), 5.71 (1H, d, J = 15.0Hz), 6.34 (1H,
t, J = 5.8Hz), 6.61 (2H, d, J = 8.4Hz), 6.79-7.41 (18H,
m), 7.48 (1H, d, J = 8.0Hz). (2) N- (2-fluorobenzyl) -5- (4-benzyloxybenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-
To a stirred solution of benzodiazepine-3-acetamide (50 mg, 0.067 mmol) in ethyl acetate (1 ml) was added a 4N solution of hydrogen chloride in ethyl acetate (1 ml). After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-benzyloxybenzyl) -2,4-
Crystals of dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (41 mg, 90%) were obtained. Melting point: 155-157 ° C Elemental analysis: C ₃₉ H ₃₆ N ₄ O ₄ ClF ・ H ₂ O Theoretical: C, 67.19; H, 5.49; N, 8.09. Found: C, 67.46; H, 5.25; N, 7.96. ¹ H-NMR (DMSO-d ₆ ) δ: 2.76-3.02 (2H,
m), 3.91 (1H, t, J = 7.4 Hz),
4.02 (2H, d, J = 5.6 Hz);
30 (2H, d, J = 5.6 Hz), 4.89
(1H, d, J = 15.0 Hz), 5.08 (2
H, s), 5.59 (1H, d, J = 15.0)
Hz), 6.72-7.55 (20H, m),
7.82 (1H, d, J = 8.4 Hz), 8.2
8 (3H, bs), 8.62 (1H, t, J =
5.2 Hz).

Example 36 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-hydroxybenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride (1) N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-hydroxybenzyl) -2,4-dioxo-2,3,4,5 -Tetrahydro-1H-1,5-benzodiazepine-3-acetamide N- (2-fluorobenzyl) -5- (4
-Benzyloxybenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (145 mg , 0.196 mmol) in ethyl acetate (2 ml) and methanol (2 ml) was added 5% palladium on carbon (60 mg). The resulting mixture was hydrogenated under normal temperature and normal pressure conditions for 4 hours. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-hydroxybenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H- 1,5-
Crystals of benzodiazepine-3-acetamide (108 mg, 85%) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.90 (1H, dd, J = 7.4,1
5.4Hz), 3.15 (1H, dd, J = 7.4,15.4Hz), 4.05 (1H, t, J =
7.4Hz), 4.24 (2H, d, J = 5.4Hz), 4.38-4.51 (4H, m), 5.4
9 (1H, bs), 5.78 (1H, d, J = 15.2Hz), 6.11 (1H, bs), 6.
23-6.33 (2H, m), 6.71-7.51 (13H, m), 7.53 (1H, d, J = 8.
(2Hz). (2) N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-hydroxybenzyl) -2,4-dioxo-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride N- (2-fluorobenzyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -5- (4-hydroxybenzyl)-
To a stirred solution of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (100 mg, 0.15 mmol) in ethyl acetate (1 ml) was added 4N hydrogen chloride acetic acid. Ethyl solution (1 ml) was added. After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-hydroxybenzyl) -2,4-dioxo-2,
Crystals of 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (81 mg, 90%) were obtained. Melting point: 196-199 ° C Elemental analysis: C ₃₂ H ₃₀ N ₄ O ₄ ClF ・ 2H ₂ O Theoretical: C, 61.49; H, 5.48; N, 8.96. Found: C, 61.12; H, 5.12; N, 8.55. ¹ H-NMR (DMSO-d ₆ ) δ: 2.52-2.69 (2H, m), 3.66 (1H, t, J
= 7.0Hz), 3.69-3.80 (2H, m), 4.07 (2H, d, J = 5.8Hz), 4.
57 (1H, d, J = 14.6Hz), 5.34 (1H, d, J = 14.6Hz), 6.40-6.
57 (5H, m), 6.70 (2H, d, J = 8.4Hz), 6.90-7.22 (8H, m),
7.60 (1H, d, J = 8.0Hz), 8.09 (3H, bs), 8.39 (1H, t, J
= 5.8Hz), 9.20 (1H, bs).

Example 37 N- (2-fluorobenzyl) -5- (4-acetamidobenzyl)-
1- (4-aminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride obtained in Example 1, (3) [4- (2-aminophenylamino)
Benzyl] carbamic acid tert-butyl ester and 4-acetamidobenzaldehyde in the same manner as in Example 11 to give N- (2-fluorobenzyl) -5- (4-acetamidobenzyl) -1- (4-aminomethylphenyl)- 2,4-dioxo-2,3,4,
Crystals of 5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride were obtained. Melting point: 206-208 ° C Elemental analysis: C ₃₄ H ₃₃ N ₅ O ₄ ClF · 1.2 H ₂ O Theoretical: C, 62.66; H, 5.47; N, 10.74. Found: C, 62.85; H, 5.69; N , 10.44. ¹ H-NMR (DMSO-d ₆ ) δ: 2.05 (3H, s),
2.68-3.00 (2H, m), 3.90 (1
H, t, J = 7.2 Hz), 4.01 (2H,
d, J = 5.4 Hz), 4.29 (2H, d,
J = 5.0 Hz), 4.89 (1H, d, J = 1)
5.0 Hz), 5.56 (2H, d, J = 15.
0 Hz), 6.72-7.48 (15H, m),
7.78 (1H, d, J = 8.0 Hz), 8.3
5 (3H, bs), 8.62 (1H, t, J =
5.0 Hz), 10.07 (1H, bs). Example 38 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-chlorobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride obtained in (3) of Example 1 [ 4- (2-aminophenylamino)
[Benzyl] carbamic acid tert-butyl ester and 4-chlorobenzaldehyde in the same manner as in Example 11 to give N-
(2-fluorobenzyl) -1- (4-aminomethylphenyl) -5-
Crystals of (4-chlorobenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride were obtained. Mp 177-179 ° C. Elemental analysis _{C 32 H 29 N 4 O 3} Cl 2 F · 0.9H 2 O theoretically:. C, 61.62; H, 4.98; N, 8.98 Found: C, 61.80; H, 4.97 ; N, 8.85. ¹ H-NMR (DMSO-d ₆ ) δ: 2.81-3.02 (2H, m), 3.94 (1H, t, J
= 6.8Hz), 4.05 (2H, d, J = 6.6Hz), 4.31 (2H, d, J = 5.2H
z), 5.00 (1H, d, J = 15.6Hz), 5.60 (2H, d, J = 15.6Hz),
6.73-7.50 (15H, m), 7.80 (1H, d, J = 8.4Hz), 8.33 (3H,
bs), 8.64 (1H, t, J = 5.2Hz).

Example 39 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (2,2-dimethylpropyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride (4- (2-aminophenylamino) obtained in (3) of Example 1
[Benzyl] carbamic acid tert-butyl ester and pivalaldehyde in the same manner as in Example 11 to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (2,2-dimethylpropyl) Crystals of -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride were obtained. Mp 187-189 ° C. Elemental analysis _{C 30 H 34 N 4 O 3} ClF · H 2 O theoretically:. C, 63.09; H, 6.35; N, 9.81 Found: C, 63.11; H, 6.11 ; N, ^{. 9.71 1 H-NMR (DMSO} -d 6) δ: 0.75 (9H, s), 2.82 (2H, d, J = 6.2H
z), 3.66 (1H, d, J = 13.8Hz), 3.85 (1H, t, J = 6.2Hz),
4.06 (2H, d, J = 6.6Hz), 4.27 (2H, d, J = 5.6Hz), 4.42 (1
H, d, J = 13.8Hz), 6.86 (1H, d, J = 8.2Hz), 7.11-7.46 (8
H, m), 7.59 (2H, d, J = 8.4Hz), 7.79 (1H, d, J = 7.6Hz),
8.32 (3H, bs), 8.58 (1H, t, J = 5.6 Hz) .Example 40 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-trifluoromethylbenzyl) -2,4-dioxo-2,3,
4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (4- (2-aminophenylamino) obtained in (3) of Example 1
[Benzyl] carbamic acid tert-butyl ester and 4-trifluoromethylbenzaldehyde in the same manner as in Example 11 to give N- (2-fluorobenzyl) -1- (4-aminomethylphenyl) -5- (4-trifluoro (Methylbenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride crystals were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.69-3.08 (2H, m), 3.97 (1H, t, J
= 7.0Hz), 4.04 (2H, d, J = 5.6Hz), 4.31 (2H, d, J = 5.8H)
z), 5.14 (1H, d, J = 16.0Hz), 5.64 (1H, d, J = 16.0Hz),
6.76-7.43 (13H, m), 7.67 (2H, d, J = 8.0Hz), 7.88 (1H,
d, J = 8.2Hz), 8.35 (3H, bs), 8.65 (1H, t, J = 5.8Hz).

