JPH09157261A - Phenylazole compound and benzotriazolodiazepine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having Cholecystokinin and gastrin- antagonizing actions, especially having a strong antagonizing action on Cholecystokinin-A receptor, and useful as a medicine for preventing and treating pancreatitis, etc. SOLUTION: A compound of formula I (R<1> , R<2> are each H, a halogen, cyano, nitro, OH, etc.; R<3> is H, a 1-5C alkyl, etc.; Ar<1> is a substituted phenyl, pyridyl, thienyl; Y<1> NHCO, NHSO2 , OCO, etc.; Z<1> is an aryl, a heteroaryl, etc.,) or its salt. For example, N-(4-(2-benzoylphenyl)-5-methyl-1,2,4-triazol-3-ylmethyl)-3,4- dichlorobenzamide. The compound of formula I is obtained by condensing an amino compound of formula II with a carboxylic acid of the formula: HOOC-Z<1> . The compound of formula I exhibits a strong and durable pancreatic enzyme- inhibiting action and a strong and durable gastric acid secretion-inhibiting action, and is useful for preventing and treating anxiety, schizophrenia, pancreatitis, cholecystitis, gastric ulcer, intestinal ulcer, hypersensitive colon syndromes, coprostasis, pancreatic cancer, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cholecystokinin (hereinafter also referred to as CCK) and gastrin antagonistic action,
In particular, the present invention relates to a novel phenylazole compound and benzotriazolodiazepine compound having a strong antagonistic action on the CCK-A receptor and is used in the medical field.

[0002]

2. Description of the Related Art So far, muscle relaxation, anticonvulsant action,
A phenyltriazole compound having an action on the central nervous system such as a sedative action, anxiolytic action, and hypnotic action (Japanese Patent Laid-Open Publication No. 5 (1999) -58242).
No. 3-59696), benzotriazolodiazepine compounds showing effects on the central nervous system such as convulsions and anti-aggressive action (JP-A-48-92399), anxiolytics, anticonvulsants, hypnotics, etc. Phenylamide compounds used as medicines or raw materials for their synthesis
No. 113952), a phenylamide compound showing an action on the central nervous system such as a muscle relaxing action and a stimulation suppressing action (JP-A-51-34136), treatment of tumor diseases, regulation of pupillary contraction, drug or Benzodiazepine compounds useful in the treatment of withdrawal symptoms caused by treatment with alcohol or abuse (JP-A-6-321917), benzodiazepine compounds having a cholecystokinin antagonistic action (JP-A-6-80649, JP-A-6-80649)
-87838) and the like are known.

Further, JP-A-49-102698 describes that a thienotriazolodiazepine compound is used as a tranquilizer and anxiolytic. Furthermore, JP-A-2-28181 and JP-A-3-2232
No. 90 discloses a thienotriazolodiazepine compound having a cholecystokinin antagonistic action.

[0004]

Problems to be Solved by the Invention Cholecystokinin (C
CK) is a neuropeptide consisting of 33 amino acids, and it also has activity in a fragment peptide (also called CCK-8) composed of 8 amino acids at the C-terminal side. On the other hand, gastrin is a peptide consisting of 34 amino acids, and is active even in pentagastrin composed of 5 amino acids at the C-terminal side, and the amino acid sequence of pentagastrin is the same as the C-terminal side of CCK. Regarding CCK receptors, the existence of different subtypes has been reported, and CC distributed mainly in peripheral tissues such as pancreas and gallbladder.
It is classified into KA receptors and CCK-B receptors distributed in central tissues. Further, the CCK-B receptor and the gastrin receptor are considered to be the same. As the physiological actions of CCK via the CCK-A receptor, secretion of pancreatic juice, promotion of insulin release, regulation of pepsinogen secretion, stimulation of gastric emptying and ileal motility, contraction of gallbladder, etc. have been reported. on the other hand,
Physiological actions of CCK through the CCK-B receptor include suppression of stomach hunger, regulation of dopaminergic nerves, regulation of pain and morphine analgesia, and memory promotion.
The KB receptor antagonist is effective for treating and preventing gastrointestinal ulcer, vomiting, appetite regulation, pain, anxiety, dementia, schizophrenia and the like.

