JPH0797371A - Benzodiazepin derivative having antiulcer activity - Google Patents

Abstract

PURPOSE:To obtain a compound having a histamine H2 receptor antagonism and a gastrin receptor antagonism and useful as an antiulcer agent having low relapse rate. CONSTITUTION:A compound of formula I [R<1> and R<3> are H, halogen, a lower alkyl, a lower alkoxy; R<2> is H or a lower alkyl; R<4> is single bond or CO; R<5> is NH, 1,4-piperadinyl, etc.; R<6> is a 1-15C alkylene, etc.; R<7> is 2-[(2-guanidino- thiazol-4-yl)methylthin]-ethylcarbamoyl, etc.], e.g. 1-methyl-3-(N'-(m-tolyl) ureido)5-(3-(2-(2-guanidino-1,3-thiazol-4-yl)methylthio (ethylcarbamoylmethylcarbamoylmethoxy)phenyl)-1,3-dihydro-2H-1,4- benzodiazepin-2-one. The compound of formula I is obtained by subjecting a compound of formula II (R<11> is OCH3, OCH2COOH, etc.) to coupling with a compound of formula III (R is NH2, etc.) by well-known acid-base reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzodiazepine derivative having antiulcer activity and a therapeutic agent for ulcer containing the same. More specifically, the present invention relates to a histamine H ₂ receptor antagonist having a low recurrence rate after treating ulcer.

[0002]

BACKGROUND OF THE INVENTION At present, the most popular drug for treating peptic ulcer is a histamine H ₂ receptor antagonist (H ₂ B). Typical H ₂ B includes cimetidine, ranitidine, roxatidine, famotidine and nizatidine. H
₂ B is an extremely excellent anti-ulcer agent, have the problem that a high recurrence rate after ulcer healing. Therefore, in the treatment of ulcers, it is an important issue to prevent the recurrence after healing as well as the reduction of pain and the disappearance of ulcers.

Various factors are believed to be involved in the recurrence of ulcers after H ₂ B treatment. For example, in clinical practice,
It is known that the gastrin level in the blood increases with the suppression of gastric acid secretion by taking H ₂ B.
It is thought to induce two causes of recurrence of ulcers. 1) Acid rebound phenomenon (blood gastrin is increased by long-term administration of anti-gastric acid secretory drug, resulting in increase of ECL cells and parietal cells to increase acid secretion), and 2) gastric mucosal defense ability Decrease (because of decreased production of prostaglandin, resulting in decreased prostaglandin in the mucosa). As a method for preventing the occurrence of these two major causes of recurrence of ulcer, blocking the action of gastrin at the receptor level is considered. Examples of such drugs having a gastrin blocker action include those described in JP-A-63-238069. However, at present, clinically applicable H ₂ B that utilizes gastrin receptor antagonism to reduce recurrence after ulcer treatment has not been provided yet.

[0004]

The present inventors have the effect of suppressing the gastric acid secretion of H ₂ B and are effective in treating ulcers, and at the same time,
As a result of intensive studies for the purpose of providing an anti-ulcer agent which also has the effect of minimizing recurrence after treatment by blocking the rise in gastrin in the blood accompanying the gastric acid secretion inhibitory action at the receptor level , Formula I:

[Chemical 6] [Wherein R ¹ and R ³ are each independently hydrogen, halogen, lower alkyl or lower alkyloxy; R ² is hydrogen or lower alkyl; R ⁴ is a single bond or —CO—;
R ⁵ is an aliphatic heterocycle or —NH—; R ⁶ is a C ₁ -C ₁₅ alkylene which may have a substituent or a C ₂ -C ₁₅ alkenylene which may have a substituent (however, The alkylene and the alkenylene may be O, within the groups themselves and / or between those groups and adjacent groups,
One or more groups selected from S and NH may be interposed); R ⁷ is any of the following groups:

[Chemical 7]

[Chemical 8]

[Chemical 9]

[Chemical 10] And a pharmaceutically acceptable salt thereof has a histamine H ₂ receptor antagonism and a gastrin receptor antagonism. Thus, the present invention was completed. did.

That is, the present invention provides compound I and its salts,
And an anti-ulcer drug containing them. Although all compounds of formula I are useful for the purposes of this invention, compounds of formula I having the definition of
Is preferred. R ¹ is hydrogen, compounds wherein R ² and R ³ are both lower alkyl; aliphatic heterocyclic ring in R ⁵ is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or dioxanyl, compounds which are particularly piperidinyl; in R ⁶ Alkylene is-
(CH ₂ CH ₂ R ⁸ ) p (CH ₂ ) qR ⁹ (CH ₂ ) r- (wherein R ⁸ and R ⁹ are each independently a single bond, O, S
Or NH; p is an integer of 0 to 5; q is an integer of 1 to 3; r is an integer of 0 to 2), in which R ⁸ is O, p is 2 or 3, and R ⁹ is a single bond. Is a compound of the formula; and alkenylene at R ⁶ is-(CH ₂ -C
^{(R 10) = CH) q-} ( where, R ¹⁰ is hydrogen, hydroxy, methyl, or halogen,; q is a group represented by from 1 represents an integer of 3) compound.

The present invention will be described in more detail below. The terms used in this specification are defined as follows. The lower alkyl means a C _{1 to} C ₆ linear or branched hydrocarbon group, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like.
The lower alkyloxy means a linear or branched alkyloxy having 1 to 6 carbon atoms, for example, methoxy,
Examples include ethoxy, propoxy, butoxy, pentyloxy and hexyloxy. Halogen means fluorine, chlorine, bromine and iodine. The aliphatic heterocycle means a 5- to 7-membered ring optionally containing one or more oxygen, sulfur or nitrogen atoms in the ring, and optionally condensed with a carbon ring or another heterocycle, Examples include pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or dioxanyl and the like. C
_1- C ₁₅ alkylene means alkylene having 1 to 15 carbon atoms, specifically, for example, methylene, ethylene, propylene, butylene, pentylene, amylene, hexylene,
Heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene and the like can be mentioned.

The alkenylene in the C ₂ -C ₁₅ alkenylene which may have a substituent means an alkenylene having 2 to 15 carbon atoms, and has at least one double bond in the chain. Examples of such alkenylene include vinylene,
1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1,3-butadienylene, 1-pentenylene, 2-pentenylene, 3-
Pentenylene, 4-pentenylene, 1,3-pentadienylene, 1,4-pentadienylene, 2,4-pentadienylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene,
1,3-hexadienylene, 1,4-hexadienylene,
1,5-hexadienylene, 2,4-hexadienylene,
2,5-hexadienylene, 3,4-hexadienylene,
3,5-hexadienylene, 1,3,5-hexatrienylene, 1-heptenylene, 2-heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-
Heptenylene, 1,3-heptadienylene, 1,4-heptadienylene, 1,5-heptadienylene, 1,6-heptadienylene, 2,4-heptadienylene, 2,5-heptadienylene, 2,6-heptadienylene, 3,5-heptadienylene, 3,6-heptadienylene, 4,6-heptadienylene, 1,3,5-heptatrienylene, 2,4,
6-heptatrienylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-
Octenylene, 6-octenylene, 7-octenylene,
1,3-octadienylene, 1,4-octadienylene,
1,5-octadienylene, 1,6-octadienylene,
1,7-octadienylene, 2,4-octadienylene,
2,5-octadienylene, 2,6-octadienylene,
2,7-octadienylene, 3,5-octadienylene,
3,6-octadienylene, 3,7-octadienylene,
4,6-octadienylene, 4,7-octadienylene,
5,7-octadienylene, 1,3,5-octatrienylene, 1,3,6-octatrienylene, 1,3,7-octatrienylene, 1,4,6-octatrienylene, 1,
4,7-octatrienylene, 1,5,7-octatrienylene, 2,4,6-octatrienylene, 2,4,7-octatrienylene, 2,5,7-octatrienylene,
1,3,5,7-octatetraenylene, 1-nonenylene, 2-nonenylene, 3-nonenylene, 4-nonenylene, 5-nonenylene, 6-nonenylene, 7-nonenylene, 8-nonenylene, 1,3-nonadienylene 1,4-
Nonadienylene, 1,5-nonadienylene, 1,6-nonadienylene, 1,7-nonadienylene, 1,8-nonadienylene, 2,4-nonadienylene, 2,5-nonadienylene, 2,6-nonadienylene, 2,7-nonadienylene,
2,8-nonadienylene, 3,5-nonadienylene, 3,
6-nonadienylene, 3,7-nonadienylene, 3,8-
Nonadienylene, 4,6-nonadienylene, 4,7-nonadienylene, 4,8-nonadienylene, 5,7-nonadienylene, 5,8-nonadienylene, 6,8-nonadienylene, 1,3,5-nonatrienylene, 1,3, 6-nonatrienylene, 1,3,7-nonatrienylene, 1,3,8-nonatrienylene, 1,4,6-nonatrienylene, 1,4,
7-nonatrienylene, 1,4,8-nonatrienylene,
1,5,7-Nonatrienylene, 1,5,8-nonatrienylene, 1,6,8-nonatrienylene, 2,4,6-nonatrienylene, 2,4,7-nonatrienylene, 2,4,8-
Nonatrienylene, 2,5,7-nonatrienylene, 2,
5,8-Nonatrienylene, 2,6,8-Nonatrienylene, 3,5,7-Nonatrienylene, 3,5,8-Nonatrienylene, 3,6,8-Nonatrienylene, 4,6,8-Nonatrienylene, 1,3, Examples thereof include 5,7-nonatetraenylene and 2,4,6,8-nonatetraenylene. The alkylene and alkenylene may be substituted with one or more substituents selected from halogen, lower alkyl and the like. A preferred substituent is halogen. Furthermore, if the hetero atom is interposed at any position in the alkylene or alkenylene chain, -CH ₂ - is -O -, -
S-, -NH- to -CH = or = CH- is -N =, =
Change to N-.

The present invention includes all salts which can be formed with the compounds of formula I. Generally, it may form a salt with an organic or inorganic acid or an organic or inorganic base, for example,
Examples of inorganic bases include alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and examples of organic bases include trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzylethylenediamine. , Ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, organic acids such as formic acid, acetic acid, trifluoroacetic acid, Examples thereof include oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. Examples of basic or acidic amino acids include arginine, lysine, ornithine, aspartic acid and glutamate. Minic acid or the like is used, but a salt with an inorganic acid or a salt with an inorganic base is particularly preferable. Also,
Without being limited to the above examples, the compound of the present invention is a pharmaceutically or pharmacologically acceptable derivative thereof, which is substantially non-toxic to warm-blooded animals and is converted into the compound of the present invention in vivo. All that is possible is the intent of the present invention.

Next, a typical method for producing compound I will be described. Compound I has formula II:

[Chemical 11] (In the formula, R ¹ , R ² and R ³ have the same meanings as defined above, and R ¹¹ represents —OCH ₃ , —OCH ₂ COOH or —OC.
_{^{H 2 -R 4 -R 5 -R 6}} -R 8 ( ^{wherein, R 4, R 5, R} 6 are as defined above, R ⁸ is -COOH or -SO ₂ NH ₂₎ compounds represented by or a The reactive derivative and the following formula:

[Chemical 12] 2- (2-guanidino) -1,3-thiazol-4-ylmethylthio) ethylamine or 1-methoxy-3-((2-guanidino-1,3-thiazol-4-yl) methylthio) propylimino

[Chemical 13] It can be obtained by appropriately coupling a 3- (3- (piperidinomethyl) phenoxynopropylamine or a reactive derivative thereof represented by the above formula by a known acid / base reaction. The intermediate compound II also has a selective antagonistic effect on the gastrin receptor.

Gastrin is cholecystokinin (CCK)
Together, it belongs to the so-called gastrin group gastrointestinal peptide hormone. The gastrin receptor is also present in the entire upper gastrointestinal tract, pancreas, liver, biliary system, etc., but is mainly present in fundus glandular wall cells and regulates gastric acid secretion. On the other hand, CCK receptors exist in peripheral areas such as the digestive tract (called CCK-A receptors) and central ones existing in the brain (CC
(Referred to as K-B receptor), and they are involved in the regulation of digestive tract motility, pancreatic juice secretion and central actions, appetite, etc., respectively. Therefore, antagonists to these receptors are used to treat the respective peptide hormone-related disorders in the gastrointestinal and central nervous system of various animals, including humans,
For example, anti-tumor drug, pancreatitis, gallbladder treatment, gallstone attack reduction, appetite improvement, irritable bowel syndrome
Syndrome) is considered to be useful for treatment. In addition, studies on receptors in the digestive tract and the central nervous system have revealed the importance of these hormones as bioactive substances (“Brain and peptide” metabolism, Vol. 18, No. 10, 33).
-44 (1981) and JP-A-63-238069).

These hormones have a close chemical relationship. That is, the gastrin and CCK peptides are C-terminal 5
Amino acid residue is common, gastrin receptor and CCK
High homology is observed with receptors, especially CCK-B receptors. For that purpose, a gastrin receptor antagonist and C
Cross-reactivity with CK-B receptor antagonists has been a problem. For example, gastrointestinal ulcer, Zolinger-Ellison syndrome,
Although gastrin receptor antagonists are considered to be useful for treating gastrin-related diseases such as sinusoidal C-cell hyperplasia and reduced gastrin activity, central side effects may occur due to cross-reactivity with CCK-B receptors. , It was difficult to achieve the therapeutic purpose sufficiently. As a matter of course, in the treatment of gastrin-related diseases, it is desirable to use a substance that specifically antagonizes the gastrin receptor in order to avoid central side effects. For example, the usefulness of gastrin receptor-specific antagonists in the treatment of gastric ulcers has been pointed out (metabolism 29 /
Seven, 1992 etc.). An anti-gastric ulcer agent having a gastrin receptor antagonistic activity has already been reported (Japanese Patent Laid-Open No. 63-2).
As described above, a substance that selectively acts only on the gastrin receptor due to its high homology with the CCK receptor has not yet been known.

Therefore, the compound II is also useful as a therapeutic agent for gastrin-related diseases such as gastric ulcer without central side effects. The compound II can be obtained, for example, from JP-A-63-2.
According to the method described in Japanese Patent No. 38069, it can be synthesized from a known compound represented by the following formula by an appropriately known method.