Example 41 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (2-naphthylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride obtained in (3) of Example 1 [ 4- (2-aminophenylamino)
Benzyl] carbamic acid tert-butyl ester and 2-naphthyl aldehyde were prepared in the same manner as in Example 11 to give N- (2-
(Fluorobenzyl) -1- (4-aminomethylphenyl) -5- (2-
Crystals of (naphthylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride were obtained. Melting point: 180-182 ° C Elemental analysis: C ₃₆ H ₃₂ N ₄ O ₃ ClF · 1.5H ₂ O Theoretical: C, 66.51; H, 5.43; N, 8.62. Found: C, 66.68; H, 5.28; N ^{, 8.59 1 H-NMR (DMSO} -d 6) δ:. 2.79-3.04 (2H, m), 3.95-4.01 (3H,
m), 4.31 (2H, d, J = 4.8Hz), 5.17 (1H, d, J = 15.4Hz),
5.74 (1H, d, J = 15.4Hz), 6.71-7.89 (19H, m), 8.31 (3H,
bs), 8.63 (1H, t, J = 4.8 Hz) .Example 42 N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
5- (4-methoxybenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride obtained in (3) of Example 1 [ 4- (2-aminophenylamino)
[Benzyl] carbamic acid tert-butyl ester and 4-methoxybenzaldehyde in the same manner as in Example 11
N- (2-fluorobenzyl) -1- (4-aminomethylphenyl)-
Crystals of 5- (4-methoxybenzyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride were obtained. Melting point 170-177 ° C Elemental analysis: C ₃₃ H ₃₂ N ₄ O ₄ ClF.H ₂ O Theoretical: C, 63.81; H, 5.52; N, 9.02. Found: C, 64.00; H, 5.55; N, ^{. 8.99 1 H-NMR (DMSO} -d 6) δ: 2.75-2.99 (2H, m), 3.73 (3H, s),
3.88 (1H, t, J = 6.2Hz), 3.97-4.04 (2H, m), 4.28 (2H, d,
J = 5.0Hz), 4.84 (1H, d, J = 14.6Hz), 5.60 (2H, d, J = 14.
6Hz), 6.64 (2H, d, J = 8.0Hz), 6.74-7.42 (13H, m), 7.8
2 (1H, d, J = 8.0Hz), 8.33 (3H, bs), 8.60 (1H, t, J = 5.0
Hz).

Example 43 N- (2-Fluorobenzyl) -1- [4- (1-amino-1-methylethyl) phenyl] -5- (4-biphenylmethyl) -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) 2-methyl-2- (4-nitrophenyl) propionic acid ethyl ester 2- (4-nitrophenyl) Acetic acid ethyl ester (25.3 g, 0.
121 mol) in N, N-dimethylformamide (250 ml) solution,
60% oily sodium hydride (10.6 g, 266 mmol) was added with stirring under ice cooling. The resulting mixture was stirred at room temperature for 20 minutes. Then, methyl iodide (16.6 ml, 266 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 12 hours.
Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave an oil of 2-methyl-2- (4-nitrophenyl) propionic acid ethyl ester (28 g, 98%). ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 1.62 (6H,
s), 4.14 (2H, q, J = 7.2Hz), 7.50 (2H, d, J = 8.0Hz), 8.
18 (2H, d, J = 8.0Hz). (2) 2-methyl-2- (4-nitrophenyl) propionic acid 2-methyl-2- (4-nitrophenyl) propionic acid ethyl ester (28 g, 118 mmol) in tetrahydrofuran (200 ml)
To a stirred solution of methanol and methanol (200 ml) was added a 1N aqueous sodium hydroxide solution (118 ml, 118 mmol). The resulting mixture was stirred at 50 ° C. for 2 hours. Concentrated hydrochloric acid (30 ml) was added to the reaction mixture, which was extracted with ethyl acetate. After washing the extract with water,
It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from diethyl ether-hexane. 2-
Methyl-2- (4-nitrophenyl) propionic acid (23.5 g, 95
%). 133-134 ° C Elemental analysis: C ₁₀ H ₁₁ NO ₄ Theoretical: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.39; H, 5.23; N, 6.71. ¹ H-NMR ( CDCl ₃ ) δ: 1.65 (6H, s), 7.57 (2H, d, J = 8.8H
z), 8.20 (2H, d, J = 8.8Hz).

(3) 1- (4-nitrophenyl) -1-methylethylamine 2-methyl-2- (4-nitrophenyl) propionic acid (23.5 g,
112 mmol), diphenylphosphoryl azide (DPPA) (24.1 m
l, 112 mmol), triethylamine (15.6 ml, 112 mmol)
And a mixture of N, N-dimethylformamide (200 ml) at 0 ° C
Stir for 1.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Toluene (200 ml) was added to the residue, and the resulting mixture was stirred for 5 hours while heating under reflux. Thereafter, 5N hydrochloric acid (125 ml) was added to the reaction solution, and the mixture was refluxed at 100 ° C for 1 hour. After cooling the reaction solution, a 5N aqueous sodium hydroxide solution (125 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. An oil of 1- (4-nitrophenyl) -1-methylethylamine (20 g, 99%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.53 (6H, s), 7.70 (2H, d, J = 9.0H
z), 8.18 (2H, d, J = 9.0Hz). (4) [1- (4-nitrophenyl) -1-methylethyl] carbamic acid tert-butyl ester 1- (4-nitrophenyl) -1- Methylethylamine (20 g, 11
1 mmol) in tetrahydrofuran (200 ml).
Tert-butyl (30.6 ml, 174 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then at 60 ° C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a solid of [1- (4-nitrophenyl) -1-methylethyl] carbamic acid tert-butyl ester (23.6 g, 80%). ¹ H-NMR (CDCl ₃ ) δ: 1.38 (9H, s), 1.64 (6H, s), 5.04 (1
H, bs), 7.56 (2H, d, J = 9.0Hz), 8.18 (2H, d, J = 9.0H
z).

(5) [1- (4-aminophenyl) -1-methylethyl] carbamic acid tert-butyl ester [1- (4-nitrophenyl) -1-methylethyl] carbamic acid
tert-butyl ester (23.6 g, 84.2 mmol) in methanol
(500 ml) solution was added 5% palladium on carbon (2.36 g). The obtained mixture was hydrogenated under normal temperature and normal pressure conditions for 2 hours. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. An oil of [1- (4-aminophenyl) -1-methylethyl] carbamic acid tert-butyl ester (21 g, 99.5%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.60 (6H, s), 4.87 (1
H, bs), 6.64 (2H, d, J = 8.6Hz), 7.19 (2H, d, J = 8.6H
z). (6) [1-Methyl-1- [4-[(2-nitrophenyl) amino] phenyl] ethyl] carbamic acid tert-butyl ester [1- (4-aminophenyl) -1-methylethyl] Carbamic acid
tert-butyl ester (21 g, 83.9 mmol), o-fluoronitrobenzene (26.5 ml, 252 mmol) and potassium carbonate (11.6
g, 83.9 mmol) was stirred at 140 ° C. for 3.5 hours.
After cooling, the reaction mixture was diluted with ethyl acetate and washed with water.
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was solidified from hexane-diisopropyl ether to give [1-methyl-1- [4-[(2-nitrophenyl) amino] phenyl] ethyl] carbamic acid tert-butyl ester (12 g, 3
9%). ¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, bs), 1.65 (6H, s), 4.96 (1
H, bs), 6.76 (1H, t, J = 8.4Hz), 7.17-7.24 (3H, m), 7.
35 (1H, d, J = 8.4Hz), 7.44 (2H, d, J = 8.8Hz), 8.19 (1H,
d, J = 8.4Hz), 9.48 (1H, bs)

(7) [1- [4-[(2-aminophenyl) amino] phenyl] -1-methylethyl] carbamic acid tert-butyl ester [1-methyl-1- [4-[(2-nitro Phenyl) amino] phenyl]
Ethyl] carbamic acid tert-butyl ester (15.5 g, 41.
To a solution of 6 mmol) in methanol (500 ml) was added 5% palladium on carbon (1.6 g). The obtained mixture was hydrogenated under normal temperature and normal pressure conditions for 2 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. A solid of [1- [4-[(2-aminophenyl) amino] phenyl] -1-methylethyl] carbamic acid tert-butyl ester (12.7 g, 89%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, bs), 1.61 (6H, s), 3.75 (2
H, bs), 4.87 (1H, bs), 5.16 (1H, bs), 6.68-7.26 (8H,
m). (8) [1- [4-[[2- (4-biphenylmethyl) aminophenyl]
Amino] phenyl] -1-methylethyl] carbamic acid tert-
Butyl ester [1- [4-[(2-aminophenyl) amino] phenyl] -1-methylethyl] carbamic acid tert-butyl ester (5.0 g, 14.6
mmol), 4-phenylbenzaldehyde (2.66 g, 14.6 mmo
Acetic acid (1.67 ml) and sodium cyanoborohydride (1.11 g, 18.3 mmol) were added to a methanol solution (125 ml) of l). Thereafter, the mixture was stirred at 60 ° C. for 1 hour. Pour the reaction into water,
Extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and [1- [4-
An oil of [[2- (4-biphenylmethyl) aminophenyl] amino] phenyl] -1-methylethyl] carbamic acid tert-butyl ester (7.2 g, 98%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, bs), 1.61 (6H, s), 4.39 (2
H, bs), 4.60 (1H, bs), 4.87 (1H, bs), 5.09 (1H, bs),
6.67-7.60 (17H, m).