[Chemical 14] Compounds of formula II in which R ¹ is hydrogen, R ² is methyl, R ³ is methyl (especially m-position) and R ¹¹ is —OCH ₂ COOCH ₃ are particularly preferred. Compound I or compound II is appropriately converted into a pharmaceutically acceptable salt by a known method. Examples of the acid addition salt include hydrochloric acid, hydrobromic acid,
Inorganic acid salts such as sulfuric acid, sulfamic acid, phosphoric acid, etc., organic acid salts such as nitric acid or acetic acid, citric acid, lactic acid, methanesulfonic acid, propionic acid, tartaric acid, maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid, etc. Is exemplified.

The usefulness of the benzodiazepine derivative of the present invention as an anti-ulcer agent will be described. We use H ₂
Various studies were conducted to develop a method for preventing recurrence of ulcer after B healing. As a result, the new finding that (1) acid rebound phenomenon and (2) decrease in gastric mucosal defense function, which cause ulcer recurrence, can be prevented by gastrin receptor antagonism, is a typical H ₂ B famotidine. And a gastrin receptor antagonist (see Experimental Example 3).
This finding naturally suggests that the gastrin receptor antagonism is effective in preventing recurrence of ulcer after H ₂ B healing.

Next, the present inventors have investigated various compounds for histamine H ₂ receptor antagonistic action and gastrin receptor antagonistic action, and the benzodiazepine derivative of the present invention has these two types of actions. It was found out (see Experimental Examples 1 and 2 described later). The above results indicate that the benzodiazepine derivative of the present invention has a low ulcer recurrence rate of H ₂
It is shown to be useful as B. When the benzodiazepine derivative of the present invention is used for treating ulcer, the derivative can be administered orally or parenterally. In the case of oral administration, the compound of the present invention is either a usual preparation, for example, a solid preparation such as tablet, powder, granule, capsule, etc .; water preparation; oily suspension; or liquid preparation such as syrup or elixir. It can also be used as a dosage form. When administered parenterally, the compound of the present invention can be used as an aqueous or oily suspension injection. In its preparation, any of the conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents and the like can be used, and other additives such as preservatives and stabilizers. It may contain an agent or the like. The dose of the compound of the present invention varies depending on the administration method, age, weight, condition of patient and type of disease, but is usually about 20 to 300 per day for an adult.
mg, preferably about 50-100 mg, may be administered in 1 to 5 divided doses. Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. In addition, in the following examples, the group of the R ⁷ portion of the compound (I) is represented by the following abbreviations.

FAA:

[Chemical 15] FAB:

[Chemical 16] TZA

[Chemical 17] TZB

[Chemical 18]

Reference Example 1 Preparation of compound IV-9

[Chemical 19] 1) Ethyl m-formylphenoxyacetate (IV-1) To a solution of m-hydroxybenzaldehyde (32.87 g, 0.296 mol) in tetrahydrofuran (100 ml) and dimethylformamide (100 ml) at 0 ° C. under nitrogen atmosphere, 60%. Sodium hydride was added.
The mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (259 g) (hexane: ethyl acetate; 10: 1-4: 1) to give 51.76 g of acetate.
(92.3%) was obtained. The eluate was used in the next step without further purification.

2) Ethyl 3- (2- (N-methyl) amino) phenylhydroxymethyl) phenoxyacetate (IV
-2) In a nitrogen atmosphere, add 1M boron trichloride solution (180 ml),
N-methylaniline (15.9 g, 0.14 while cooling with ice)
A solution of 8 mol) in benzene (90 ml) was added dropwise. The mixture was heated to reflux for 3 hours (hydrogen chloride gas evolved). The solution was cooled to 0 ° C., and the aldehyde (IV-
1; 30 g, 0.144 mol) and triethylamine (35
A solution of g, 0.346 mol) in benzene (90 ml) was mixed. The mixture was stirred at room temperature for 1 hour. Ice-cooled dilute hydrochloric acid was added. The aqueous layer was separated, and the organic layer was extracted with diluted hydrochloric acid.
The aqueous layers were combined, made basic with 10% sodium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ether, and 35.13 g (77.3) of alcohol compound (IV-2) was crystallized.
%) Was obtained. mp = 94-95 ° C

3) 2- (N- (chloroacetyl) -N-
Methylamino) -3 ′-(carboethoxymethoxy) benzophenone (IV-3) At 0 ° C. under a nitrogen atmosphere, chloroacetyl chloride (7.
A solution of 56 g, 66.9 mmol) in dichloromethane (20 ml) was added with amino alcohol (IV-2; 20.85 g, 6).
A solution of 6.11 mmol) and pyridine (5.30 g) in dichloromethane (70 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. Ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual acetone (20
To the 0 ml) solution, Jone's reagent was added dropwise at 0 ° C. The mixture was stirred for 1 hour and water was added. The mixture was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The residue was crystallized from ether to obtain 24.17 g (93.8%) of a ketone body (IV-3). mp
= 130-131 ° C

4) 1-Methyl-5- (3- (carboethoxymethyloxy) phenyl) -1,3-dihydro-2
H-1,4-benzodiazepin-2-one (IV-4) Benzophenone (IV-3; 23.0 obtained in 3) above.
g, 59.0 mmol), sodium iodide (9.0 g, 6
0.0 mmol), and ammonium carbonate (60 g, 0.
A suspension of 624 mmol) in acetonitrile (650 ml) was stirred at room temperature for 3 days. The insoluble material was distilled off under reduced pressure.
The residue was dissolved in ethyl acetate, the solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (220 g) (hexane: ethyl acetate; 1: 1) to give benzophenone 2
0.35 g (97.9%) was obtained.

5) 1-methyl-5- (3- (carboxymethoxy) phenyl) -1,3-dihydro-2H-1,
4-Benzodiazepin-2-one (IV-5) The ester (IV-4; 33.95 g, 9) obtained in 4) above.
4.4% in a solution of 6.3 mmol) in methanol (100 ml)
100 ml of aqueous sodium hydroxide solution was added. The solution was left at room temperature for 20 hours. Water was added, the mixture washed with ether, acidified with 10% hydrochloric acid and continuously extracted with chloroform for 30 hours. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 31.5 g of crude carboxylic acid (99.5
%) Was obtained. The product was used in the next step without further purification.

6) 1-Methyl-3-methoxyimino-5
-(3- (carbomethoxymethoxy) phenyl) -1,
3-dihydro-2H-1,4-benzodiazepine-2-
On (IV-6) The crude carboxylic acid obtained in the above 5) (IV-5; 22.5 g,
To a solution of 80.2 mmol) in dimethylformamide (400 ml) was added potassium t-butoxide (22.5 g, 0.201 mol) at -20 ° C under a nitrogen atmosphere. The mixture was stirred at -20 ° C for 20 minutes, a solution of isoamylnitrile (9.8 g, 83.7 mmol) in dimethylformamide (30 ml) was added at -20 ° C, and the mixture was stirred for 1 hour. A solution of dimethylsulfate (20 ml, 0.211 mol) in dimethylformamide (30 ml) was added at -20 ° C. Mixture-2
The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 15 hours. Ethyl acetate was added, the solution was washed with water, 5% sodium carbonate, 5% hydrochloric acid solution, and water, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The residue was flash chromatographed on silica gel (250 g) (ethyl acetate: hexane; 1 :).
1 and 3: 2) to give a 4: 1 mixture of methoxime (20 g) isomers. Recrystallization from methanol: ether gave 10.1 g (32.9%) of crystals of the major isomer. mp = 97-99 ° C. The mother liquor was purified by flash chromatography on silica gel (130 g) (ethyl acetate: hexane (1: 1 → 3: 2) to give a product isomer ratio of about 3: 2 7.44 g (2).
4.2%, yield 57.1%) was obtained.

7) 1-Methyl-3-amino-5- (3-
Carbomethoxymethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV
-7) The methoxime obtained in 6) above (IV-6; 20.8 g, 5
A solution of 4.6 mmol) and 5% ruthenium-carbon (5.3 g) in methanol (150 ml) was hydrogenated with hydrogen (17 kg / cm ² ) at 65 ° C. for 20 hours. Final pressure is 9kg /
It was cm ² . The catalyst was filtered and the filtrate was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate and extracted with 5% aqueous hydrochloric acid. The extract was washed with ethyl acetate and made basic with aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used in the next step without purification.

8) 1-Methyl-3- (N '-(m-tolyl) ureido) 5- (3-carbomethoxymethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2- On (IV-8) Crude amine (IV-7; 13.5 g, 38.
2 mmol), triethylamine (7 ml) and m-tolyl isocyanate (4.96 g, 37.3 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 20 hours. Ethyl acetate was added, the mixture was washed with water, 50% aqueous hydrochloric acid, and aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 10.8 g of the desired substance. The mother liquor was subjected to flash chromatography on silica gel (100 g) (ethyl acetate: hexane; 1: 1 and ethyl acetate),
Crystallization from ether gave 2.65 g of the desired compound (yield 7
4.2%). mp = 227-231 ° C

9) 1-Methyl-3- (N '-(m-tolyl) ureido) 5- (3-carboxymethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-9) Ether (IV-8; 11.78 g, 2) obtained in the above 8)
4.2 mmol of a methanol suspension and 0.5 N sodium hydroxide (120 ml) were heated at 60 ° C. for 30 minutes, and the solution was left at room temperature for 2 hours. Water was added, the solution was washed with chloroform, concentrated to 500 ml, acidified with dilute hydrochloric acid and extracted with chloroform-methanol (4: 1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from ether to give the desired carboxylic acid 10.89 g.
(95.2%) was obtained. mp = 154-157 ° C. IRνmax (KBr): 3370, 1734,164
4,1600,1552 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.31 (3H,
s), 3.49 (3H, s), 4.65 (2H, s),
5.54 (1H, s), 6.83 (1H, m), 7.0
5-7.45 (10H, m), 7.64 (1H, m) Elemental analysis _{(C 26 H 24 N 4 O} 5 0.7H 2 O as) Found: C, 64.36; H, 5 . 48; N, 11.8.
0 Calculated value: C, 64.37; H, 5.28; N, 11.5
5

Reference Example 2 1-Methyl-3- (N '-(m-tolyl) ureido)-
5- (3-anisyl) -1,3-dihydro-2H-1,
Preparation of 4-benzodiazepin-2-one (IV-96)

[Chemical 20]

[Chemical formula 46] 1) 2-N-methylanilino-3-anisylcarbinol (IV-191) In accordance with the production method of the compound (IV-2) described in Reference Example 1, m
-Synthesized from anisaldehyde. Yield 84.7%. mp = 84 ° C. IRνmax (nujol): 3320, 3150, 161
3,1606,1583,1500 cm ^-1 . NMR (CDCl ₃ ) δ: 2.78 (3H, s), 3.
79 (3H, s), 5.81 (1H, s), 6.68
(2H, m), 6.84 (1H, m), 6.96 (3
H, m), 7.25 (2H, m) Elemental analysis (as C ₁₅ H ₁₇ NO ₂ ) Found: C, 73.97; H, 7.14; N, 5.92 Calculated: C, 74 .05; H, 7.04; N, 5.76 2) 2- (N-methyl-N-chloroacetylamino)-
3'-Methoxybenzophenone (IV-92) Compound IV-191 was prepared in the same manner as in the production of compound IV-3.
Was converted to IV-192. Yield 54.9%. NMR (CDCl ₃ ) δ: 3.09 (3H, s), 3.
86 (3H, s), 3.92 (2H, m), 7.01-
7.7 (8H, m) 3) 1-methyl-5- (m-anisyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (I
V-193) Compound IV-192 was prepared in the same manner as in the production of compound IV-4.
Was converted to IV-193. Yield 87.0%. NMR (CDCl ₃ ) δ: 3.41 (3H, s), 3.
78 (1H, d, J = 10.8Hz), 3.84 (3
H, s), 4.81 (1H, d, J = 10.8 Hz),
6.95-7.4 (7H, m), 7.55 (1H, m) 4) 1-methyl-3- (hydroxyimino) -5- (3
-Anisyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-194) Compound IV-193 in a similar manner to the preparation of compound IV-6.
Was converted to compound 1V-194. Yield 91.8%. NMR (CDCl ₃ ) δ: 3.47 (3H, s), 3.
85 (3H, s), 7.05 to 7.5 (7H, m),
7.57 (1H, m) 5) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3-anisyl) -1,3-dihydro-2H
-1,4-benzodiazepin-2-one (IV-19
6) Compound IV-194 in the same manner as in the production of compound IV-7.
Was converted to IV-196. Yield 69.6% (from oxime). mp = 216-217 ° C. IRνmax (nujol): 3300, 1677, 164
2,1565 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 3.48 (3H, s), 3.83 (3H, s),
6.85 (1H, m), 7.0-7.5 (10H,
m), 7.61 (1H, m) Elemental analysis (as C ₂₅ H ₂₄ N ₄ O ₃ ) Found: C, 68.95; H, 5.67; N, 12.6.
9

Reference Example 3

[Chemical 21] 1) 2- (3- (3-piperidinomethyl) phenoxy)
Propylcarbamoyl) ethylamine (III-34)
Preparation of N-butoxycarbonyl-β-alanine (1.89)
g), a mixture of 3- (3- (piperidinomethyl) phenoxy) propylamine (2.32 g), dicyclohexylcarbodiimide (2.06 g) and 1-hydroxybenzotriazole (0.135 g) in tetrahydrofuran is stirred at room temperature for 3 hours. . The crystals formed are filtered and washed with tetrahydrofuran. The filtrate is concentrated under reduced pressure and the residue obtained is dissolved in ethyl acetate. The insoluble matter is filtered off and the filtrate is concentrated. The residue was chromatographed [A: 150 g of silica gel, methylene chloride / methanol (9: 1 → 4:
1); then B: 150 g of silica gel, ethyl acetate / methanol (9: 1)]. NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.
44 (2H, m), 1.59 (4H, m), 1.99
(2H, m), 2.40 (4H, m), 3.42 (4
H, m), 4.05 (2H, t, J = 6.0 Hz),
6.78 (1H, m), 6.92 (2H, s), 7.2
1 (1H, m) IRvmax (film): 3320, 1692, 16
46, 1527, 1169 cm ^-1