(9) N- (4-biphenylmethyl) -N- [2- [4- (1-
tert-butoxycarbonylamino-1-methyl) phenylamino] phenyl] malonamic acid ethyl ester [1- [4-[[2- (4-biphenylmethyl) aminophenyl] amino] phenyl] -1-methylethyl] carbamic acid Tert-butyl ester (6.0 g, 11.8 mmol) in tetrahydrofuran (1
Triethylamine (1.81 m
l, 13 mmol) and ethylmalonyl chloride (1.66 ml, 1
A solution of 3 mmol) in tetrahydrofuran (3 ml) was added.
After the resulting mixture was stirred at 0 ° C. for 1 hour, triethylamine (0.822 ml, 5.90 mmol) and ethylmalonyl chloride (0.755 ml, 5.9 mmol) were added. The reaction solution was stirred at 0 ° C. for 5 minutes, poured into ice water, and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and N- (4-biphenylmethyl) -N- [2- [4- (1-tert-
Butoxycarbonylamino-1-methyl) phenylamino]
[Phenyl] malonamic acid ethyl ester (4.8 g, 65%)
Oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.4 Hz), 1.37 (9H, b
s), 1.58 (6H, s), 3.22 (1H, d, J = 15.7Hz), 3.33 (1H,
d, J = 15.7Hz), 4.07 (2H, q, J = 7.4Hz), 4.82 (1H, d, J =
13.4Hz), 4.91 (1H, bs), 5.01 (1H, d, J = 13.4Hz), 5.64
(1H, bs), 6.76-7.59 (17H, m). (10) N- (4-biphenylmethyl) -N- [2- [4- (1-tert-butoxycarbonylamino-1-methyl) phenylamino ] Phenyl] malonamic acid N- (4-biphenylmethyl) -N- [2- [4- (1-tert-butoxycarbonylamino-1-methyl) phenylamino] phenyl] malonamic acid ethyl ester (4.62 g, 7 .43
mmol) of tetrahydrofuran (18 ml) and methanol (54 ml) was added with a 1N aqueous solution of sodium hydroxide (14.9 ml). The resulting mixture is
The mixture was stirred at ℃ for 10 minutes and at room temperature for 2 hours. Water was added to the reaction solution, which was washed with diisopropyl ether. Potassium hydrogen sulfate (2.0 g, 14.9 mmol) was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give N- (4-biphenylmethyl) -N- [2
An oil of-[4- (1-tert-butoxycarbonylamino-1-methyl) phenylamino] phenyl] malonamic acid (3.3 g, 74%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (9H, bs), 1.54 (6H, s), 3.20 (1
H, d, J = 19.6Hz), 3.31 (1H, d, J = 19.6Hz), 4.43 (1H,
d, J = 14.4Hz), 4.91 (1H, bs), 5.50 (1H, d, J = 14.4Hz),
6.58 (2H, d, J = 8.4Hz), 6.88-7.62 (15H, m).

(11) 5- (4-biphenylmethyl) -1- [4- (1-t
ert-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine N- (4-biphenylmethyl) -N- [2 -[4- (1-tert-Butoxycarbonylamino-1-methyl) phenylamino] phenyl] malonamic acid (2.69 g, 4.53 mmol) in N, N-dimethylformamide (270 ml) was added to an ice-cooled stirred solution. -Dimethylaminopyridine (553 mg, 4.53 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.61 g, 13.6 m
mol) was added. The resulting mixture was stirred at room temperature for 48 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and 5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2, An amorphous solid of 4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.41 g, 54%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (9H, bs), 1.49 (3H, s), 1.52 (3
H, s), 3.57 (2H, s), 4.72 (1H, d, J = 14.8Hz), 4.82 (1
H, bs), 5.90 (1H, d, J = 14.8Hz), 6.57 (2H, d, J = 8.6H
z), 6.85 (1H, d, J = 7.6Hz), 7.05-7.58 (14H, m). (12) 5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino- 1-methylethyl) phenyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetic acid methyl ester 5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.3
g, 2.26 mmol) in a stirred solution of N, N-dimethylformamide (20 ml) in 60% oily sodium hydride (199 mg, 4.97 mmo
l) was added. After stirring at room temperature for 30 minutes, methyl bromoacetate
(0.257 ml, 2.71 mmol) was added. After stirring the obtained mixture at room temperature for 1 hour, the reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2, 4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester
(0.81 g, 56%) oil was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (9H, bs), 1.47 (3H, s), 1.51 (3
H, s), 3.15-3.20 (2H, m), 3.71 (3H, s), 3.96 (1H, t,
J = 7.0Hz), 4.75 (1H, d, J = 14.8Hz), 4.79 (1H, bs), 5.8
6 (1H, d, J = 14.8Hz), 6.51 (2H, d, J = 8.8Hz), 6.87 (1H,
d, J = 8.4Hz), 7.07-7.59 (14H, m).

(13) 5- (4-biphenylmethyl) -1- [4- (1-te
rt-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid 5- (4-biphenylmethyl)- 1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-
1N hydroxylation in a stirred solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid methyl ester (0.78 g, 1.2 mmol) in tetrahydrofuran (8 ml) and methanol (8 ml) Aqueous sodium solution (3 ml, 3 mmol) was added. The resulting mixture was stirred at 60 ° C. for 1 hour. After cooling the reaction solution,
Water and potassium hydrogen sulfate (0.41 g, 3 mmol) were added. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. Concentrate under reduced pressure to give 5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-2,3,4,5 -Tetrahydro
An oil of -1H-1,5-benzodiazepine-3-acetic acid (0.75 g, 98%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (9H, s), 1.47 (3H, s), 1.50 (3
H, s), 3.20 (2H, d, J = 6.6Hz), 3.92 (1H, t, J = 6.6Hz),
4.76 (1H, d, J = 14.4Hz), 4.80 (1H, bs), 5.85 (1H, d,
J = 14.4Hz), 6.52 (2H, d, J = 8.8Hz), 6.87 (1H, d, J = 7.4
Hz), 7.13-7.59 (14H, m). (14) N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino-1-methyl Ethyl) phenyl] -2,4-dioxo-2,3,4,5-tetrahydro
-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.2 g, 0.32 mmol) in N, N-dimethylformamide (2 m
l) 2-Fluorobenzylamine
(0.057 ml, 0.35 mmol), diethyl cyanophosphate (0.057
ml, 0.38 mmol), triethylamine (0.057 ml, 0.38 mmo
l) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether
N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1-
[4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine-3-acetamide (160 mg, 69%)
A non-crystalline solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, bs), 1.47 (3H, s), 1.51 (3
H, s), 3.02 (2H, d, J = 6.8Hz), 4.06 (1H, t, J = 6.8Hz),
4.41-4.62 (2H, m), 4.73 (1H, d, J = 14.6Hz), 4.81 (1H,
bs), 5.84 (1H, d, J = 14.6Hz), 6.37 (1H, t, J = 7.0Hz),
6.48 (2H, d, J = 8.4Hz), 6.84 (1H, d, J = 8.0Hz), 6.99-
7.57 (18H, m). (15) N- (2-fluorobenzyl) -1- [4- (1-amino-1-methylethyl) phenyl] -5- (4-biphenylmethyl) -2,4- Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-
3-acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- [4
-(1-tert-butoxycarbonylamino-1-methylethyl)
Phenyl] -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5
-Benzodiazepine-3-acetamide (160 mg, 0.2 mmol)
To a stirred solution of ethyl acetate (1 ml) was added a 4N solution of hydrogen chloride in ethyl acetate (1 ml). The resulting mixture is allowed to stand at room temperature
After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl ether to give N- (2-fluorobenzyl) -1- [4-
(1-Amino-1-methylethyl) phenyl] -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-
Benzodiazepine-3-acetamide hydrochloride (140 mg, 86
%) Of an amorphous solid. ¹ H-NMR (DMSO-d ₆ ) δ: 1.53 (6H, s), 2.76-2.99 (2H, m),
3.94 (1H, t, J = 6.6Hz), 4.30 (2H, d, J = 5.6Hz), 4.99 (1
H, d, J = 15.2Hz), 5.70 (1H, d, J = 15.2Hz), 6.66 (2H,
d, J = 8.8Hz), 6.80 (1H, d, J = 8.4Hz), 7.12-7.68 (17H,
m), 7.88 (1H, d, J = 8.4Hz), 8.51 (3H, bs), 8.63 (1H,
t, J = 5.6Hz).