2) Production of compound (III-31, 32, 33, 35) According to the reaction of 1), the corresponding N-BOC amino acid is coupled and then deprotected to synthesize. The physical constants of the protected form of each compound are shown below. a) N-BOC- (2- ( 2- Kuanijino 3-thiazol-4-ylmethylthio) ethylcarbamoyl methylamine IRνmax (CHCl _3): 3430,1675,16
20,1540 cm ^-1 NMR (CDCl ₃ + CD ₃ OD)
δ: 1.46 (9H, s), 2.68 (2H, t, J =
7 Hz), 3.41 (2H, t, J = 7 Hz), 3.6
6 (2H, s), 3.73 (2H, s), 6.47 (1
H, s) Elemental analysis _{(C 14 H 24 N 6 S} 2 O 3 H 2 O as) Found: C, 41.73; H, 6.18 : N, 20.7
9; S, 15.72 calculated: C, 41.36; H, 6.45; N, 20.6
7; S, 15.77b) N-BOC-2- (2- (2-
Guanidino-1,3-thiazolyl-4-ylmethylthio) ethylcarbamoyl) ethylamine mp = 124-125 ° C. IRνmax (KBr): 3380,3115,170
0, 1658, 1608, 1550, 1514 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.44 (9H,
s), 1.76 (2H, qui, J = 7Hz), 2.1
7 (2H, t, J = 7Hz), 2.69 (2H, t, J
= 7 Hz), 3.10 (2H, t, J = 7 Hz), 3.
36 (2H, t, J = 6Hz), 3.65 (2H,
s), 6.45 (1 H, s) Elemental analysis (as C ₁₆ H ₂₈ N ₆ O ₃ S) Found: C, 46.02; H, 6.65; N, 19.9.
7; S, 15.40 calculated: C, 46.13; H, 6.78; N, 20.1
7; S, 15.40 c) N-BOC-3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethylamine IRvmax (film): 3300, 1705, 16
62,1528 cm ^-1 NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.
45 (2H, m), 1.57 (4H, m), 2.00
(2H, m), 2.40 (4H, m), 3.46 (2
H, s), 3.51 (2H, t, J = 7 Hz), 3.7
7 (2H, d, J = 6Hz), 4.08 (2H, t, J
= 6 Hz), 6.75-7.0 (2H), 7.15-
7.25 (2H) Elemental analysis (C ₂₂ H ₃₅ N ₃ as O ₄₎ Found: C, 64.87; H, 8.71 ; N, 10.0
6 Calculated value: C, 65.16; H, 8.70; N, 10.3
6

D) N-BOC-3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) propylamine IRνmax (CHCl ₃ ): 3465,3325,1
702, 1664, 1603, 1588, 1490 cm
^-1 NMR (CDCl ₃ ) δ: 1.438 (9H, s),
1.59 (4H, m), 1.81 (2H, qui.J =
7Hz), 2.01 (2H, qui.J = 6Hz),
2.22 (2H, t, J = 7Hz), 2.40 (4H,
m), 3.17 (2H, q, J = 7Hz), 3.41-
3.53 (4H), 4.80 (1H, m), 6.42
(1H, br.s), 6.78 (1H, m), 6.86
-6.97 (2H), 7.22 (1H, t, J = 8H
z)

Example 1 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (2- (2-guanidino-1,3-thiazol-4-yl) methylthio) ethylcarbamoylmethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1, 4-benzodiazepin-2-one (IV-21), 1-methyl-3-
(N '-(m-tolyl) ureido) -5- (3- (2-
(2- (2-guanidino-1,3-thiazol-4-yl) methylthio) ethylcarbamoylethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-22) and 1-methyl-3- (N ′-(m-tolyl) ureido) -5- (3- (3- (3- (2-guanidino-1) ，
3-thiazol-4-yl) methylthio) ethylcarbamoylpropylcarbamoylmethoxy) phenyl)-
1,3-Dihydro-2H-1,4-benzodiazepine-
Preparation of 2-one (IV-23)

[Chemical formula 22] The coupling between the carboxylic acid (IV-9) and the amine (III-30) was performed by the following method. Carboxylic acid (IV
-9) (236 mg, 0.499 mmol), 3- (2- (2
-Guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) methylamine dihydrochloride (2
17 mg, 0.601 mmol), N, N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (140
mg, 0.730 mmol) and 1-hydroxybenzotriazole monohydrate (30 mg, 0.197 mmol) in dimethylformamide (7 ml) and triethylamine (0.
The solution in 25 ml) is stirred at room temperature overnight and concentrated at 1 mm Hg. Water is added and the solids are collected by filtration, washed with water, dried and subjected to flash chromatography (silica gel, 50 g; chloroform / methanol (9: 1)) in chloroform / methanol (9: 1). The eluate is solidified in methanol / chloroform and dried to give the coupled product IV-21 (200 mg, 53.9%). Carboxylic acid (IV-9) and amine (III-31) and carboxylic acid (IV-9) and amine (III-32) were coupled in the same manner as above to give the corresponding product (IV-22). And (IV-23) yield 8
Obtained at 7.0% and 57.7%.

Compound IV-21 mp = 145-147 ° C. IRνmax (KBr): 3360,1656,161
0,1541 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 2.65 (2H, t, J = 7Hz), 3.38.
(2H, t, J = 7Hz), 3.49 (3H, s),
3.62 (2H, s), 3.94 (2H, s), 4.5
7 (2H, s), 5.48 (1H, s), 6.45 (1
H, s), 6.83 (1H, m), 7.05-7.46.
(10H, m), 7.63 (1H, m) Elemental analysis (as C ₃₈ H ₃₈ N ₁₀ O ₅ S ₂ 1.2H ₂ O) Found: C, 55.06; H, 5.36; N , 18.
20; S, 8.14 Calculated: C, 54.99; H, 5.33; N, 18.
32; S, 8.39 Compound IV-22 mp = 141-143 ° C IRνmax (KBr): 3340, 1645, 161
2,1545 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.31 (3
H, s), 2.43 (2H, t, J = 6Hz), 2.5
6 (2H, t, J = 7Hz), 3.32 (2H, t, J
= 7 Hz), 3.49 (5H, s), 3.57 (2H,
t, J = 6 Hz), 4.50 (2H, s), 5.46
(1H, s), 6.42 (1H, s), 6.85 (1
H, m), 7.02-7.46 (14H, m), 7.6.
3 (1H, m) Elemental analysis (C ₃₆ H ₄₅ N ₁₀ O ₅ S ₂ H ₂ O) Found: C, 55.72; H, 5.60; N, 18.
16; S, 8.04 calculated: C, 55.80; H, 5.46; N, 18.
08; S, 8.28 Compound IV-23 IRvmax (KBr): 3360, 1645, 161.
0,1543 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.84 (2H,
qui, J = 7 Hz), 2.18 (2H, t, J = 7H)
z), 2.30 (3H, s), 2.63 (2H, t, J
= 7 Hz), 2.33 (2H, t, J = 6 Hz), 3.
34 (2H, t, J = 6Hz), 3.48 (3H,
s), 3.60 (2H, s), 4.51 (2H, s),
5.48 (1H, s), 6.44 (1H, s), 6.8
3 (1H, m), 7.07-7.47 (10H, m),
7.63 (1 H, m) Elemental analysis (as C ₃₇ H ₄₂ N ₁₀ O ₅ S ₂ O.3H ₂ O) Found: C, 57.37; H, 5.55; N, 17.
83; S, 8.10 Calculated: C, 57.24; H, 5.53; N, 18.
04; S, 8.26

Example 2 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV
-24), 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (3- (piperidinomethyl) phenoxy) propylcarbamoylethylcarbamoylmethoxy) phenyl) -1,3 -Dihydro-2H-
1,4-benzodiazepin-2-one (IV-25),
1-methyl-3- (N '-(m-tolyl) ureido)-
5- (3- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylpropylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-26) and 1- Methyl-3- (N '-(m-tolyl) ureido) -5-
(3- (5- (3- (piperidinomethyl) phenoxy))
Propylcarbamoylpentylcarbamoylmethoxy)
Preparation of Phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-27)

[Chemical formula 23]

Triethylamine (0.4 ml) was converted to carboxylic acid IV-9 (236 mg, 0.499 mmol), N, N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (145 mg), amine III-33 dihydrochloride ( Thirty
A mixture of 0 mg, 0.756 mmol) and 1-hydroxypentazriazole monohydrate (30 mg) in dimerulformamide (7 ml) was added dropwise under ice cooling. The mixture is stirred at room temperature overnight, concentrated at 1 mm Hg, 40 ° C. Add water and collect solids by filtration and chromatograph (silica gel, 2
5 g; Purification by chloroform / methanol (5: 1) to give solid IV-24, 186 mg (48.9%). In the same manner as above, acid IV-9 and amine III-3
4, III-35, III-36 by coupling with the corresponding compounds IV-25, IV-26 and IV
Yields of -27 60.9%, 60.9% and 62.2%
Got with.

Compound IV-24 amorphous powder IRνmax (KBr): 3320,1670,164
3,1610,1600,1565 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
62 (4H, m), 1.96 (2H, qui., J = 6)
Hz), 2.27 (3H, s), 2.47 (4H,
m), 3.42 (3H, s), 3.46 (2H, q, J
= 6 Hz), 3.52 (2H, m), 4.00 (4H,
m), 4.49 (2H, s), 5.52 (1H, d, J
= 8 Hz), 6.72-6.92 (4H), 7.05-
7.40 (11H, m), 7.50-7.63 (2H,
m), 7.67 (1 H, s) Elemental analysis (as C ₄₃ H ₄₉ N ₇ O ₆ 1.2 H ₂ O) Found: C, 66.01; H, 6.66; N, 12.
75 Calculated: C, 66.09; H, 6.63; N, 12.
55

Compound IV-25 amorphous powder IRνmax (KBr): 3320,1670,164
2, 1611, 1600, 1555 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
61 (4H, m), 1.87 (2H, m), 2.28
(3H, s), 2.45 (6H, m), 3.32 (2
H, q, J = 6 Hz), 3.43 (3H, s), 3.5
0 (2H, s), 3.63 (2H, q, J = 6Hz),
3.95 (2H, t, J = 6Hz), 4.46 (2H,
s), 5.52 (1H, d, J = 8Hz), 6.56
(1H, t, J = 5Hz), 6.72 (1H, m),
6.80-7.40 (16H, m), 7.55 (1H,
m), 7.60 (1 H, s) Elemental analysis (as C ₄₄ H ₅₁ N ₇ O ₆ H ₂ O) Found: C, 66.48; H, 6.77; N, 12.
60 Calcd: C, 66.73; H, 6.75; N, 12.
38

Compound IV-26 amorphous powder IR vmax (KBr): 3400, 3320, 167
1,1642, 1610, 1554 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
61 (4H, m), 1.75-2.05 (4H), 2.
22 (2H, t, J = 7Hz), 2.28 (3H,
s), 2.55 (4H, m), 3.38 (4H, m),
3.44 (3H, s), 3.50 (2H, s), 3.9
9 (2H, t, J = 6Hz), 4.48 (2H, s),
5.52 (1H, d, J = 8Hz), 6.63 (1H,
m), 6.75 (1H, m), 6.79-7.42 (1
6H, m), 7.57 (1H, m), 7.70 (1H,
s) Elemental analysis (as C ₄₅ H ₅₃ N ₇ O ₆ H ₂ O) Found: C, 67.13; H, 6.69; N, 12.
30 Calcd: C, 67.06; H, 6.88; N, 12.
17

Compound IV-27 amorphous powder (from methanol-water) IRvmax (KBr): 3300,1670,164
0, 1608, 1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.20-1.72 (12
H), 1.91 (2H, qui.J = 6.0 Hz),
2.16 (2H, t, J = 7.2Hz), 2.28 (3
H, s), 2.43 (4H, br.s), 3.31 (2
H, q, J = 6.6 Hz), 3.42 (2H, t, J =
6.0 Hz), 3.45 (3 H, s), 3.49 (2
H, s), 4.01 (2H, t, J = 6.1Hz),
4.49 (2H, s), 5.54 (1H, d, J = 7.
8 Hz), 6.23 (1H, br.s), 6.62-
7.44 (17H, m), 7.63 (1H, s) Elemental analysis _{(C 47 H 57 O 6 N} 7 0.8H 2 O as) Found: C, 67.82; H, 7.04 ; N, 11.
93 Calcd: C, 67.98; H, 7.11; N, 11.
81

Example 3 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (3- (3-
Preparation of (piperidinomethyl) phenoxy) propylcarbamoyl) prop-3-enylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-28)

[Chemical formula 24] (1) 4-azido-but-2-enoic acid (compound III-
47) 4-Bromo-but-2-enoic acid (825 mg, 5.0 mmo
l) and sodium azide (1.0 g, 15.3 mmol)
The mixture in HMPA (5 ml) is stirred at room temperature for 2 hours.
Ethyl acetate is added, the mixture is washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. (2) 3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) prop-3-enylazide (Compound III-48) 3- (3- (piperidinomethyl) phenoxy) propylamine (Compound III-28) (1.0 g) And the product (III-47) of the above (1) (0.60 g) were coupled in the same manner as in Example 1 to give compound III
-48 (1.063 g, 73.9%) is obtained. (3) 3- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) prop-3-enylamine (Compound III-49) The azide (III-48, 1.30) produced in the above (2).
g, 3.64 mM) and triphenylphosphine (1.
A solution of 0 g, 3.82 mM) in tetrahydrofuran (20 ml) is stirred at room temperature overnight. Water (3 ml) is added and the solution is heated at reflux for 30 minutes. The volatile substances are distilled off under reduced pressure, the residue is dissolved in ethyl acetate and the solution is extracted with dilute hydrochloric acid. The extract is washed with ethyl acetate and extracted with chloroform. The solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 810 mg (70.1%) of a solid. (4) Carboxylic acid (IV-9) (473 mg, 1.001)
mmol) and amine (III-49) (360 mg, 1.08)
6 mmol) was coupled in the same manner as in Example 2 to obtain 444 mg (56.5%) of compound (IV-28).

Compound IV-28 IRvmax (KBr): 3380, 3310, 167
0,1641, 1610 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
63 (4H, m), 1.91 (2H, quint, J =
6.1 Hz), 2.24 (3H, s), 2.48 (4
H, br. s), 3.43 (5H, s), 3.53 (2
H, s), 3.88-4.12 (4H, m), 4.51.
(2H, s), 5.52 (1H, d, J = 7.8H
z), 5.90 (1H, d, J = 15.6 Hz), 6.
65-7.46 (19H, m), 7.56 (1H,
m), 7.84 (1H, s ) Elemental analysis _{(C 45 H 51 N 7 O} 6 1.5H 2 O as) Found: C, 66.31; H, 6.61 ; N, 12.
23 Calcd: C, 66.48; H, 6.70; N, 12.
06

Example 4 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (3- (3-
(Piperidinomethyl) phenoxy) propylcarbamoyl) -2-chloro-prop-3-enylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4
-Preparation of benzodiazepin-2-one (IV-33)

[Chemical 25] 1) N-Boc-propargylamine (IV-29) A solution of di-t-butyl dicarbonate (7.0 g, 32 mM) in acetone (6 ml) was mixed with propargylamine (1.65).
3 g, 30 mM) acetone (8 ml) and water (1 m
l) The solution was added dropwise under ice cooling. The solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was chromatographed using silica gel (115 g), hexane: ethyl acetate (0-35%) to give 4.118 g of colorless solid (yield 88.4).
%) Was obtained.

2) 4- (Boc-amino) but-2-ynoic acid (IV-30) 3M solution of ethylmagnesium bromide in ether (8
ml, 24 mM) to the compound (IV-29) (1.552 g,
10 mM) in tetrahydrofuran (10 ml),
It was added dropwise at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. The mixture was added to the mixture for 5 minutes at 0 ° C., 30 minutes at room temperature,
Dry carbon dioxide gas was introduced. Water was added. The mixture was washed with ether, acidified with 10% citric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.682 g of crude acid (84.
4%). This was used in the next step without purification. 3) N-Boc-3- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) propa-ynylamine (IV-31) Coupling was performed in the same manner as in the above method, and the yield was 5
The target compound was obtained at 6.0%.

4) 3- (3- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) -2-chloro-propa-enylamine (IV-32) Compound (IV-31) (719 mg, 1.67 mM) in ethyl acetate To a stirred solution in (8 ml) was added 4N-HCl in ethyl acetate (4 ml). The mixture was stirred at room temperature for 16 hours. The precipitated material is decanted and collected, and water (20 m
dissolved in l). The solution was made basic with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 549 mg of an oily substance.
(89.6%) was obtained.

5) Compound (IV-33) Coupling was performed in the same manner as in Example 2 above to obtain the title compound in a yield of 60.4%. IRvmax (KBr): 3380, 1676, 161
0.1554 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
62 (4H, m), 1.93 (2H, quint, J =
6.2 Hz), 2.26 (3 H, s), 2.45 (4
H, br. s), 3.26-3.60 (4H, m),
3.44 (3H, s), 3.98 (2H, t, J = 5.
7Hz), 4.14 (2H, m), 4.56 (2H,
s), 5.48 (1H, d, J = 7.8Hz), 6.2
0 (1H, s), 6.66-7.00 (7H, m),
7.04-7.43 (10H, m), 7.48-7.6.
9 (2H, m), 7.82 (1H, br.s) elemental analysis _{(C 45 H 50 N 7 O} 6 Cl 0.3H as ₂ O) Found: C, 65.41; H, 6.23 N, 12.0
7; Cl, 4.51 calcd: C, 65.45; H, 6.18; N, 11.8.
7; Cl, 4.29

Example 5 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (2- (2-
Guanidino-1,3-thiazol-4-yl) methylthio) ethylcarbamoyl) propyl) -piperazinocarbomethoxy) phenyl-1,3-dihydro-2H-1,
4-benzodiazepin-2-one (IV-44) and its hydrochloride salt

[Chemical formula 26] 1) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-carboethoxypropylpiperazino) carbomethoxy) phenyl-1,3-dihydro-
2H-1,4-benzodiazepin-2-one (IV-3
7) Carboxylic acid (IV-9) (945 mg, 2.000 mmol)
And N- (3-ethoxycarbonyl) propylpiperazine (401 mg, 2.001 mmol) were coupled in the same manner as in Example 2 to give compound (IV-37) in a yield of 65.6.
Earned in%. The residue was recrystallized from methanol-ether. mp = 179-182 ° C. IRνmax (KBr): 3360,1721,167
8,1631,1608,1551 cm ^-1 NMR (CDCl ₃ ) δ: 1.26 (3H, t, J =
7.2 Hz), 1.81 (2H, qui, J = 7.2H)
z), 2.30 (3H, s), 2.34 (2H, t, J
= 7.2 Hz), 2.41 (6 H, m), 3.46 (3
H, s), 3.54 (2H, m), 3.62 (2H,
m), 4.14 (2H, q, J = 7.2Hz), 4.7
0 (2H, s,), 5.55 (1H, d, J = 8.2H
z), 6.85 (1H, d, J = 6.6 Hz), 6.9.
4 (1H, d, J = 8.2 Hz), 7.03-7.42
(11H, m), 7.59 ( 1H, m) Elemental analysis _{(C 36 H 42 O 6 N} 6 0.2H 2 O as) Found: C, 65.57; H, 6.62 ; N, 13 ．
10 Calculated: C, 65.68; H, 6.49; N, 12.
77

2) Compound (IV-44) The ester obtained in 1) above (814 mg, 1.243 m)
M) was warmed and dissolved in methanol (22 ml). The solution was cooled to room temperature. 1N sodium hydroxide (3 ml) was added. The solution was left at room temperature for 18 hours and concentrated under reduced pressure.
Dilute hydrochloric acid was added. The solution was left at room temperature for 18 hours and concentrated under reduced pressure. Dilute hydrochloric acid was added, the precipitate was collected by filtration, and benzene was added. Distill off volatiles to remove water,
After drying at 0.1 mmHg, 809 mg (98.
2%) was obtained. This was used in the next step without purification. Coupling was done according to the usual method, yield 59.6%
Gave the title compound. IRvmax (KBr): 3335, 1640, 160
7,1540 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.77 (2H,
qui, J = 7.0 Hz), 2.20 (2H, t, J =
7.0 Hz), 2.30 (3H, s), 2.34 (2
H. t. J = 7.2 Hz), 2.42 (4H, m),
2.68 (2H, t, J = 6.4Hz), 3.40 (2
H, t, J = 6.4 Hz), 3.49 (3H, s),
3.45-3.75 (4H, m), 3.62 ((2H,
s), 4.74 (2H, s), 5.50 (1H, s),
6.44 (1H, s), 6.82 (1H, m), 7.0
0-7.45 (10H, m), 7.62 (1H, m) Elemental analysis (hydrochloride, C ₄₁ H ₄₉ O ₅ N ₁₁ S ₂ 3HCl 0.3.
5H ₂ O) Found: C, 51.24; H, 5.62; Cl, 10.
91; N, 16.21; S, 6.53 Calculated: C, 51.38; H, 5.57; Cl, 11.
11; N, 16.08; S, 6.69

Example 6 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (2- (3- (3-
(Piperidinomethyl) phenoxy) propylcarbamoyl) ethylpiperazinocarbomethoxy) phenyl)-
1,3-Dihydro-2H-1,4-benzodiazepine-
2-on (IV-46)

[Chemical 27] 1) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2-carboethoxyethylpiperazino) carbomethoxy) phenyl) -1,3-dihydro-
2H-1,4-benzodiazepin-2-one (IV-3
6) Carboxylic acid (IV-9) (634 mg, 1.342 mmol)
And N- (2-ethoxycarbonyl) ethylpiperazine (259 mg, 1.391 mmol) were coupled in the same manner as in Example 2 to give compound (IV-36) in a yield of 62.9%.
Got with. IRvmax (KBr): 3345, 1730, 166
0,1608,1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7)
Hz), 2.29 (3H, s), 2.35-2.57
(6H), 2.71 (2H, t, J = 7Hz), 3.4
6 (3H, s), 3.54 (2H, m), 3.63 (2
H, m), 4.16 (2H, q, J = 7 Hz), 4.7
0 (2H, s), 5.56 (1H, d, J = 8Hz),
6.85 (1H, d, J = 6Hz), 6.99 (1H,
d, J = 8 Hz), 7.03-7.42 (11H,
m), 7.59 (1H, m ) Elemental analysis _{(C 35 H 40 N 6 O} 6 0.5H as ₂ O) Found: C, 64.93; H, 6.27 ; N, 12.8
1 Calculated value: C, 64.70; H, 6.36; N, 12.9
Three

2) Compound (IV-46) Coupling was performed in the same manner as in Example 1 above to obtain the title compound (IV-46) in a yield of 66.5%. Amorphous powder IRνmax (KBr): 3330,1643,159
9,1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
61 (4H, m), 1.99 (2H, qui, J = 6H
z), 2.28 (3H, s), 2.42 (10H,
m), 2.64 (2H, t, J = 6Hz), 3.44
(5H, s), 3.50 (6H, m), 4.02 (2
H, t, J = 6 Hz), 4.64 (1H, d, J = 13)
Hz), 4.68 (1H, d, J = 13 Hz), 5.5
5 (1H, d, J = 8 Hz), 6.7-6.92 (3
H, m), 6.95-7.42 (13H, m), 7.4.
6-7.63 (3H) Elemental analysis _{(C 48 H 58 N 8 O} 6 0.9H as ₂ O) Found: C, 67.05; H, 7.01 ; N, 13.1
5 Calculated value: C, 67.10; H, 7.02; N, 13.0
Four

3) Compound (IV-47) Yield 60.7% IRνmax (KBr): 3325,1665,164
0, 1608, 1598, 1550 cm ^-1 NMR (CDCl ₃ ) δ: 1.46 (2H, m), 1.
63 (4H, m), 1.82 (2H, m), 1.99
(2H, qui, J = 6.2 Hz), 2.20-2.5
5 (12H, m), 2.29 (3H, s), 3.33-
3.72 (8H, m), 3.44 (3H, s), 4.0
6 (2H, t, J = 5.9Hz), 4.67 (1H,
d, J = 8.2 Hz), 6.34 (1H, br.s),
6.73-6.92 (3H, m), 6.98-7.42
(13H, m), 7.57 (1H, m), 7.74 (1
H, br. s) Elemental analysis (as C ₄₉ H ₆₀ N ₈ O ₆ H ₂ O) Found: C, 67.00; H, 7.08; N, 12.9.
9 Calculated value: C, 67.26; H, 7.14; N, 12.8
1

Example 7 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (2- (3- (3-
(Piperidinomethyl) phenoxy) carbamoylmethylthio) ethylcarbamoylmethoxy) phenyl-1,3
-Dihydro-2H-1,4-benzodiazepin-2-one (IV-50)

[Chemical 28] From N-BOC-ethanethiol to Ueda et al. [I. Ued
a, K. Ishi, K .; Shinozaki, M .; Se
iki, H .; Arai and M.D. Hatanak
a, Chem. Pharm. Bull, 38 , 3035
(1990)] and IV-4 synthesized by a method similar to
9 and the coupling were carried out in the same manner as in Example 2 to obtain the title compound (IV-50) in a yield of 85.2%. Amorphous powder (from methanol-water) IRvmax (KBr): 3310,1670,164
2,1610,1552 cm ^-1 NMR (CDCl ₃ ) δ: 1.43 (2H, m), 1.
98 (2H, qui, J = 6.1 Hz), 2.28 (3
H, s), 2.44 (4H, m), 2.73 (2H,
t, J = 6.7 Hz), 3.23 (2H, s), 3.4
5 (3H, s), 3.40-3.59 (6H), 4.0
3 (2H, t, J = 5.8Hz), 4.46 (2H,
s), 5.54 (1H, d, J = 8.2Hz), 6.7.
5-6.91 (3H, m), 6.94-7.40 (15
H, m), 7.57 (1H, m), 7.64 (1H, b
r. s) Elemental analysis (as C ₄₅ H ₅₃ N ₇ O ₆ S 0.3H ₂ O) Found: C, 65.52; H, 6.50; N, 12.1
1; S, 3.63 calculated: C, 65.48; H, 6.55; N, 11.8
8; S, 3.88

Example 8 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (1-amino-3- (2-guanidino-1,3-thiazol-4-yl) methylthio) propyliminosulfonyl) propyl) carbamoyl) methoxy) phenyl)- 1,3-Dihydro-2H-1,4-benzodiazepin-2-one (IV-55) and its 3R-isomer (IV-56)
And the 3S-isomer (IV-57)

[Chemical 29] 1) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-sulfamoylpropylcarbamoylmethoxy) phenyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-52) 3-aminopropanesulfonamide (IV-51) and compound (IV-9) were coupled according to a conventional method,
Compound (IV-52) was obtained with a yield of 88.8%. Similarly, 3-aminopropanesulfonamide and compound (IV
-9) 3R-form (IV-16) or 3S-form (IV-)
18) is reacted to give 3 of the corresponding compound (IV-52).
The R form (IV-53) and the 3S form (IV-54) were obtained in yields of 89.3% and 81.0%, respectively.