Example 44 N- (2-Fluorobenzyl) -1- [4- (aminomethyl) phenyl] -5- (4-biphenylmethyl) -7-chloro-2,4-dioxo-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) [4-[(5-chloro-2-nitrophenyl) amino] benzyl] carbamic acid tert-butyl ester Example 1 from (4-aminobenzyl) carbamic acid tert-butyl ester and 4-chloro-2-fluoronitrobenzene
It was synthesized by the same method as (1). ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 4.35 (2H, d, J = 5.6 Hz),
4.92 (1H, bs), 6.72 (1H, dd, J = 1.0,9.2Hz), 7.11 (1H,
d, J = 1.0Hz), 7.23 (2H, d, J = 8.5Hz), 7.37 (2H, d, J = 8.
5Hz), 8.16 (1H, d, J = 9.2Hz), 9.52 (1H, bs). (2) [4-[(2-amino-5-chlorophenyl) amino] benzyl] carbamic acid tert-butyl ester [4 It was synthesized from tert-butyl ester of-[(5-chloro-2-nitrophenyl) amino] benzyl] carbamic acid in the same manner as in Example 1, (2). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.4
0-2.60 (2H, m), 4.23 (2H, d,
J = 5.4 Hz), 4.78 (1H, bs), 5.2
3 (1H, bs), 6.70-7.18 (7H,
m).

(3) [4-[[2- (4-biphenylmethylamino) -5-chlorophenyl] amino] benzyl] carbamic acid tert-butyl ester [4-[(2-amino-5-chlorophenyl) amino] It was synthesized from benzyl] carbamic acid tert-butyl ester in the same manner as in Example 1, (3). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 4.23 (2H, d, J = 5.4Hz),
4.36 (2H, s), 4.75 (1H, bs), 5.13 (1H, bs), 6.60-7.60
(15H, m). (4) N- (4-biphenylmethyl) -N- [2- [4- (tert-butoxycarbonylaminomethyl) phenylamino] phenyl] malonamic acid ethyl ester [4-[[2- The compound was synthesized from (4-biphenylmethylamino) -5-chlorophenyl] amino] benzyl] carbamic acid tert-butyl ester in the same manner as in Example 43 (9). ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.47 (9H,
s), 3.29 (1H, d, J = 18Hz), 3.30 (1H, d, J = 18Hz), 4.09
(2H, q, J = 7.0Hz), 4.22 (2H, d, J = 5.8Hz), 4.76 (1H,
d, J = 14.0Hz), 4.75 (1H, bs), 5.04 (1H, d, J = 14.0Hz),
5.76 (1H, s), 6.73-6.89 (4H, m), 7.12-7.16 (2H, m),
7.32-7.56 (10H, m).

(5) 5- (4-biphenylmethyl) -1- [4- (tert
-Butoxycarbonylaminomethyl) phenyl] -7-chloro
-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine N- (4-biphenylmethyl) -N- [2- [4- (tert-butoxycarbonylaminomethyl) phenyl It was synthesized from ethyl [amino] phenyl] malonamic acid in the same manner as in (10) and (11) of Example 43. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.56 (2H, s), 4.23 (2
H, d, J = 5.7Hz), 4.66 (1H, d, J = 14.8Hz), 4.79 (1H, b
s), 5.87 (1H, d, J = 14.8Hz), 6.63 (2H, d, J = 8.6Hz),
6.80 (1H, d, J = 2.6Hz), 7.10-7.56 (13H, m). (6) 5- (4-biphenylmethyl) -1- [4- (tert-butoxycarbonylaminomethyl) phenyl] -7 -Chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
Acetic acid methyl ester 5- (4-biphenylmethyl) -1- [4- (tert-butoxycarbonylaminomethyl) phenyl] -7-chloro-2,4-dioxo-2,
The compound was synthesized from 3,4,5-tetrahydro-1H-1,5-benzodiazepine in the same manner as in Example 43 (12). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.16 (2H, d, J = 7.2H
z), 3.71 (3H, s), 3.93 (1H, t, J = 7.2Hz), 4.22 (2H,
m), 4.70 (1H, d, J = 14.6Hz), 4.79 (1H, bs), 5.84 (1H,
d, J = 14.6Hz), 6.56 (2H, d, J = 8.2Hz), 6.82 (1H, d, J =
2.2Hz), 7.10 (1H, d, J = 8.2Hz), 7.08-7.57 (11H, m).

(7) N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- [4- (tert-butoxycarbonylaminomethyl) phenyl] -7-chloro-2,4-dioxo- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- [4- (tert-butoxycarbonylaminomethyl) phenyl] -7-chloro- 2,4-dioxo-2,
3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid
It was synthesized from the methyl ester in the same manner as (13) and (14) of Example 43. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.02 (2H, d, J = 6.6H
z), 4.04 (1H, t, J = 6.6Hz), 4.24 (2H, m), 4.50 (2H, t,
J = 5.1Hz), 4.68 (1H, d, J = 14.8Hz), 4.75 (1H, bs), 5.
83 (1H, d, J = 14.8Hz), 6.27 (1H, m), 6.54 (2H, d, J = 8.
4Hz), 6.79 (1H, d, J = 2.2Hz), 7.05-7.55 (17H, m). (8) N- (2-fluorobenzyl) -1- [4- (aminomethyl) phenyl] -5- (4-biphenylmethyl) -7-chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
Acetamide hydrochloride N- (2-fluorobenzyl) -5- (4-biphenylmethyl) -1- [4
-(tert-Butoxycarbonylaminomethyl) phenyl] -7-
The compound was synthesized from chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide in the same manner as in Example 43 (15). ¹ H-NMR (DMSO-d ₆ ) δ: 2.76-3.03 (2H,
m), 3.94-4.00 (3H, m), 4.3
0 (2H, d, J = 5.4 Hz), 5.50 (1
H, d, J = 15.2 Hz), 5.64 (1H,
d, J = 15.2 Hz), 6.75 (1H,
d, J = 2.6 Hz), 6.82 (2H, d, J)
= 8.0 Hz), 7.10-7.65 (16H,
m), 7.88 (1H, d, J = 9.0 Hz),
8.32 (3H, bs), 8.63 (1H, t,
J = 5.8 Hz).

Example 45 N-phenyl-1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine-3-acetamide hydrochloride (1) N-phenyl-5- (4-biphenylmethyl) -1- (4-tert-
(Butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-
Acetamide 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4, obtained in the same manner as in (1) of Example 1. N-N-dimethylformamide (2 ml) of 5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.2 g, 0.33 mmol) was added to an ice-cooled stirred solution of aniline (62 mg, 0.66 mmol), 4-dimethylamino pyridine (4
0 mg, 0.32 mmol) and WSC (73 mg, 0.38 mmol) were added.
The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N-phenyl-5- (4-
(Biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (144 mg,
(63%) solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 3.16-3.23 (2H, m), 4.0
9 (1H, t, J = 7.0Hz), 4.21 (2H, d, J = 6.2Hz), 4.75 (1H,
bs), 4.79 (1H, d, J = 15.0Hz), 5.82 (1H, d, J = 15.0Hz),
6.62 (2H, d, J = 8.4Hz), 6.83 (1H, dd, J = 1.4,8.2Hz),
7.06-7.56 (18H, m), 7.96 (1H, s). (2) N-phenyl-1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2, 3,4,5-tetrahydro-
1H-1,5-benzodiazepine-3-acetamide N-phenyl-5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,
To a stirred solution of 3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (144 mg, 0.21 mmol) in ethyl acetate (1 ml) was added a 4N solution of hydrogen chloride in ethyl acetate (1 ml). Was.
After the obtained mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N-phenyl-1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine-3-acetamide hydrochloride (110 mg, 84%)
A non-crystalline solid was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 3.06-3.14 (2H, m), 3.97-4.10 (3H,
m), 5.07 (1H, d, J = 15.0Hz), 5.70 (1H, d, J = 15.0Hz),
6.85 (2H, d, J = 8.0Hz), 7.05 (1H, t, J = 7.2Hz), 7.23-
7.63 (18H, m), 7.89 (1H, d, J = 7.8Hz), 8.30 (3H, bs),
10.23 (1H, s).