Compound IV-52 mp = 145-147 ° C. IRνmax (KBr): 3325,1647,161
0.1550 cm ^-1 NMR (DMSO) δ: 1.84 (2H, m), 2.2
4 (3H, s), 2.94 (2H, m), 3.24 (2
H, m), 3.41 (3H, s), 4.49 (2H,
s), 5.24 (1H, d, J = 8.4 Hz), 6.7.
-6.82 (3H, m), 7.05-7.26 (6H,
m), 7.31-7.55 (4H, m), 7.63-
7.81 (2H), 8.27 (1H, m), 8.99
(1H, s) Elemental analysis _{(C 29 H 32 O 6 N} 6 S 1.5H as ₂ O) Found: C, 56.22; H, 5.55 ; N, 13.7
2; S, 4.81 Calcd: C, 56.21; H, 5.69; N, 13.5
6; S, 5.17

Compound IV-53 (3R-isomer) [α] _D +45.7 (24 ° C., c 0.945, DM
F) Elemental analysis (as C ₂₉ H ₃₂ N ₆ O ₆ S O.5H ₂ O) Found: C, 57.95; H, 5.66; N, 13.
83; S, 5.22 calculated: C, 57.89; H, 5.53; N, 13.
97; S, 5.33 Compound IV-54 (3S-isomer) [α] _D- 48.3 (24 ° C, c 1.003, D
MF) Elemental analysis _{(C 29 H 32 N 6 O} 6 S 0.5H as ₂ O) Found: C, 57.84; H, 5.67 ; N, 13.
82; S, 5.21 calculated: C, 57.89; H, 5.53; N, 13.
97; S, 5.33

2) Compounds IV-55, IV-56 and IV-57 imidate (III-106, 350 mg, 1.28 m
A solution of M) in methanol (6.5 ml) was added to a solution of sulfonamide (IV-52, 375 mg, 0.633 mM) in dimethylformamide (5 ml). The solution was left at room temperature for 15 days. Water was added and the solid was filtered off and subjected to flash chromatography using silica gel and chloroform: methanol (9: 1). The solid was dissolved in methanol and water was added. The solid was collected by filtration and dried to give powder 239 mg (45.3%), sulfonamide 1
26 mg (33.6%) were recovered. IRvmax (KBr): 3375, 1650, 161
0, 1548, 1323, 1163, 1112 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.06 (2H,
qui, J = 7.0 Hz), 2.30 (3H, s),
2.47 (2H, t, J = 7.3Hz), 2.79 (2
H, t, J = 7.3 Hz), 3.02 (2H, t, J =
7.2 Hz), 3.46 (2H, t, J = 6.6H)
z), 3.49 (3H, s), 3.59 (2H, s),
4.53 (2H, s), 5.46 (1H, s), 6.4
8 (1H, s), 6.83 (1H, d, J = 6.2H
z), 7.01-7.46 (10H, m), 7.64
(1H, m) Elemental analysis (C ₃₇ as _{H 43 N 11 O 6 S 3} ) Found: C, 53.06; H, 5.30 ; N, 18.3
6; S, 11.28 Calculated value: C, 53.28, H, 5.20; N, 18.4
9; S, 11.53 Similarly, imidate (III-108) and sulfonamide (IV-54) were coupled in methanol for 7 days to give 3S-isomer (IV-57) in a yield of 65.1.
Earned in%. Moreover, the 3R-isomer (IV-56) was obtained by the reaction with sulfonamide (IV-53).

Compound IV-57 (3S-isomer ) [α] _D -19.2 (24 ° C, c 1.032, DM
F) Elemental analysis (as C ₃₇ H ₄₃ N ₁₁ O ₆ S ₃ H ₂ O) Found: C, 52.24; H, 5.54; N, 18.
16; S, 11.17 calculated: C, 52.16; H, 5.32; N, 18.
08; S, 11.29 Compound IV-56 (3R isomer) [α] _D +31.9 (24 ° C, c 1.154, DM
F) Elemental analysis (as C ₃₇ H ₄₃ N ₁₁ O ₆ S ₃ 0.5H ₂ O) Found: C, 52.75; H, 5.33; N, 18.
45; S, 11.66 Calculated: C, 52.71; H, 5.26; N, 18.
28; S, 11.41

Example 9 1-Methyl-3- (N '-(m
-Tolyl) ureido) -5- (3- (3- (1-amino-3- (2-guanidino-1,3-thiazol-4-yl) methylthio) propyliminosulfonylamino) propylcarbamoyl) methoxy) phenyl)- 1,3-
Dihydro-2H-1,4-benzodiazepin-2-one (IV-60)

[Chemical 30] 1) 3-aminopropane aminosulfonamide (IV-
58) Bromide (III-113, in HMPA (30 ml)
1.80 g, 8.29 mM) and sodium azide (1.2 g, 18.46 mM) were stirred at 50 ° C. for 2 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. IRνmax (film): 2092 cm ^{-1 To a} solution of the residue in tetrahydrofuran (30 ml) was added triphenylphosphine (2.18 g, 8.31 mM).
The solution was stirred at room temperature for 18 hours. Add water (6 ml),
The solution was heated to reflux for 30 minutes and concentrated under reduced pressure. Add water,
The insoluble material was filtered off and the filtrate was washed with ethyl acetate. The solution was concentrated under reduced pressure to give 750 mg of amine (59.1).
%) Was obtained. This was used in the next step without purification.

2) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-aminosulfonylaminopropyl) carbamoylmethoxy) phenyl-1,
3-dihydro-2H-1,4-benzodiazepine-2-
On (IV-59) The amine (IV-58) was reacted with the compound (IV-9) in the same manner as in Example 8 (1) to give the sulfonamide (I
V-59) was obtained with a yield of 95.6%. mp = 136-138 ° C. IRνmax (KBr): 3315,1646,161
1,1554, 1320, 1153 cm ⁻¹ NMR (DMSO) δ: 1.61 (2H, qui, J =
6.6 Hz), 2.24 (3H, s), 2.85 (2
H, q, J = 6.6 Hz), 3.16 (2H, q, J =
6.4 Hz), 3.41 (3H, s), 4.47 (2
H, s), 5.24 (1H, d, J = 8.4 Hz),
6.45 (1H, t, J = 6.4Hz), 6.47 (2
H, s), 6.74 (1H, d, J = 6.4 Hz),
7.06-7.25 (6H, m), 7.31-7.53
(4H, m), 7.63-7.80 (2H), 8.13
(1H, t, J = 5.8Hz ), 8.98 (1H, s) Elemental analysis _{(C 29 H 33 N 7 O} 6 as S) Found: C, 57.56; H, 5.68 ; N , 16.
26; S, 5.00 Calculated: C, 57.32; H, 5.43; N, 16.
13; S, 5.28

3) Compound (IV-60) In the same manner as in Example 8, the sulfonamide (IV-59) was coupled with the compound (III-108) to give the compound (III-60) in a yield of 29.9. Earned in%. IRvmax (KBr): 3360, 1650, 160
8,1545,1322,1122 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.73 (2H,
qui, J = 6.3 Hz), 2.30 (3H, s),
2.43 (2H, t, J = 7.2Hz), 2.7982
H, t, J = 7.2 Hz), 2.99 (2H, t, J =
6.3 Hz), 3.42 (2H, t, J = 6.3H)
z), 3.48 (3H, s), 3.55 (2H, s),
4.52 (2H, s), 5.46 (1H, s), 6.3
8 (1H, s), 6.83 (1H, m), 6.97-
7.46 (10 H, m), 7.63 (1 H, m) Elemental analysis (as C ₃₇ H ₄₂ N ₁₂ O ₆ S ₃ ) Found: C, 52.12; H, 5.26; N, 19 .7
4; S, 11.17 calculated: C, 52.34; H, 5.22; N, 19.8.
0; S, 11.33

Example 10 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (NB)
oc-N- (3- (3- (3-piperidinomethyl) phenoxy) propylcarbamoylmethyl) amino) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2
H-1,4-benzodiazepin-2-one (IV-6
1) and 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (N- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoylmethyl) amino) ethyl Carbamoylmethoxy) phenyl)
-1,3-Dihydro-2H-1,4-benzodiazepin-2-one (IV-62)

[Chemical 31]

Amine (III-135) and acid (IV-
9) were coupled with in the same manner as in Example 2 to obtain the title compound (IV-61) in a yield of 42.4%. IRνmax (KBr): 3350, 1665, 161
0.1601 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.37 (11
H, br. s), 1.98 (2H, m), 2.30 (3
H, s), 2.44 (4H, br.s), 3.48 (1
1H, br. s), 3.78 (2H, s), 4.01.
(2H, m), 4.47 (2H, br.s), 5.50
(1H, s), 6.74-6.96 (4H, m), 7.
05-7.46 (11H, m), 7.62 (1H, m) Elemental analysis _{(C 50 H 62 N 8 O} 8 0.8H 2 O as) Found: C, 65.46; H, 7 . 02; N, 12.5
6 Calculated: C, 65.45; H, 6.99; N, 12.2
1

Compound (IV-61) (280 mg, 0.
To a solution of 31 mM) in ethyl acetate (6 ml) was added N-hydrogen chloride in ethyl acetate (2 ml) under ice cooling. The suspension was stirred at room temperature for 20 hours. A solid substance (272 mg) was collected by filtration. IRvmax (KBr): 3360, 1670, 159
8 cm ^-1 NMR (CD ₃ OD) δ: 1.35-2.00 (6H,
m), 2.01 (2H, m), 2.29 (3H, s),
2.95 (2H, m), 3.15-3.50 (6H,
m), 3.50-3.72 (2H, m), 3.58 (3
H, s), 3.87 (2H, s), 4.08 (2H,
t, J = 6 Hz), 4.25 (2H, s), 4.64
(2H, s), 5.56 (1H, s), 6.85 (1
H, d, J = 7 Hz), 6.99-7.57 (13H,
m), 7.74 (1H, d, J = 8Hz), 7.90
(1H, m) Elemental analysis (as C ₄₅ H ₅₄ N ₈ O ₆ 2.5HCl 0.3H ₂ O) Found: C, 60.27; H, 6.45; Cl, 9.7.
1; N, 12.44 calculated: C, 60.09; H, 6.40; Cl, 9.8
5; N, 12.46

Example 11 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (3,6-dioxa-7- (3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) heptylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H -1,4-
Benzodiazepin-2-one (IV-66) and its hydrochloride, and 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (2- (3- (3 −
(Piperidinomethyl) phenoxy) propylcarbamoylmethoxy) ethoxy) ethoxy) carbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-67) and its hydrochloride salt

[Chemical 32]

Amine (III-149) and acid (IV-
9) was coupled with Example 2 in the same manner as in Example 2 to obtain the title compound (IV-66) or (IV-67) in a yield of 69.0% and 66.2%, respectively. Compound IV-66 IRνmax (KBr): 3325,662,1608
cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
59 (4H, m), 2.02 (2H, qui, J = 6H
z), 2.29 (3H, s), 2.40 (4H, m),
3.43 (5H, s), 3.45-3.70 (10H,
m), 3.99 (2H, t, J = 6Hz), 4.09
(2H, s), 4.49 (2H, s), 5.38 (1
H, d, J = 8 Hz), 6.69-7.42 (17H,
m), 7.47 (1H, m), 7.58 (1H, m),
7.85 (IH, br. S) Elemental analysis _{(C 47 H 57 N 7 O} 8 1.3H 2 O as) Found: C, 64.70; H, 6.75 ; N, 11.
44 calcd: C, 64.78; H, 6.89; N, 11.
25 hydrochloride _{(C 47 H 57 N 7 O} 8 1.1HCl 0.5H 2 O as) Found: C, 62.83; H, 6.71 ; Cl, 4.
27; N, 11.05 Calcd: C, 62.92; H, 6.64; Cl, 4.
35; N, 10.93

Compound IV-67 hydrochloride IRvmax (KBr): 3400, 3300, 306
0,1668,1639,1608,1552 cm ^-1 NMR (CD ₃ OD) δ: 1.35-1.90 (6H,
m), 1.98 (2H, quint, J = 6.6H)
z), 2.29 (3H, s), 2.91 (2H, m),
3.30-3.60 (8H, m), 3.51 (3H,
s), 3.57 (4H, s), 3.62 (4H, s),
3.94 (2H, s), 4.03 (2H, t, J = 6.
1Hz), 4.19 (2H, s), 4.53 (2H,
s), 5.39 (1H, s), 6.82 (1H, m),
6.98-7.24 (8H, m), 7.29-7.43
(5H, m), 7.64 (1H, d, J = 8.0H
z), 7.75 (1 H, m) Elemental analysis (as C ₄₉ H ₆₁ N ₇ O ₉ 1.2 HCl H ₂ O) Found: C, 61.69; H, 6.91; N, 10.
50; Cl, 4.36 Calcd: C, 61.70; H, 6.78; N, 10.
28; Cl, 4.46

Example 12 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (2-
(2- (2- (2-guanidino 1,3-thiazole-
4-yl) methylthio) ethylcarbamoylmethoxy)
Ethoxy) ethoxycarbamoylmethoxy) phenyl)
-1,3-Dihydro-2H-1,4-benzodiazepin-2-one (IV-68)

[Chemical 33] The amine (III-154) and the acid (IV-9) were coupled in the same manner as in Example 1 to give the title compound (IV-
68) was obtained with a yield of 69.5%. IRvmax (KBr): 3300, 1655, 160
5,1541 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 2.65 (2H, t, J = 6.8Hz), 3.3.
6-3.70 (16H, m), 3.48 (3H, s),
3.98 (2H, s), 4.52 (2H, s), 5.4
8 (1H, s), 6.45 (1H, s), 6.83 (1
H, m), 7.01-7.47 (10H, m), 7.6.
3 (1H, m) Elemental analysis (as C ₄₁ H ₅₀ N ₁₀ O ₈ S ₂ 2H ₂ O) Found: C, 53.93; H, 6.00; N, 15.4.
3; S, 6.95 Calcd: C, 54.04; H, 5.97; N, 15.3
7; S, 7.04

Hydrochloride IRνmax (KBr): 3300, 1670, 163
8,1610,1550 cm ^-1 NMR (CD ₃ OD) DNA: 2.28 (3H,
s), 2.59 (2H, t, J = 7.0Hz), 3.3
4-3.66 (14H, m), 3.49 (3H, s),
3.73 (2H, s), 3.94 (2H, s), 4.5
4 (2H, s), 5.36 (1H, s), 6.81 (1
H, m), 6.96 (1H, s), 7.05-7.23.
(5H, m), 7.27-7.40 (4H, m), 7.
61 (1H, d, J = 8.2 Hz), 7.71 (1H,
m) Elemental analysis _{(C 41 H 50 N 10 O} 8 S 2 HCl 0.5H as ₂ O) Found: C, 53.68; H, 5.77 ; N, 15.3
3; S, 6.75, Cl, 3.50 Calculated: C, 53.50; H, 5.69; N, 15.2
2; S, 6.97; Cl, 3.85

Example 13 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (2-
(3- (2- (2-guanidino 1,3-thiazole-
4-yl) methylthio) ethylcarbamoylpropyloxy) ethoxy) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV-71) and its hydrochloride salt