Example 46 N- (2-phenylethyl) -1- (4-aminomethylphenyl) -5-
(4-biphenylmethyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide hydrochloride (1) N- (2-phenylethyl) -5- (4-biphenylmethyl) -1-
(4-tert-butoxycarbonylaminomethylphenyl) -2,
4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide 5- (4-biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2, 4-dioxo-2.3,5-tetrahydro-1H-1,5-benzodiazepine-3-acetic acid (0.2 g, 0.33 m
mol) of N, N-dimethylformamide (2 ml) was added to an ice-cooled stirred solution of 2-phenylethylamine (0.046 ml, 0.35 mmol
l), diethyl cyanophosphate (0.059 ml, 0.40 mmol) and triethylamine (0.055 ml, 0.40 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was solidified from diethyl ether to give N- (2-phenylethyl) -5-
(4-Biphenylmethyl) -1- (4-tert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2.3,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (84 mg,
36%) of an amorphous solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.81 (2H, t, J = 7.4Hz),
2.91-2.96 (2H, m), 3.50-3.55 (2H, m), 4.05 (1H, t, J =
6.8Hz), 4.21 (2H, d, J = 5.8Hz), 4.73 (1H, bs), 4.77 (1
H, d, J = 14.6Hz), 5.81 (1H, d, J = 14.6Hz), 5.95 (1H, b
s), 6.59 (2H, d, J = 8.4Hz), 6.82 (1H, d, J = 8.4Hz), 7.0
7 (2H, d, J = 8.4Hz), 7.19-7.56 (17H, m). (2) N- (2-phenylethyl) -1- (4-aminomethylphenyl) -5- (4-biphenylmethyl ) -2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide
Hydrochloride N- (2-phenylethyl) -5- (4-biphenylmethyl) -1- (4-t
(ert-butoxycarbonylaminomethylphenyl) -2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-3-acetamide (84 mg, 0.12 mmol) in ethyl acetate (1
ml) into a 4N solution of hydrogen chloride in ethyl acetate (1 m
l) was added. After stirring the resulting mixture at room temperature for 1 hour,
It was concentrated under reduced pressure. The residue was solidified from ethyl ether to give N- (2-phenylethyl) -1- (4-aminomethylphenyl) -5- (4-biphenylmethyl) -2,4-dioxo-2,3,4,5 -Tetrahydro-1H-1,5-benzodiazepine-3-acetamide
An amorphous solid of the hydrochloride (65 mg, 85%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.66-2.95 (2H, m), 3.20-3.27 (2H,
m), 3.93 (1H, t, J = 7.0Hz), 3.98 (2H, d, J = 6.0Hz),
5.05 (1H, d, J = 15.4Hz), 5.65 (1H, d, J = 15.4Hz), 6.78-
7.65 (21H, m), 7.84 (1H, d, J = 7.6Hz), 8.22 (1H, t, J =
5.6Hz), 8.23 (3H, bs).

The pharmacological action of the compound of the present invention will be specifically described below, but it should not be construed that the invention is limited thereto. The genetic engineering method using E. coli is described in Molecular Cloning (T. Maniatis et al.), 198
The method described in the ninth edition was followed. (1) Cloning of Human Somatostatin Receptor Protein Subtype 1 (SSTR1) DNA Nucleotide sequence of a known human SSTR1 cDNA [Proc. Natl. Acad. Sci. ., US
A), Vol. 89, pp. 251-255, 1992], DNA oligomers S1-1 and S1-2 were synthesized. The sequence of S1-1 was 5′-GGTCGACCTCA
GCTAGGATGTTCCCCAATG-3 ′ (SEQ ID NO: 1), and the sequence of S1-2 is 5′-GGTC
GACCCGGGCTCAGAGCGTCGTGAT-
3 ′ (SEQ ID NO: 2). As a template, human chromosomal DNA (Clontech, Catalog No. CL6550)
-1) was used. To 0.5 ng of the DNA was added 25 pmol of each of the above DNA oligomers, and a polymerase chain reaction was carried out using 2.5 units of Pfu DNA polymerase (Stratagene). The composition of the reaction solution is the Pf
The instructions attached to the uDNA polymerase were followed. The reaction conditions were repeated at 35 cycles of 94 ° C. for 1 minute, 63 ° C. for 1 minute, and 75 ° C. for 2 minutes.
When the reaction solution was subjected to 1% agarose gel electrophoresis, a DNA fragment of a target size (about 1.2 kb) was specifically amplified. The DNA fragment was recovered from an agarose gel according to a conventional method, and pUC1 cleaved at the HincII site.
18 and transformed into competent cells, Escherichia coli JM109. A transformant having a plasmid containing the DNA fragment was selected, and an automatic nucleotide sequence analyzer ALF D using a fluorescent dye was selected.
Insert DNA with NA sequencer (Pharmacia)
When the nucleotide sequence of the fragment was confirmed, the amino acid sequence predicted from the nucleotide sequence completely matched the sequence described in the above-mentioned literature.

(2) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 1 (SSTR1) DNA pAKKO-111 was used as an expression vector in CHO (Chinese hamster ovary) cells. pAK
KO-111 was constructed as follows. JP-A-5-076
No. 385, pTB1417 to Hind II
I and ClaI treatments allow the SRα promoter and p
A 1.4 kb DNA fragment containing an olyA addition signal was obtained. In addition, pTB348 [Biochemical and
Biophysical Research Communications (Biochem. Biophys. Res. Commun.), 128, 256
-264, 1985], a 4.5 kb DNA fragment containing the dihydrofolate reductase (DHFR) gene was obtained by treatment with ClaI and SalI. After these DNA fragments were blunt-ended by T4 polymerase treatment,
By ligating with T4 ligase, a pAKKO-111 plasmid was constructed. Next, the human SS obtained in the above (1)
After digesting 5 μg of the plasmid having the TR1 DNA fragment with the restriction enzyme SalI, 1% agarose gel electrophoresis was performed to recover a 1.2 kb DNA fragment encoding human SSTR1. And the expression vector p
1 μg of AKKO-111 (5.5 kb) was digested with SalI to create a cloning site for inserting a human SSTR1 DNA fragment. The expression vector fragment and the 1.2 kb DNA fragment were ligated using T4 DNA ligase, and the reaction mixture was subjected to E. coli JM10 by the calcium chloride method.
9 and human / SSTR1 D
An expression plasmid pA1-11-SSTR1 in which the NA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escherichia coli JM109 / pA-1-1.
Displayed as 1-SSTR1.

(3) CHO (dh) of human somatostatin receptor protein subtype 1 (SSTR1) DNA
Introduction and expression into fr ⁻ ) cells 1 × 10 ⁶ CHO (dhfr ⁻ ) cells were collected at a diameter of 8 cm.
Ham F containing 10% fetal bovine serum using a Petri dish
The cells were cultured for 24 hours in 12 medium, and the cells were added to the human SSTR1 cDNA expression plasmid 1 pA-
10 μg of 1-11-SSTR1 was added to the calcium phosphate method (Cellfect Transfection Kit; Pharmacia).
a)). Twenty-four hours after the introduction, the medium was changed to DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies with this medium (that is, DHFR + cells) were selected. Further, the selected cells were cloned from a single cell by the limiting dilution method, and the somatostatin protein activity was measured by the following method. Human SSTR cDNA
The expression cell line was added to a measuring buffer [50 mM Tris-HCl, 1
mM EDTA, 5 mM magnesium chloride, 0.1%
BSA, 0.2 mg / ml bacitracin, 10 μg
/ Ml leupeptin, 1 μg / ml pepstatin,
200 units / ml of aprotinin (pH 7.
5)] and increase the cell number to 2 × 10 ⁴ per 200 μl.
Adjusted to individual. Dispense 200 μl into tubes and add 5 nM
[ ¹²⁵ I] -Somatostatin-14 (2000 Ci / m
mol, Amersham) and add 2 μl.
Incubation was performed at 5 ° C for 60 minutes. In addition, a tube to which 2 μl of somatostatin-14 (10 ⁻⁴ M) was added was also incubated to measure the amount of non-specific binding (NSB). Washing buffer [50 mM Tris-HCl, 1 mM EDTA, 5 mM magnesium chloride (p
H7.5)] (1.5 ml), and the mixture was filtered through a GF / F glass fiber filter (Whatman), and the same buffer (1.
5 ml). [ ¹²⁵ I] of the filter paper was measured with a γ-counter. Thus, a cell line with high somatostatin binding property, SSTR1-8-3, was selected.

(4) Cloning of Human Somatostatin Receptor Protein Subtype 2 (SSTR2) DNA The nucleotide sequence of the known human SSTR2 cDNA [Proceding of the National Academy of Sciences USA Acad.Sci., US
A), Vol. 89, pp. 251-255, 1992] to synthesize DNA oligomers PT-1 and PT-2. The sequence of PT-1 is 5'-GGTCGACACCA
TGGACATGGCGGATGAG-3 ′ (SEQ ID NO: 3), and the sequence of PT-2 is 5′-GGTCG
ACAGTTCAGACTACTGGTTTGG-3 '
(SEQ ID NO: 4). Human pituitary cDNA (Clontech, catalog number 7173-1) was used as a template. To 1 ng of the cDNA, 25 pmol of each of the DNA oligomers was added, and a polymerase chain reaction was carried out using 2.5 units of Taq DNA polymerase (Takara Shuzo Co., Ltd.). The composition of the reaction solution was in accordance with the instructions attached to the Taq DNA polymerase. Reaction conditions are 94 ° C
For 30 seconds, at 52 ° C. for 20 seconds, and at 72 ° C. for 60 seconds.
As a cycle, 30 cycles were repeated. Reaction solution 1
When electrophoresed on a% agarose gel, a DNA fragment of the target size (about 1.1 kb) was specifically amplified. The DNA fragment was recovered from an agarose gel according to a conventional method, and pUC118 cleaved at a Hinc II site.
And transformed into competent cells, Escherichia coli JM109. The D
Two transformants (No. 5 and No. 7) having the plasmid containing the NA fragment were selected, and the base of the inserted DNA fragment was selected using an automatic base sequence analyzer 373A DNA sequencer (manufactured by Applied Biosystems) using a fluorescent dye. After confirming the sequence, it was confirmed that the sequence between SalI and BstPI of No. 5 strain was 77
No. 1 point mutation was confirmed in the sequence of the 0 base fragment.
One point mutation was confirmed in the sequence of the 360 base fragment between BstPI and SalI of the strain. Then, No. No. 5 BstPI-SalI fragment and No. 5 7 strains of BstPI
The remaining fragment excluding -SalI was purified by agarose electrophoresis, and a plasmid was constructed by connecting these fragments by a ligation reaction. When the nucleotide sequence of the DNA fragment inserted into this plasmid was confirmed, it completely matched the sequence described in the above-mentioned literature.

(5) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 2 (SSTR2) DNA As an expression vector in CHO (Chinese hamster ovary) cells, pAKKO-111 described in (2) above is used.
Was used. The human SSTR2cD obtained in the above (4)
5 μg of the plasmid having the NA fragment was digested with the restriction enzyme SalI.
After digestion with, a 1% agarose gel electrophoresis was performed to recover a 1.1 kb DNA fragment encoding human SSTR2. And the expression vector pAKKO-11
1 (5.5 kb) was digested with SalI, and
A cloning site for inserting the STR2 DNA fragment was created. The expression vector fragment and 1.1 kb DN
The A fragment was ligated using T4 DNA ligase, and the reaction mixture was introduced into E. coli JM109 by the calcium chloride method.
C01 was obtained. This transformant is designated as Escherichia coli JM109 / pAC01.

(6) CHO (dh) of human somatostatin receptor protein subtype 2 (SSTR2) DNA
Introduction and expression into fr ⁻ ) cells 1 × 10 ⁶ CHO (dhfr ⁻ ) cells were collected at a diameter of 8 cm.
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in a 12-medium medium, the human SSTR2 cDNA expression plasmid pAC0 obtained in the above (5) was added to the cells.
1, 10 μg of calcium phosphate method (Cell Phect Trans
fection Kit; Pharmacia). Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Furthermore, the selected cells were cloned from a single cell by the limiting dilution method, and a cell line highly expressing human SSTR2, SSTR2
-HS5-9 was selected.

(7) Cloning of Human Somatostatin Receptor Protein Subtype 3 (SSTR3) DNA Base sequence of known human SSTR3 cDNA [Molecular Endocrinol.
2136-2142, 1992].
Oligomers, S3-1 and S3-2, were synthesized. S3-
The sequence of 1 is 5'-GGTCGACCTCCAACCAT
GGACATGCTTCATC-3 '(SEQ ID NO: 5)
And the sequence of S3-2 is 5′-GGTCCGACTT.
TCCCCAGGCCCCTACAGGGTA-3 ′ (SEQ ID NO: 6). As a template, human chromosomal DNA
(Clontech, catalog number CL6550-1) was used. To 0.5 ng of the DNA, 25 pmol of each of the DNA oligomers was added, and a polymerase chain reaction was performed using 2.5 units of Pfu DNA polymerase (Stratagene). The reaction solution composition followed the instructions attached to Pfu DNA polymerase. The reaction conditions are 9
One cycle of 4 ° C. for 1 minute, 63 ° C. for 1 minute, and 75 ° C. for 2 minutes was repeated for 35 cycles. 1% reaction solution
Electrophoresis on an agarose gel revealed that a DNA fragment of the desired size (about 1.3 kb) was specifically amplified. The amino acid sequence predicted from the nucleotide sequence completely matched the sequence described in the literature.

(8) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 3 (SSTR3) DNA pAKKO-111 described in (2) above was used as an expression vector in CHO cells. Plasmid 5 μl containing the human SSTR3 DNA fragment obtained in (7) above
g was digested with the restriction enzyme SalI and subjected to 1% agarose gel electrophoresis to encode human SSTR3.
A 3 kb DNA fragment was recovered. Then, 1 μg of the expression vector pAKKO-111 (5.5 kb) was added to Sa.
After digestion with I1, a cloning site for inserting the human SSTR3 DNA fragment was created. The expression vector and a 1.3 kb DNA fragment were ligated using T4 DNA ligase, and the reaction mixture was subjected to a calcium chloride method using Escherichia coli JM.
109, and human / SSTR3
An expression plasmid pA1-11-SSTR3 in which the DNA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escherichia col
i) Displayed as JM109 / pA-1-11-SSTR3.

(9) CHO (dh) of human somatostatin receptor protein subtype 3 (SSTR3) DNA
Introduction and expression into fr ⁻ ) cells 1 × 10 ⁶ CHO (dhfr ⁻ ) cells were transferred to an
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in 12 medium, the cells were added to the human SSTR3 DNA expression plasmid pA-1 obtained in (5) above.
10 μg of 11-SSTR3 was introduced by the calcium phosphate method. Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Further, the selected cells were cloned from single cells by the limiting dilution method, and the somatostatin receptor protein expression ability of these cells was measured by the binding assay described in (3) above. Thus, a cell line with high somatostatin binding activity, SSTR3-15-
19 was selected.

(10) Cloning of Human Somatostatin Receptor Protein Subtype 4 (SSTR4) DNA Nucleotide Sequence of Known Human SSTR4 DNA [Proc. Of National Institute of Science, USA Acad.Sci., US
A), 90, 4196-4200, 1993], DNA oligomers S4-1 and S4-2 were synthesized. The sequence of S4-1 is 5'-GGCTCGAGT
CACATCATGCGCCCCCCTCG-3 ′ (SEQ ID NO: 7), and the sequence of S4-2 is 5′-GGGC
TCGAGCTCTCCAGAAGGTGGGTGG-
3 ′ (SEQ ID NO: 8). As a template, human chromosomal DNA (Clontech, Catalog No. CL6550)
-1) was used. To 0.5 ng of the DNA, 25 pmol of each of the DNA oligomers was added, and a polymerase chain reaction was performed using 2.5 units of Pfu DNA polymerase (Stratagene). The composition of the reaction solution is PfuD
The instructions attached to the NA polymerase were followed. The reaction conditions were 35 cycles, with 1 cycle at 94 ° C., 1 minute at 66 ° C., and 2 minutes at 75 ° C. When the reaction solution was subjected to 1% agarose gel electrophoresis, a DNA fragment of a target size (about 1.2 kb) was specifically amplified. When the nucleotide sequence of the DNA fragment was confirmed by the method described in the above (1), the amino acid sequence predicted from the nucleotide sequence was completely identical to the sequence described in the literature.