[Chemical 34] 1) 1-methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (2- (3- (carbomethoxy) propyloxy) ethoxy) ethylcarbamoylmethoxy) phenyl)- 1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-69) Amine (III-163) and acid (IV-9) were coupled in the same manner as above to give compound IV-69 in yield 6
Obtained at 7.4%. IRνmax (CHCl ₃ ): 3440, 1732, 1
678,1602 cm ^-1 NMR (CDCl ₃ ) δ: 1.90 (2H, qui, J
= 7 Hz), 2.30 (3H, s), 2.40 (2H,
t, J = 7 Hz), 3.47 (3H, s), 3.48
(2H, t, J = 7Hz), 3.50-3.62 (8
H, m), 3.67 (3H, s), 4.49 (2H,
s), 5.56 (1H, d, J = 8Hz), 6.85
(1H, m), 6.92-7.43 (13H, m),
7.60 (1H, m). Elemental analysis _{(C 35 H 41 N 5 O} 8 0.7H 2 O as) Found: C, 62.43; H, 6.18 ; N, 10.
67 Calcd: C, 62.52; H, 6.36; N, 10.
42

2) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2- (3-carboxypropyloxy) ethoxy) ethylcarbamoylmethoxy) phenyl) -1,3 -Dihydro-2H-1,4-benzodiazepin-2-one (IV-70) ester (IV-69) (940mg, 1.425m
M) was dissolved in methanol (25 ml) and dichloromethane (5 ml). Dichloromethane was distilled off and 10%
Aqueous sodium hydroxide solution (4 ml) was added. The solution was stirred at room temperature for 3 hours. Ice water was added and the mixture was concentrated to half volume. 10% Hydrochloric acid (6 ml) was added, the solid was collected by filtration and dried to obtain 845 mg (91.8%). IRvmax (KBr): 3320, 1675, 164
0,1611 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.86 (2H,
qui, J = 7 Hz), 2.31 (3H, s), 2.3
7 (2H, t, J = 8Hz), 3.49 (2H, t, J
= 7 Hz), 3.51 (3H, s), 3.57 (8H,
br. s), 4.53 (2H, s), 5.56 (1H,
s), 6.83 (1H, m), 7.07-7.50 (1
0H, m), 7.69 (1H , m) Elemental analysis _{(C 34 H 39 N 5 O} 8 0.8H 2 O as) Found: C, 61.86; H, 6.16 ; N, 10.
69 Calcd: C, 61.86; H, 6.20; N, 10.
61

3) Compound (IV-71) Coupling was carried out in the same manner as in Example 1 to give compound (IV-7).
1) was obtained with a yield of 81.4%. mp = 119-122 ° C. (MeOH) IRνmax (kBr): 3320, 1650, 161
0 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.86 (2H,
qui, J = 7 Hz), 2.26 (2H, t, J = 8H)
z), 2.30 (3H, s), 2.60 (2H, t, J
= 7 Hz), 3.30-3.65 (12H, m), 3.
48 (3H, s), 3.62 (2H, s), 4.52
(2H, s), 5.48 (1H, s), 6.55 (1
H, s), 6.83 (1H, m), 6.98-7.47.
(10H, m), 7.63 (1H, m) Elemental analysis (as C ₄₁ H ₅₀ N ₁₀ O ₇ S ₂ H ₂ O) Found: C, 56.21; H, 5.97; N, 16 ．
18; S, 7.07 Calculated: C, 56.15; H, 5.98; N, 15.
97; S, 7.31 hydrochloride (as C ₄₁ H ₅₀ N ₁₀ O ₇ S ₂ 1.3 HCl H ₂ O) found: C, 53.10; H, 5.94; Cl, 5.
04; N, 15.17; S, 7.07 Calculated: C, 53.27; H, 5.81; Cl, 4.
99; N, 15.15; S, 6.91.

Example 14 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (2-
(3- (3- (piperidinomethyl) phenoxy) propylcarbamoyl) propyloxy) ethoxy) ethylmethoxy) phenyl) -1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-72) and its hydrochloride salt

[Chemical 35] Coupling was performed in the same manner as in Example 2 to give compound (IV-7
2) was obtained with a yield of 85.1%. IRvmax (KBr): 3300, 1670, 164
0,1610 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
60 (4H, m), 1.85-2.06 (4H, m),
2.29 (3H, s), 2.34 (2H, t, J = 8H
z), 2.42 (4H, m), 3.44 (3H, s),
3.47 (12H, br.s), 3.55 (2H,
s), 4.00 (2H, t, J = 6Hz), 4.49
(2H, s), 5.54 (1H, d, J = 8Hz),
6.54 (1H, m), 6.68-7.48 (17H,
m), 7.58 (1H, m), 7.95 (1H, br.
s) Elemental analysis _{(C 49 H 61 N 7 O} 8 0.8H 2 as O) Found: C, 66.13; H, 7.01 ; N, 11.
07 Calcd: C, 66.09; H, 7.09; N, 11.
01 hydrochloride (as C ₄₉ H ₆₁ N ₇ O ₈ HCl H ₂ O) Found: C, 63.10; H, 6.84; Cl, 3.
74; N, 10.62 Calcd: C, 63.25; H, 6.93; Cl, 3.
81; N, 0.54

Example 15 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (2-
(3- (3- (Piperidinomethyl) phenoxy) propylcarbamoyl) methoxy) ethoxy) ethylpiperazinocarbomethoxy) phenyl) -1,3-dihydro-2
H-1,4-benzodiazepin-2-one (IV-7
3)

[Chemical 36] Coupling was performed in the same manner as in Example 2 to give compound (IV-7
3) was obtained with a yield of 72.7%. IRvmax (KBr): 3345, 1660, 161
0.1599 cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (2H, m), 1.
59 (4H, m), 1.99 (2H, qui, J = 6H
z), 2.29 (3H, s), 2.33-2.64 (1
0H, m), 3.43 (3H, s), 3.47 (2H,
s), 3.47 (2H, s), 3.49-3.75 (1
2H, m), 3.99 (2H, t, J = 6Hz), 4.
03 (2H, s), 4.67 (1H, d, J = 13H
z), 4.74 (1H, d, J = 13 Hz), 5.55
(1H, d, J = 8Hz), 6.70-6.94 (4
H, m), 6.98-7.41 (13H, m), 7.5
8 (1H, m), 7.70 (1H, s) Elemental analysis (as C ₅₁ H ₆₄ N ₈ O ₈ H ₂ O) Found: C, 65.42; H, 7.17; N, 12.
30 Calcd: C, 65.51; H, 7.11; N, 11.
98 hydrochloride IRνmax (KBr): 3400, 3300, 166
7,1640,1608,1599 cm ⁻¹ Elemental analysis (C ₅₁ H ₆₄ N ₈ O ₈ 2.1HCl · 1.8H ₂
Found: C, 59.55; H, 6.83; N, 11.
11; Cl, 7.20 Calcd: C, 59.70; H, 6.85; N, 10.
92; Cl, 7.26

Example 16 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (2-
(2- (2- (guanidino-1,3-thiazole-4-
Iyl) methylthio) ethylcarbamoyl) methoxy) ethoxy) ethylpiperazinocarbomethoxyphenyl)-
1,3-Dihydro-2H-1,4-benzodiazepine-
2-on (IV-74)

[Chemical 37] Coupling was performed in the same manner as in Example 1, and the compound (IV-7
4) was obtained with a yield of 65.3%. IRvmax (KBr): 3320, 1650, 160
0 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H, s),
2.49 (4H, m), 2.58 (2H, t, J = 6H
z), 2.66 (2H, t, J = 7Hz), 3.37-
3.66 (12H, m), 3.48 (3H, s), 3.
62 (2H, s), 3.98 (2H, s), 4.73
(2H, s), 5.50 (1H, s), 6.46 (1
H, s), 6.82 (1H, m), 7.01-7.48.
(10H, m), 7.62 ( 1H, m) Elemental analysis _{(C 43 H 53 N 11 O} 7 S 0.7H 2 O as) Found: C, 56.61; H, 6.01 ; N, 16.
84; S, 6.89 Calcd: C, 56.59; H, 6.01; N, 16.
88; S, 7.03 hydrochloride IRvmax (KBr): 3300, 1660, 160.
0 cm ⁻¹ elemental analysis (C ₄₃ H ₅₃ N ₁₁ O ₇ S ₂ 2.2 HCl 1.8
H ₂ O as) Found: C, 51.14; H, 5.92 ; Cl, 7.5
2; N, 15.14; S, 6.39 Calcd: C, 51.00; H, 5.85; Cl, 7.7
0; N, 15.21; S, 6.33

Example 17 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (2-
(2- (N'-cyano-N "-(3- (3- (piperidinomethyl) phenoxy) propyl) guanidino) ethoxy) ethoxy) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4- Benzodiazepin-2-one hydrochloride (IV-79)

[Chemical 38] Coupling was performed in the same manner as in Example 2 to give compound (IV-7
9) was obtained with a yield of 69.6%. IRvmax (KBr): 3310, 2160, 167
0.1642, 1580 cm ^-1 NMR (CDCl ₃ ) δ: 1.45 (2H, m), 1.
74 (4H, m), 1.90 (2H, quint, J =
5.8 Hz), 2.29 (3 H, s), 2.65 (4
H, br. s), 3.24 (2H, m), 3.30-
3.85 (14H, m), 3.43 (3H, s), 3.
98 (2H, t, J = 5.9Hz), 4.51 (2H,
s), 5.51 (1H, d, J = 7.8Hz), 5.9
8 (1H, t, J = 5.6 Hz), 6.23 (1H, b
r. s), 6.75-5.90 (3H, m), 6.92
-7.03 (2H, m), 7.06-7.42 (11
H, m), 7.47 (1H, d, J = 7.8Hz),
7.59 (1H, m), 8.28 (1H, br.s) Elemental analysis (as C ₄₉ H ₆₀ N ₁₀ O ₇ 1.5H ₂ O) Found: C, 63.52; H, 6. 86; N, 15.2
5 Calculated value: C, 63.52; H, 6.87; N, 15.0
9

Example 18 1-Methyl 1-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (N'-
Cyano-N "-(3- (3- (piperidinomethyl) phenoxy) propyl) guanidino) ethylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-80)

[Chemical Formula 39] Coupling was performed in the same manner as in Example 2 to give compound (IV-8
0) was obtained with a yield of 62.1%. IRvmax (KBr): 3320, 2160, 167
5,1580 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.49 (2H,
m), 1.67 (4H, m), 2.01 (2H, qu
i, J = 6 Hz), 2.30 (3H, s), 2.55
(4H, br.s), 3.20-3.45 (6H,
m), 3.48 (3H, s), 3.61 (2H, br.
s), 4.03 (2H, t, J = 6Hz), 4.50
(2H, s), 5.48 (1H, s), 6.79-6.
95 (3H, m), 6.99-7.47 (12H,
m), 7.63 (1H, m) Elemental analysis (as C ₄₅ H ₅₂ N ₁₀ O ₅ 1.5H ₂ O) Found: C, 64.12; H, 6.46; N, 16.
82 Calcd: C, 64.34; H, 6.60; N, 16.
68

Example 19 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (4- (3-
(2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) prop-3-enyl) piperazinocarbomethoxy) phenyl) -1,3-
Dihydro-2H-1,4-benzodiazepin-2-one (IV-177)

[Chemical 40] 1) N-Boc-N '-(3- (2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) prop-3-enyl) piperazine (IV-
175) Compound (IV-175) was coupled in the same manner as above.
Was obtained in a yield of 45.4%. NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.
39 (4H, t, J = 9.4Hz), 2.71 (2H,
t, J = 6.4 Hz), 3.12 (2H, d, J = 6.
0Hz), 3.43 (6H, m), 3.65 (2H,
s), 6.47 (1H, d, J = 15.6 Hz), 6.
44 (1H, s), 6.78 (1H, dt, J = 15.
2, 6.2 Hz)

2) Compound (IV-177) The Boc-protected compound (IV-175) obtained in 1) was treated with 4N hydrochloric acid in ethyl acetate to give the amine hydrochloride (IV-1).
76) was obtained. Then, coupling was carried out in the same manner as above to obtain the compound (IV-177) in a yield of 37.6%. NMR (CDCl ₃ + CD ₃ OD) δ: 2.28 (3H,
s), 2.3-2.5 (8H, m), 2.71 (2H,
t, J = 6.4 Hz), 3.05 (2H, m), 3.4
-3.7 (6H, m), 3.47 (3H, s), 3.6
4 (2H, s), 4.75 (2H, s), 5.50 (1
H, s), 5.93 (1H, d, J = 15.2 Hz),
6.51 (1H, s), 6.71 (1H, dt, J = 1
5.2, 6.6 Hz), 6.81 (1 H, m), 6.9
5-7.5 (10H, m), 7.62 (1H, m) dihydrochloride IRvmax (nujol): 3280, 1672, 1
638,1610,1555 cm ^-1 Elemental analysis (as C ₄₁ H ₄₉ N ₁₁ O ₅ S ₂ Cl ₂ 1.4H ₂ O) Found: C, 52.61; H, 5.58; N, 16.2
9; S, 6.54; Cl, 7.94 Calcd: C, 52.60; H, 5.58; 16.4
6; S, 6.85; Cl, 7.57

Example 20 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (3-
(2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) prop-2-enylpiperazino) ethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (IV
-203)

[Chemical 41] 1) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3-hydroxyphenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (I
V-197) Starting from m-anisaldehyde, Sugazawa et al. [T. Sugazawa, M .; Adachi and
K. Sasakara, J .; Heterocycle
c. Chem. , 16 , 445 (1979)] to produce a benzodiazepine skeleton, and Bock et al. [M. G. Bock, R.A. M. Di Pardo, B .;
E. Ejans. K. E. Little, D.R. F. Ve
ber, R.A. M. Freidinger, J. et al. Hirs
hfield and J.H. P. Springer,
J. Org. Chem. 52 , 3232 (1987)].
1-Methyl-3- (N '-(m-
Trilyl) ureido) -5- (3-anisyl) -1,3-
Dihydro-2H-1,4-benzodiazepin-2-one (IV-196) (428 mg) in dichloromethane (25
ml) in a nitrogen atmosphere and boron tribromide (0.
A solution of 3 ml) in dichloromethane (5 ml) was added dropwise at -20 ° C. The mixture was stirred at -20 ° C for 8 hours and poured into ice-water. The mixture was extracted with dichloromethane-methanol.
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is silica gel (30 g) and chloroform:
Chromatography with methanol (20: 1) and recrystallization from ethyl acetate gave compound (IV-19
7) 282 mg (68.1%) was obtained.

2) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2-tetrahydropyranyloxy) ethoxyphenyl-1,3-dihydro-2H
-1,4-benzodiazepin-2-one (IV-19
8) A mixture of compound (IV-197) (3.0 g), 2-tetrahydroxyethyl bromide (3.02 g) and potassium carbonate (5.03 g) in acetonitrile (50 ml) was heated under reflux for 18 hours. Add water and collect the solids by filtration.
It was washed with water, dried and recrystallized from ethyl acetate to give compound (IV
-198) 2.0 g (50.9%) was obtained. mp = 118-122 ° C. 3) 1-methyl-3- (N ′-(m-tolyl) ureido) -5- (3- (2-hydroxy) ethoxyphenyl-1,3-dihydro-2H-1,4. -Benzodiazepin-2-one (IV-199) Compound (IV-198) (2.00 g) and p-toluenesulfonic acid (0.15 g) in methanol (20 ml)
The solution was heated to reflux for 4 hours. Aqueous sodium hydrogen carbonate solution was added, and the solid matter was collected by filtration, washed with water, dried and recrystallized from ethyl acetate to obtain 1.50 g of compound (IV-199) (88.
8%). mp = 156-158 ° C

4) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (2-methanesulfonyloxy) ethoxyphenyl) -1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-200) A solution of methanesulfonyl chloride (603 mg) in dichloromethane (10 ml) was added with compound (IV-199) (1.20).
A solution of 8 g) in dimethylformamide (15 ml), triethylamine (4 ml) and dichloromethane (20 ml) was added dropwise at -20 ° C. The solution was stirred at −20 ° C. for 1 hour, poured into dilute hydrochloric acid and extracted with dichloromethane: methanol. The extract was washed with water and concentrated under reduced pressure. Water was added, the solid was collected by filtration, washed with water, and dissolved in dichloromethane: methanol. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crystalline residue was washed with benzene and dried to obtain 1.27 g (89.8%) of compound (IV-200).

5) Compound (IV-203) Compound (IV-200) (225 mg), compound (IV-176) (230 mg) obtained in Example 19 and potassium carbonate (2.5 g) in acetonitrile (5 ml). The mixture was heated to reflux for 20 hours. Dichloromethane: methanol was added and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was silica gel (30 g), chloroform: methanol: ammonium hydroxide (5: 1: 0.125).
Chromatography on the compound (IV-2
03) 120 mg (34.7%) was obtained. NMR (CDCl ₃ + CD ₃ OD) δ: 2.30 (3H,
s), 2.55 (4H, br.s), 2.62 (6H,
br. s), 2.70 (2H, t, J = 6.7Hz),
2.83 (2H, t, J = 5.6Hz), 3.12 (2
H, d, J = 5.4 Hz), 3.45 (2H, t, J =
5.6 Hz), 3.48 (3H, s), 3.65 (2
H, s), 4.14 (2H, t, J = 5.6 Hz),
5.50 (1H, s), 5.95 (1H, d, J = 1
5.4 Hz), 6.47 (1H, s), 6.7-6.9.
(2H, m), 7.02 (2H, m), 7.1-7.5
(8H, m), 7.62 (1H, m) 0.1-N hydrochloric acid (4.2 ml) was added to the residue. Methanol was added until the solid dissolved and the volatiles were distilled off under reduced pressure. IRvmax (nujol): 3280, 1676, 160
5,1554 cm ^-1 Elemental analysis (C ₄₁ H ₄₉ N ₁₁ S ₂ O ₄ 3HCl 1.1H ₂
Found: C, 51.53; H, 5.70; N, 16.2.
2; Cl, 11.44; S, 6.89 Calculated: C, 51.66; H, 5.73; N, 16.1
6; Cl, 11.16; S, 6.73

Example 21 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (2- (3-
(2- (2-guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) propylpiperazino) ethoxy) phenyl) -1,3-dihydro-2H-
1,4-benzodiazepin-2-one (IV-204)

[Chemical 42] Compound (IV-204) was obtained in a yield of 11.1% in the same manner as in Example 20. NMR (CDCl ₃ ) δ: 1.80 (2H, m), 2.
26 (3H, s), 2.2-2.9 (16H, m),
3.42 (2H, t, J = 6.5Hz), 3.43 (3
H, s), 3.60 (2H, s), 4.14 (2H,
m), 5.54 (1H, d, J = 8.0 Hz), 6.3
8 (1H, s), 6.8-7.7 (12H, m) hydrochloride IRνmax (nujol): 3280,16790,16
05,1554 cm ^-1 Elemental analysis (C ₄₁ H ₅₁ N ₁₁ O ₄ S ₂
3.3HCl 0.9H ₂ O) Found: C, 51.32; H, 6.00; N, 15.8.
9; Cl, 12.10; S, 6.65 Calcd: C, 51.16; H, 5.87; N, 16.0
1; Cl, 12.15; S, 6.66

Example 22 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (3- (2-
(2- (guanidino-1,3-thiazol-4-ylmethylthio) ethylcarbamoyl) propylcarbamoyloxy) phenyl) -1,3-dihydro-2H-1,4
-Benzodiazepin-2-one (IV-226)

[Chemical 43] 1) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-benzyloxycarbonyl) propylcarbamoyloxy) phenyl) -1,3-dihydro-2H-1,4 -Benzodiazepin-2-one (I
V-223) Phenyl derivative (IV) in dichloromethane (30 ml)
-197) (708 mg), 3- (benzyloxycarbonyl) propyl isocyanate (905 mg) and a few drops of triethylamine were stirred at room temperature for 2 days. The volatiles were distilled off under reduced pressure. The residue was treated with silica gel (50
g) and chromatography with chloroform: methanol (20: 1) to give compound (IV-22
3) 1.19 g (quantitative) was obtained. It was again chromatographed on ethyl acetate: hexane (2: 1) silica gel.

2) 1-Methyl-3- (N '-(m-tolyl) ureido) -5- (3- (3-carboxypropylcarbamoyloxy) phenyl) -1,3-dihydro-
2H-1,4-benzodiazepin-2-one (IV-2
24) A mixture of ester (IV-223) (0.98 g) and 5% palladium / C (230 mg) in methanol (20 ml) and ethyl acetate (10 ml) in the presence of hydrogen at 30
Stir for minutes. The catalyst was filtered and washed with methanol.
The filtrate was concentrated under reduced pressure, and compound (IV-224) 0.72 g
(85.7%) was obtained. 3) Compound (IV-226) Coupling was performed in the same manner as in Example 2 above to give compound (IV-
226) 40 mg (24.9%) was obtained. IRvmax (nujol): 3330, 1696, 165
0, 1603, 1540 cm ^-1 NMR (CDCl ₃ + CD ₃ OD) δ: 1.82 (2H,
qui, J = 7.0 Hz), 2.20 (2H, t, J =
7.2 Hz), 2.42 (3 H, s), 2.67 (2
H, t, J = 6.7 Hz), 3.2-3.4 (4H,
m), 3.44 (3H, s), 3.64 (2H, s),
5.32 (1H, s), 6.44 (1H, s), 6.8
5-7.0 (2H, m), 7.1-7.5 (9H,
m), 7.62 (1H, m) Elemental analysis (as C ₃₆ H ₄₀ N ₁₀ O ₅ S ₂ 1.2H ₂ O) Found: C, 55.61; H, 5.51; N, 17. 9
3; S, 8.13 Calcd: C, 55.54; H, 5.49; N, 17.9
9; S, 8.24

Example 23 1-Methyl-3- (N'-
(M-Tolyl) ureido) -5- (3- (5- (5-
(3- (3- (Piperidinomethyl) phenoxy) propylamino) thia-3,4-diazol-5-yl) pentylcarbamoylmethoxy) phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (I
V-230)

[Chemical 44] 1) 2- (3- (3- (3- (piperidinomethyl) phenoxy) propylamino) -5- (3-carbomethoxy) propylamido) thia-3,4-diazole (IV-22
7) 4-Carbomethoxybutyric acid chloride (350 mg, 2.13)
a solution of mM) in dichloromethane (5 ml) was added to the amine (IV-
219) (513 mg, 1.476 mM) and triethylamine (1 ml) in dichloromethane (20 ml). The solution was stirred at room temperature for 5 hours, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was treated with silica gel (4
0g) and chloroform: methanol (10: 1) and chromatographed from dichloromethane: ether to give compound (IV-227) as a solid.
Obtained 550 mg (78.3%).

2) 2- (3- (3- (3- (piperidinomethyl) phenoxy) propylamino) -5- (5-hydroxypentylamino) thia-3,4-diazole (IV
-228) Amide (IV-227) (527 mg, 1.108 mM) and lithium aluminum hydride (85 mg, 2.239 m)
A mixture of M) in tetrahydrofuran (20 ml) was stirred at room temperature for 2 hours and heated under reflux for 3 hours. Ethyl acetate and then brine were added under ice cooling. The insoluble material was filtered and extracted with chloroform: methanol (9: 1). The filtrate was concentrated under reduced pressure and the residue was chromatographed using silica gel (20 g), chloroform: methanol (10: 1 to 7: 1) to give 392 mg of compound (IV-228).
(83.9%) was obtained.

3) 2- (3- (3- (piperidinomethyl) phenoxy) propylamino) -5- (5-azidopentylamino) thia-3,4-diazole (IV-2
29) The above alcohol (IV-228) (392 mg, 0.93)
To a solution of 0 mM) in tetrahydrofuran (5 ml) was added a solution of 0.5 M hydrazonic acid and triphenylphosphine (270 mg, 1.03 mM) in benzene (2 ml). Diethyl azodicarboxylate (180mg, 1.03m
A solution of M) in tetrahydrofuran (1 ml) was added under ice cooling. The mixture was stirred at room temperature for 20 hours. The volatile substances were distilled off under reduced pressure. The residue was chromatographed on silica gel (40 g), chloroform: methanol (10: 1) to give compound (IV-229) 222 mg (5).
2.2%) was obtained as an oil. 4) Compound (IV-230) A mixture of azide (IV-229) (222 mg, 0.486 mM) and 5% palladium / C (100 mg) in methanol (2.5 ml) was stirred in the presence of hydrogen for 20 hours. The catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure, the residue (186 mg, 89.0%) and carboxylic acid (IV-9) (250 mg, 0.529 mM) were treated in the same manner as described above, and compound (IV-230) 160 mg (41.
8%). IRνmax: 3374, 3343, 1670, 160
1,1555,1516 cm ^-1 NMR (CDCl ₃ ) δ: 1.16 (2H, qui, J
= 6.9 Hz), 1.45 (6H, m), 1.62 (4
H, m), 2.03 (2H, qui, J = 6.2H
z), 2.26 (3H, s), 2.46 (4H, m),
3.10 (2H, q, 6.6Hz), 3.27 (2H,
m), 3.43 (5H, s), 3.51 (2H, s),
4.02 (2H, t, J = 6.0Hz), 4.47 (1
H, d, J = 15.0 Hz), 4.52 (1H, d, J
= 15.0 Hz), 5.41 (2H, m), 5.58
(1H, d, J = 8.2 Hz), 6.62 (1H, t,
J = 5.8 Hz), 6.71-7.43 (5H, m),
7.58 (1H, m), 7.88 (1H, d, J = 8.
2 Hz), 8.10 (1 H, s) Elemental analysis (as C ₄₈ H ₅₈ N ₁₀ O ₅ S 0.9 H ₂ O) Found: C, 63.82; H, 6.71; N, 15.3
8; S, 3.56 calculated: C, 63.82; H, 6.67; N, 15.5.
1; S, 3.55

Experimental Example 1 The pharmacological effects of the compounds prepared in the above-mentioned examples were evaluated by antagonizing the gastrin receptor using guinea pig gastric mucosa, and using mouse cerebral cortex CCK receptor (CCK-B receptor) and pancreas. The two items of the antagonism against the CCK receptor (CCK-A) that were present were examined in vitro.

Experimental animals : Male Sprague Dawley rats (body weight 220 to 270 g), male Hartley guinea pigs (body weight 450 to 600 g) or male ddY mice (body weight 24 to 30 g) were used. Drug: L-365,26 as a gastrin receptor antagonist
0 (the compound described in Example 281 of JP-A-63-238069), and the others were commercially available.

(1) In vitro gastrin receptor antagonism Preparation of gastric gland: Male Hartley guinea pig (weight 450-600
Immediately after slaughtering of g), the stomach is taken out, the greater curvature is incised, and the contents are washed in cold water. 2. Krebs Bicarb Solution (Krebs Bicarb Solution)
After washing with onate Solution) (ice cooling), wipe the mucus lightly with absorbent cotton soaked with 1M NaCl (ice cooling) and wash with Krebs solution. 3. The mucous membrane surface is lightly wiped with absorbent cotton soaked with Krebs solution, the mucous membrane is peeled off using a slide glass, added to Hank's Balanced Solt Solution containing 0.1% BSA, and washed.

4. 0.1 exfoliated mucous membrane dissolved in Hank's solution
% Collagenase solution is added, and the mixture is incubated at 37 ° C. for 20 minutes with intermittent light shaking. Decant the supernatant, add 0.1% collagenase solution,
Incubate for another 20 minutes. Aspiration and discharge are repeated 3 to 4 times using a 5.20 ml syringe to separate cells (not isolated cells, 5 to 10 adherent gastric glands) and filter (200 nylon mesh). . After centrifugation at 6.270 xg (1000 rpm) for 3 minutes, the supernatant is discarded, 0.2% neutral protease (EC3.4.24.) Solution dissolved in Hank's solution is added, and the mixture is incubated at 37 ° C for 15 minutes. After centrifugation at 7.270 × g (1000 rpm) for 3 minutes, the supernatant is discarded, Krebs solution containing 0.1% BSA and 25 mg / 100 ml bacitracin is added, and the cells are washed by pipetting in the same manner. Repeat 3 times. All the above operations are performed under aeration of 95% CO ₂ -5% O ₂ . 8. Count the number of viable cells. An equal volume of 0.4% trypan blue is added to 50 μl of the cell solution, shaken lightly to stain dead cells, and then the number of viable cells is counted. Dilute to 10 ⁶ cells / ml in incubation medium, seal and keep on ice until use.