(11) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 4 (SSTR4) DNA pAKKO-111 described in (2) above was used as an expression vector in CHO cells. Plasmid 5 having the human SSTR4 DNA fragment obtained in (10) above
After digesting μg with the restriction enzyme Xhol, 1% agarose gel electrophoresis was performed to recover a 1.2 kb DNA fragment encoding human SSTR4. Then, 1 μg of the above-described expression vector pAKKO-111 (5.5 kb) was digested with SalI to prepare a cloning site for inserting a human SSTR4 DNA fragment. The expression vector fragment and the 1.2 kb DNA fragment were ligated using T4 DNA ligase, and the reaction mixture was introduced into Escherichia coli JM109 by the calcium chloride method.
An expression plasmid pA1-11-SSTR4 in which the STR4 DNA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escheric
hia coli) JM109 / pA-1-11-SSTR4.

(12) CHO (d) of human somatostatin receptor protein subtype 4 (SSTR4) DNA
Introduction and expression into hfr ⁻ ) cells CHO (dhfr ⁻ ) cells 1 × 10 ⁶ cells were collected at a diameter of 8 cm.
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in a 12-medium medium, the human SSTR4 DNA expression plasmid pA-1 obtained in the above (8) was added to the cells.
11-SSTR4, 10 μg was introduced by the calcium phosphate method. Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Further, the selected cells were cloned from single cells by the limiting dilution method, and the somatostatin receptor protein expression ability of these cells was measured by the binding assay described in (3) above. Thus, a cell line with high somatostatin binding activity, SSTR4-1-2,
Was selected.

(13) Cloning of Human Somatostatin Receptor Protein Subtype (SSTR5) DNA Base sequence of known human SSTR5 cDNA [Biochem.
Biophys. Res. Commun., 195, 844-852.
P. 1993], a DNA oligomer, S5-
1 and S5-2 were synthesized. The sequence of S5-1 is 5′-
GGTCGACCACCCATGGAGCCCCTGTTT
CCC-3 ′ (SEQ ID NO: 9), and the sequence of S5-2 is 5′-CCGTCGACACTCTCACAGCT.
TGCTGG-3 ′ (SEQ ID NO: 10). As a template, human chromosomal DNA (Clontech, catalog number CL6550-1) was used. 0.5 ng of the DNA
25 pmol of each of the DNA oligomers was added to
1. Pfu DNA polymerase (Stratagene Co., Ltd.)
The polymerase chain reaction was performed using 5 units. The reaction solution composition followed the instructions attached to Pfu DNA polymerase. The reaction conditions were 35 cycles, with 1 cycle at 94 ° C., 1 minute at 66 ° C., and 2 minutes at 75 ° C. When the reaction solution was subjected to electrophoresis on a 1% agarose gel, DNA of a target size (about 1.1 kb) was obtained.
The fragment was specifically amplified. When the nucleotide sequence of the DNA fragment was confirmed by the method described in the above (1), the amino acid sequence predicted from the nucleotide sequence was completely identical to the sequence described in the literature.

(14) Construction of Expression Plasmid for Human Somatostatin Receptor Protein Subtype 5 (SSTR5) DNA pAKKO-111 described in (2) above was used as an expression vector in CHO cells. Plasmid 5 having the human SSTR5 DNA fragment obtained in (13) above
After digesting μg with the restriction enzyme SalI, 1% agarose gel electrophoresis was performed to recover a 1.1 kb DNA fragment encoding human SSTR5. Then, 1 μg of the above-mentioned expression vector pAKKO-111 (5.5 kb) was digested with SalI to prepare a cloning site for inserting a human SSTR5 DNA fragment. The expression vector fragment and the 1.1 kb DNA fragment were ligated using T4 DNA ligase, and the reaction mixture was introduced into Escherichia coli JM109 by the calcium chloride method.
An expression plasmid pA1-11-SSTR5 in which the STR5 DNA fragment was inserted in the forward direction with respect to the promoter was obtained. This transformant was transformed into Escheric
hia coli) JM109 / pA-1-11-SSTR5.

(15) CHO (d) of human somatostatin receptor protein subtype 5 (SSTR5) DNA
Introduction and expression into hfr ⁻ ) cells CHO (dhfr ⁻ ) cells 1 × 10 ⁶ cells were collected at a diameter of 8 cm.
Ham F containing 10% fetal bovine serum using a Petri dish
After culturing for 24 hours in 12 medium, the human SSTR5 cDNA expression plasmid pA-
5-11 μS of 1-11-SSTR was introduced by the calcium phosphate method. Twenty-four hours after the introduction, the medium was changed to a DMEM medium containing 10% dialyzed fetal bovine serum, and cells forming colonies in this medium (that is, DHFR ⁺ cells) were selected. Further, the selected cells were cloned from single cells by the limiting dilution method, and the somatostatin receptor protein expression ability of these cells was measured by the binding assay described in (3) above. Thus, a cell line with high somatostatin binding activity, SSTR5-32-
4 was selected.

Experimental Example 1 Preparation of CHO Cell Membrane Fraction Containing Human Somatostatin Receptor Human somatostatin receptor expressing CHO cell line, SS
TR1-8-3, SSTR2-HS5-9, SSTR3
-15-19, SSTR4-1-2, or SSTR
5-32-4 (10 ⁹⁾ was centrifuged and resuspended in phosphate was added 5 mM EDTA buffered saline (PBS-EDTA). A cell homogenate buffer (10 mM NaHCO ₃ , 5 mM EDTA, pH =
7.5) was added, and the mixture was homogenized using a Polytron homogenizer. The supernatant obtained by centrifugation at 400 × g for 15 minutes was further centrifuged at 100,000 × g for 1 hour,
A precipitate of the membrane fraction was obtained. The precipitate was added to 2 ml of assay buffer (25 ml of Tris-HCl, 1 ml of EDTA, 0.1 ml
1% BSA (bovine serum albumin), 0.25 ml PM
SF, 1 μg / ml pepstatin, 20 μg / ml leupeptin, 10 μg / ml phosphoramidone, pH = 7.
5) and centrifuged at 100,000 × g for 1 hour. The membrane fraction collected as a precipitate was suspended again in 20 ml of assay buffer, aliquoted, stored at -80 ° C, and thawed at each use.

Experimental Example 2 Determination of ¹²⁵ I-Somatostatin Binding Inhibition Rate The membrane fraction prepared in Example 1 was diluted with an assay buffer to 3 μg / ml, and 173 μl was dispensed into tubes. 2 μl of compound dissolved in DMSO and 200 pM
Of radiolabeled somatostatin ( ¹²⁵ I-somatostatin: Amersham) was added simultaneously. To determine maximum binding, 2 μl of DMSO and 200 μl
A reaction solution was prepared by adding 25 μl of M ¹²⁵ I-somatostatin. Also, to measure non-specific binding,
2 μl of 100 μM somatostatin dissolved in DMSO
And a reaction mixture containing 25 μl of 200 pM ¹²⁵ I-somatostatin. After reacting at 25 ° C for 60 minutes, the reaction solution was subjected to suction filtration using a polyethylene imine-treated Whatman glass filter (GF-B). After filtration, it remained on the filter paper using a γ-counter.
The radioactivity of ¹²⁵ I-somatostatin was measured. Formula PBM = (B-NSB) / (B O -NSB) × 100 (PBM: Percent Maximum Binding, B: radioactivity when compound was added, B _O: maximum binding radioactivity, NS
B: non-specific binding radioactivity) was calculated to determine the binding rate (%) of each test substance. The binding ratio was determined by changing the concentration of the test substance, and the concentration (IC ₅₀ value) of the test substance that inhibited 50% binding was calculated from the Hill plot. The reactivity (IC ₅₀ value, μM) of each of the compounds shown below to each human somatostatin receptor, as determined by the above method, showed an activity of 10 μM or less for any of the human somatostatin receptors. Compounds from Example 1 to Example 46

[0133]

The compound (I) or a salt thereof of the present invention has an excellent somatostatin receptor agonistic action and low toxicity, and thus can be a safe preventive / therapeutic agent for diseases associated with this action. .

[0134]

[Sequence List] <110> Takeda Chemical Industries, Ltd. <120> Fused Ring Compounds, their Production Method and Agents <130> A98201 <150> JP 10-298941 <151> 1998-10-20 <160> 10 <210 > 1 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> <400> 1 GGTCGACCTC AGCTAGGATG TTCCCCAATG 30

<210> 2 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> <400> 2 GGTCGACCCG GGCTCAGAGC GTCGTGAT 28

<210> 3 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> <400> 3 GGTCGACACC ATGGACATGG CGGATGAG 28

<210> 4 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> <400> 4 GGTCGACAGT TCAGATACTG GTTTGG 26

<210> 5 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> <400> 5 GGTCGACCTC AACCATGGAC ATGCTTCATC 30

<210> 6 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> <400> 6 GGTCGACTTT CCCCAGGCCC CTACAGGTA 29

<210> 7 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> <400> 7 GGCTCGAGTC ACCATGAGCG CCCCCTCG 28

<210> 8 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> <400> 8 GGGCTCGAGC TCCTCAGAAG GTGGTGG 27

<210> 9 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> <400> 9 GGTCGACCAC CATGGAGCCC CTGTTCCC 28

<210> 10 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> <400> 10 CCGTCGACAC TCTCACAGCT TGCTGG 26

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 43/00 111 A61P 43/00 111 C07D 403/04 C07D 403/04

Claims (16)

[Claims] (1) Formula (I): [In the formula, ring B is a cyclic hydrocarbon group which may have a substituent; Z is a hydrogen atom or a cyclic group which may have a substituent; R ¹ has a hydrogen atom and a substituent An optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group; R ² represents an optionally substituted amino group; D represents a bond or a divalent group; E is a bond, -CO-,-CON (R ^a )-,-C
OO-,-N (R ^a ) CON (R ^b )-,-N (R ^a ) COO-,-N (R ^a ) SO ₂ -,-N (R ^a )-,-
O-, -S-, -SO- or -SO _2- (R ^a and R ^b independently represent a hydrogen atom or a hydrocarbon group which may have a substituent);
G represents a bond or a divalent group; L represents a bond or a divalent group; A represents a hydrogen atom or a substituent; X and Y each represent a hydrogen atom or an independent substituent; R
² indicates that a ring may be formed with ² and the atoms on the B ring. Or a salt thereof. (2) E is -CO-, -CON (R ^a )-, -COO-, -N (R ^a ) CON (R ^b )
-,-N (R ^a ) COO-,-N (R ^a ) SO ₂ -,-N (R ^a )-,-O-,-S-,-SO- or
The compound according to claim 1, wherein -SO _2- (R ^a and R ^b independently represent a hydrogen atom or a hydrocarbon group which may have a substituent). 3. L is (1) a bond or (2) i) a C _1-6 alkyl group, ii) halogeno-C _1-6 alkyl group, iii) phenyl group, iv) benzyl group, v) substituent Vi) a hydroxy group optionally having a substituent, and vii) a C _1-6 alkyl group, a phenyl group optionally having a substituent or a substituent. May have 1 to 5 substituents selected from a carbamoyl group or a thiocarbamoyl group, each of which may be substituted with an optionally substituted heterocyclic group;
The compound according to claim 1, which is a divalent hydrocarbon group which may be via O- or -S-. 4. The compound according to claim 1, wherein Z is a cyclic group which may have a substituent. 5. The compound according to claim 1, wherein D is a divalent group bonded to the ring via a carbon atom. 6. The compound according to claim 1, wherein the ring B is a benzene ring which may have a substituent and L is a C _1-6 alkylene group. 7. The compound according to claim 1, wherein G represents a divalent hydrocarbon group which may have a substituent, and ring B does not form a ring with R ² . 8. A is a hydrogen atom, B is a benzene ring, Z is a halogen-substituted phenyl group and R ¹ is (1) hydroxy, (2) phenyl, (3) C _1-6 alkyl-carbonyl or C _6-14 aryl-carbonyl, and (4) each substituted with a substituent selected from an amino group optionally substituted with C _1-6 alkyl-sulfonyl or C _6-14 aryl-sulfonyl. Good C _1-6 alkyl or C
The compound of claim 1 wherein a _7-14 aralkyl group. 9. X and Y independently represent a hydrogen atom, halogen, hydroxy, C _1-6 alkoxy, halogeno-C _1-6 alkoxy, C _7-14 aralkyloxy, benzoyl-C _1-6 alkoxy, hydroxy- C _1-6 alkoxy, C _1-6 alkoxy-carbonyl-C _1-6 alkoxy, C _3-14 cycloalkyl-C _1-6 alkoxy, imidazol-1-yl-C
_1-6 alkoxy, C _7-14 aralkyloxy-carbonyl-C _1-6 alkoxy or hydroxyphenyl-C _1-6 alkoxy; a benzene ring in which ring B may be substituted with C _1-6 alkoxy, or R ² A tetrahydroisoquinoline ring or an isoindoline ring formed by bonding with: Z is a halogen, formyl, halogeno-C _1-6 alkyl, C _1-6
C _6-14 aryl group optionally having 1 to 3 substituents selected from alkoxy, C _1-6 alkyl-carbonyl, oxo and pyrrolidinyl, C _3-10 cycloalkyl group, piperidyl group, thienyl Group, furyl group,
Pyridyl group, thiazolyl group, indanyl group or indolyl group; A is a hydrogen atom; D is a C _1-6 alkylene group; G may contain a bond or phenylene, and may be substituted with phenyl A C _1-6 alkylene group;
R ¹ represents a hydrogen atom, (1) halogen, (2) nitro, (3) C _1-6 alkyl optionally substituted with C _1-6 alkyl-carbonyl, benzoyloxycarbonyl and C _1-6 alkylsulfonyl. Selected amino, optionally having one or two substituents, (4) (i) hydroxy, C _1-6 alkyl-carbonyl, carboxy or C _1-6 alkoxy-
C _1-6 alkyl optionally substituted with carbonyl, (i
i) phenyl optionally substituted with hydroxy, (iii)
Benzoyl or (iv) hydroxy optionally substituted with mono- or di-C _1-6 alkylamino-carbonyl, (5) C _3-6 cycloalkyl, (6) hydroxy or halogeno-C _1-6 alkyl. Optionally substituted phenyl and (7) thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl, each of which may be substituted with a substituent selected from a C _1-6 alkyl group and a C _2-6 alkenyl group R ² represents (1) an unsubstituted amino group, (2) a C _6-14 aryl group or a C _7-14 aralkyl group;
Piperidyl group or (3) (i) benzyl, (ii) C _1-6 alkyl optionally substituted with amino or phenyl, (iii)
Mono- or di-C _1-6 alkyl-carbamoyl, or mono- or di-C _1-6 alkyl-thiocarbamoyl, (iv) C _1-6 alkoxy-carbonyl, (v) C _1-6 alkyl-sulfonyl, (vi) piperidylcarbonyl and (v
ii) C _1-6 optionally substituted with halogen or amino
An amino optionally having one or two substituents selected from alkyl-carbonyl; E is a bond, -CON
(R ^a )-, -N (R ^a ) CO-, -N (R ^a ) CON (R ^b )-
(R ^a and R ^b are each a hydrogen atom or a C _1-6 alkyl group); L is may have via -O-, and optionally substituted by C _1-6 alkyl C _1-6 alkylene group The compound according to claim 1, which is 10. X and Y each independently represent a hydrogen atom, a halogen,
Hydroxy or C _1-6 alkoxy; a ring B bonded to a benzene ring, R ² , a tetrahydroisoquinoline ring or an isoindoline ring; Z is a phenyl group optionally substituted with halogen, D is a C _1-6 alkylene group, G is a C _1-6 alkylene group; R ¹ is (1) hydroxy, (2) phenyl and (3)
C _1-6 alkyl - carbonyl or C _1-6 alkylsulfonyl-substituted C _1-6 substituted respectively with selected substituents from an amino optionally alkyl or C _7-14 aralkyl group nil; R ² is an unsubstituted amino group; is E -CONH-; claim L is C _1-6 alkylene group 1
A compound as described. (11) A prodrug of the compound of (1) or a salt thereof. 12. A compound of the formula (IIa): [In the formula, R ^2a may be protected, an amino group which may be substituted, and other symbols are as defined in claim 1. And a reactive derivative or a salt thereof represented by the formula (III): [The symbols in the formula are as defined in claim 1. By reacting with a compound of the formula (Ia-a): [The symbols in the formula are as defined above. Wherein the compound of the formula (Ia) or a salt thereof is optionally subjected to a deprotection reaction. [The symbols in the formula are as defined above. ] A method for producing a compound or a salt thereof. (13) A pharmaceutical composition comprising the compound according to (1) or a salt thereof. 14. The pharmaceutical composition according to claim 13, which is a somatostatin receptor function regulator. 15. The pharmaceutical composition according to claim 14, wherein the somatostatin receptor function regulator is a somatostatin receptor agonist. 16. The pharmaceutical composition according to claim 13, which is an agent for preventing or treating diabetes, obesity, diabetic complications or intractable diarrhea.