Binding Assay a) Preparation of Test Compound Approximately 2 mg each was weighed into a 20 ml glass vial,
Dissolve in DMSO solution to make 1 mM concentration. Then, using a tube, prepare 250 μM (final concentration 10 μM) diluted with 50% DMSO solution. Further, each 1/10 concentration is diluted to 25 nM (final concentration 1 nM). 10 μl of test compound and [ ¹²⁵ I] gastrin (5n in a tube)
M) 10 μl and cells (10 ⁶ cells / ml) 230 μl are added. After incubating at 25 ° C for 30 minutes,
Centrifuge at 3000 rpm for 5 minutes and aspirate the supernatant. Add 0.5 ml of ice-cooled Krebs solution, mix gently, and immediately centrifuge to remove the supernatant by suction. Radioactivity is measured by a gamma counter. The total binding number was measured in the same manner by using 10 μl of 50% DMSO solution instead of the test compound, and the nonspecific binding number was measured by using 10 μl of human gastrin I (50 μM). e) Calculation of IC _50: IC _50; specific binding number of the test compound (total binding count (cpm) one non-specific bound counts (cpm))
Was calculated and determined.

(2) In vitro CCK-A and -B receptor antagonistic action Preparation of CCK receptor preparation: Male ddY mouse (body weight 24 to
After decapitating 30 g), the cerebral cortex (CCK-B) and pancreas (CCK-A) were rapidly removed. Preparation of receptor specimen (crude membrane fraction): 1. The mouse is killed by decapitation, and immediately the cerebrum and pancreas are taken out and washed with a pre-cooled PBS solution to separate the cortex from the cerebrum. 2. The cerebral cortex and pancreas are 50 mM Tris buffer (p
Wash again with H7.4, cooling). 3. Weigh each to 1.5-2.0 g / vial and store at −80 ° C. until use.

4. Add 10 volumes of 50 mM Tris buffer, homogenize (7 strokes) with a Teflon-glass homogenizer, and further homogenize for 20 seconds with a Polytron homogenizer. 5. Centrifuge at 40,000 xg for 15 minutes to obtain a pellet. 6. Add 10-fold volume of 50 mM Tris buffer, homogenize for 20 seconds with a Polytron homogenizer, and centrifuge in the same manner to obtain a pellet (repeat twice, measure protein amount). 7. 10 times volume of incubation buffer 10 mM
HEPES, 130 mM NaCl, 4.7 mM KC
1, 5 mM MgCl ₂ .6H ₂ O, 1 mM EGTA,
5 mg / ml BSA and 0.25 mg / ml bacitrosin) were added, and the mixture was mixed with a Polytron homogenizer to give 20
After homogenizing for 2 seconds, the cerebral cortex was finally diluted 40-fold and the pancreas was diluted 200-fold with the same buffer.
B and CCK-A receptor specimens.

Displacement Assay a) Preparation of Test Compound Approximately 2 mg each was weighed into a 20 ml glass vial,
Dissolve in DMSO solution to make 1 mM concentration. Next, using a Shionogi tube, 250 μM in 50% DMSO solution
Make (final concentration 10 μM) diluted. Furthermore, 1/10
Dilute to 25 nM (final concentration 1 nM) for each concentration.
20 μl of test compound in a tube, [ ³ H] CCK-8
Add 10 μl (50 nM) and 470 μl of receptor preparation. After incubating at 25 ° C. for 90 minutes, suction filtration (Whatman glass microfilter, GF / C) and washing with cold 50 mM Tris buffer three times are performed. 5
Add ml of Aquasol-2 octyl, leave for a few hours after shaking and count radioactivity for 5 minutes. To measure the total number of binding, 20 μl of 50% DMSO solution was used instead of the test compound,
For the measurement of the number of nonspecific binding, cerulein
The same procedure was performed using 20 μl of (25 nM). e) IC ₅₀ IC ₅₀ : Specific binding number of test compound (total binding number (dpm)
The number was determined by calculating the number of non-specific bindings (dpm). The results are summarized in Tables 1 and 2 below.

Experimental Example 2 PA ₂ was determined by the following method, and the histamine H ₂ receptor antagonistic activity in vitro was examined. A male Hartley guinea pig (body weight 450-600 g) was exsanguinated to death, the right atrium was removed, and a Magnus device (Krebs bicarbonate buffer aerated with 95% O ₂ and 5% CO ₂ at 30 ° C.)
Suspended. The chronotropic effect was investigated by cumulatively administering this device histamine. Calculation of pA ₂ which is a parameter of histamine H ₂ receptor antagonism was determined as a negative logarithm of the antagonist required for parallel translocation of the histamine dose-response curve to the high concentration side by 2 times. Kazunari Takayanagi Basic Medicine Development Course V (edited by Kyosuke Tsuda, Hisashi Nogami,
Chijinkan) p731-776, Tokyo (1974) and Van Rossum J.
M., Arch.Int.Pharmacodyn. Ther. 143: 299-330 (196
3)]. The results are shown in Table 2.

[0094]

[Table 1]

[0095]

[Table 2]

[0096]

[Table 3]

[0097]

[Table 4]

[Chemical formula 45]

Experimental Example 3 In this Experimental Example, in order to show the usefulness of the benzodiazepine derivative of the present invention, a combination of a histamine H ₂ receptor antagonist (H ₂ B) and a compound having a gastrin receptor antagonistic action was used. The effect of reducing or preventing recurrence of ulcer was investigated based on the enhancement of gastric acid secretion (rebound effect), which is said to lead to the recurrence of ulcer after continuous administration, and the resistance of gastric mucosa after withdrawal.

Experimental Materials Male Sprague Dawley rats (body weight 2
40-280 g) was used. Famotidine as H ₂ B and L-365,260 as gastrin receptor antagonist
Was used. The combination drug is famotidine (molecular weight 337.
Since 4) and L-365,260 (molecular weight 398.44) have almost the same molecular weight, they were prepared at a mixing ratio of 1: 1. For administration famotidine and L-365,260 are 1
0 mg was used by suspending it in 1 ml of vehicle (Vehicle: 0.5% methylcellulose solution). The mixture is a mixture of equal amounts of each suspension.

Administration method The dose (1.0 ml or 3.0 ml / kg) of each test substance was placed in an injection cylinder, and a stainless steel oral sonde needle equipped with this was inserted.
(φ1.2 × L80 mm) was directly inserted into the stomach through the mouth of the rat to perform forced administration. Experimental method A. Single-dose experiment (1) Water immersion restraint stress gastric injury (single-dose experiment) Rats (body weight 27
0-290 g) was orally administered with the test compound, and 30 minutes later, stress was applied by the following method. That is, the rats were placed in a stress cage (produced by Natsume Seisakusho) of the Todai Pharmaceutical Co., Ltd., and immersed in a water tank at 23 ° C. up to the height of the thorax ridge, and stress was applied [Takagi Chem. Pharm. Bull (Tokyo)
12 465-472 (1964)]. After 7 hours, the rat was pulled up from the water tank to kill it with ether, and the stomach was extracted. The excised stomach was injected with 13 ml of 1% formalin solution into the stomach and immersed in the same concentration of formalin solution for 10 minutes to be fixed. The stomach was incised along the greater curvature and extended on a glass plate (hereinafter abbreviated as formalin treatment). The major axis (mm) of each lesion (hemorrhagic erosion) generated in the glandular stomach was measured under a dissecting microscope (× 10).

B. Continuous administration experiment: (A) Vehicle (0.5% methylcellulose solution) administration group (1 ml / kg) (B) Famotidine 10 mg / kg / day continuous administration group (famotidine 10 mg suspended in 0.5% methylcellulose 1 ml), Or famotidine 30 mg / kg / day administration group (C) L-365,260 10 mg / kg / day continuous administration group (D) (famotidine + L-365,260) 10 mg / k each
g / day combination drug administration group

(2) Basal acid secretion after withdrawal by continuous administration of famotidine Famotidine 10 or 30 mg was administered to rats fed normally.
/ Kg was orally administered once a day for 1 week continuously. After the last dose,
Basal gastric acid secretion (total acid excretion) at the time of drug interruption is 10 mg /
For the kg / day continuous administration group, immediately after the final administration, after 24 hours and 48 hours (2 days), and for the 30 mg / kg / day continuous administration group immediately after the final administration, 3 days and 4 days after, respectively, the pylorus ligation method, respectively. (4 hour method) [Shay H.
Gastroenterology, 5 43-61 (1945)] was measured in. That is, the rat was laparotomized under ether anesthesia and the pylorus was ligated. After 4 hours, the stomach was removed again under ether anesthesia, and the stored gastric juice was collected. Gastric juice should be centrifuged (30
00 rpm. After 10 minutes), pH and acidity were measured.
The acidity was titrated with N / 10 NaOH to pH 7.0. Total acid secretion (μEq / 4 hours) by product of acidity and liquid volume
Was calculated.

(3) Aspirin-induced gastric mucosal injury to gastric mucosa after continuous administration of famotidine Famotidine was continuously administered and 200 mg / kg of aspirin was orally administered to the rat on the 2nd day of drug withdrawal. Seven hours later, the stomach was removed under ether anesthesia, and after treatment with a 1% formalin solution, the length (mm) of gastric mucosal injury occurring in the glandular stomach was measured, and the sum was used as the injury coefficient. The rats were fasted for 24 hours before administration of aspirin (however, water was freely given).

Experimental Results (1) Gastric injury due to water immersion restraint stress

[Table 5] Any dose of L-365,260 (1 or 3 mg / kg)
Did not suppress the occurrence of stress gastric injury. The famotidine dose of 3 mg / kg was significantly suppressed. In the combination drug group, a stronger inhibitory effect than any single drug was observed at any dose (Table 3).
reference).

(2) Basal acid secretion after withdrawal by continuous administration of famotidine

[Table 6]

[0106]

[Table 7]

[0107]

[Table 8]

In the famotidine (10 mg / kg / day) continuous administration group, basal gastric acid secretion was significant (P <0.0) immediately after the drug holiday.
Suppressed by 5), significant at 48 hours after drug holiday (P <0.05)
It was recognized that there was a significant increase. On the other hand, famotidine (30m
(g / kg / day) In the continuous administration group, basal gastric acid secretion was suppressed significantly (P <0.05) immediately after withdrawal, but significantly (P <0.05) increased 4 days after withdrawal. (See Tables 4, 5, and 6).

[0109]

[Table 9] On the other hand, the blood gastrin level increased significantly (P <0.05) as compared with the control group immediately after the end of continuous administration as the acid excretion was suppressed. There was almost no difference from the control group until the day after. Famotidine (10 mg / kg) and L-365, L-365, increased the acid excretion after withdrawal by continuous administration of famotidine 10 mg / kg / day.
The combination with 260 (10 mg / kg) tended to suppress the promotion of acid excretion. There was no difference in acid excretion between the control group and the L-365,260 single administration group for 1 week (see Table 7).

(3) Aspirin-induced gastric mucosal damage to gastric mucosa after continuous administration of famotidine

[Table 10] Many linear lesions due to aspirin occurred in the body of the stomach. As is clear from the table, the famotidine continuous administration group,
It showed a significant (P <0.05) deterioration compared with the control group, and the combination administration group of famotidine and L-365,260 suppressed this significantly (P <0.05). In addition, L-365,26
The 0 continuous administration group showed a worsening tendency, but it was not significant.

After the continuous administration of famotidine, the basal acid secretion was enhanced (acid rebound) after the drug was withdrawn (day 2).
This is considered to be a common phenomenon of H ₂ B. Further, when the reactivity of the gastric mucosa of the famotidine continuous administration group to the aspirin gastric mucosal injury was examined, the ulcer index significantly deteriorated on the 2nd day of drug interruption. This is in agreement with the point at which the above acid rebound was observed. From this, it was suggested that the defense mechanism of the gastric mucosa of famotidine treatment is weakened. Furthermore, the facilitating effects of acid rebound and aspirin gastric mucosal injury by famotidine were observed in L-365,260.
It was revealed that it can be suppressed by using a mixture with These results generally indicate that the development of gastric disorders after H ₂ B ulcer treatment can be prevented by the combined use with gastrin receptor antagonists (see Table 8). The above results strongly suggest that the benzodiazepine derivative of the present invention is useful as an anti-ulcer therapeutic agent that does not cause recurrence of ulcer after treatment or has reduced recurrence.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI technical display location C07D 277: 00) (72) Inventor Yasunobu Ishihara 61 Nishikujo Needle Kojimachi, Minami-ku, Kyoto City, Kyoto Prefecture

Claims (7)

[Claims] 1. Formula I: [Wherein R ¹ and R ³ are each independently hydrogen, halogen, lower alkyl or lower alkyloxy; R ² is hydrogen or lower alkyl; R ⁴ is a single bond or —CO—;
R ⁵ is an aliphatic heterocycle or —NH—; R ⁶ is a C ₁ -C ₁₅ alkylene which may have a substituent or a C ₂ -C ₁₅ alkenylene which may have a substituent (however, The alkylene and the alkenylene may be O, within the groups themselves and / or between those groups and adjacent groups,
One or more groups selected from S and NH may be interposed); R ⁷ is any of the following groups: [Chemical 3] [Chemical 4] [Chemical 5] Represents a benzodiazepine derivative or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R ¹ is hydrogen and R ² and R ³ are both lower alkyl. 3. The compound according to claim 1, wherein the aliphatic heterocycle is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or dioxanyl. 4. The alkylene is-(CH ₂ CH ₂ R ⁸ ) p.
(CH ₂ ) qR ⁹ (CH ₂ ) r- (wherein R ⁸ and R
⁹ are each independently a single bond, O, S or NH; p
Is an integer of 0 to 5; q is an integer of 1 to 3; r is an integer of 0 to 2). 5. The compound according to claim 4, wherein R ⁸ is O, p is 2 or 3, and R ⁹ is a single bond. 6. The alkenylene is-(CH ₂ --C
The compound according to claim 1, which is a group represented by (R ¹⁰ ) = CH) q- (wherein R ¹⁰ is hydrogen, hydroxy, methyl, or halogen; q represents an integer of 1 to 3). 7. An anti-ulcer agent containing the compound according to claim 1.