In recent years, in the study of pancreatitis, CCK has become CC
It has been reported to be involved in the onset, progression and exacerbation of pancreatitis via the KA receptor. Pancreatitis is a condition in which pancreatic tissue is digested by enzymes secreted by the pancreas itself (autolysis)
However, pancreatic enzyme inhibitors such as trypsin inhibitor are mainly used for the treatment. However, the effect is not always satisfactory, and a drug having a higher therapeutic effect is required. Unlike an enzyme inhibitor, a CCK-A receptor antagonist suppresses pancreatic enzyme secretion itself and is useful as a novel therapeutic and prophylactic agent for pancreatitis. It is also useful for the treatment and prevention of gallbladder disorders, irritable bowel syndrome, gastrointestinal ulcers, vomiting, pancreatic cancer, constipation and the like.

As a review article on the physiological actions of CCK and the usefulness of CCK antagonists from a therapeutic standpoint, for example, Annual Review of Pharmacology and Toxicology (Annu. Rev. Pharmacol. Toxicol.) No. 31. Volume, page 469, 1991. For the compound having a CCK-A antagonistic action, Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 27,
1597, Proglumide in 1984, Journal of Medicinal Chemistry (J. Med. Chem.).
Volume 31, 2235, Devasepide in 1988 etc.
[3 (S) -1,3-dihydro-3- (2-indolecarbonylamino) -1-methyl-5-phenyl-2H
-1,4-benzodiazepin-2-one], a benzodiazepine compound represented by JP-A-5-1558.
No. 71 discloses 2-acylamino-5-thiazole derivatives and the like. However, these compounds are not effective in vitro or in vivo on CCK.
-It is not satisfactory in terms of selectivity for A receptor, physicochemical properties (solubility in water, etc.), bioavailability, safety, etc.

[0007]

The present inventors have found that CCK-
As a result of intensive studies aimed at providing a useful compound capable of selectively blocking the A receptor and being used for the prevention and treatment of various diseases related to peripheral CCK, a certain phenylazole The inventors have found that the compound and the benzotriazolodiazepine compound achieve the object, and have completed the present invention. That is, the present invention is as follows.

General formula

[0009]

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[In the formula, R ¹ and R ² are the same or different and each is hydrogen, halogen, cyano, nitro, a hydroxyl group, or a carbon number of 1 to 1.
5 alkyls, 1 to 5 carbons alkoxy, 1 to 1 carbons
A haloalkyl of 2 and a formula — (CH ₂ ) n ¹ COOR ⁴ (in the formula, n ¹ represents 0 or an integer of 1 to 5. R ⁴ represents hydrogen, alkyl having 1 to 5 carbons, and 3 to 7 carbons. A group represented by cycloalkyl or aralkyl).
Formula ^{_{- (CH 2) n 2 R}} 5 (.R 5 shown in the formula, n ² is an integer of 0 or 1 to 5 5-
Indicates a tetrazolyl group. ) Groups represented by or ^{_{formula, - (CH 2) n 3}} N (R 6) (R 7) (.R 6 shown in the formula, n ³ is 0 or an integer of 1 to 5, R ⁷
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, R ⁶ and R ⁷ may combine with adjacent nitrogen atoms to form a heterocycle. ) Is shown.

R ³ is hydrogen, alkyl having 1 to 5 carbon atoms, 1
~ Alkyl having 1 to 5 carbon atoms substituted with 3 hydroxyl groups, cycloalkyl having 3 to 7 carbon atoms, 1 to 3 on the aromatic ring
Aralkyl substituted with pieces of hydroxyl, heteroarylalkyl, formula ^{_{- (CH 2) n 4 COOR}} 8 ( wherein, .R ⁸ n ⁴ is represents an integer of 0 or 1 to 5 hydrogen, 1 to carbon atoms 5 represents alkyl, aralkyl or cycloalkyl having 3 to 7 carbon atoms),
Formula ^{_{- (CH 2) n 5 N}} (R 9) (R 10) ( wherein, n ⁵ is an integer of 0 or 1~5 .R ^9, R ¹⁰
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, R ⁹ and R ¹⁰ may combine with adjacent nitrogen atoms to form a heterocycle. Group represented by the formula:-(CH ₂ ) n ⁶ CON (R ¹¹ ) (R ¹² ) (In the formula, n ⁶ represents 0 or an integer of 1 to 5. R ¹¹ , R ¹²
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, ¹¹ and R ¹² may combine with an adjacent nitrogen atom to form a heterocycle. Or a group represented by the formula: — (CH ₂ ) n ⁷ R ¹³ (wherein, n ⁷ represents 0 or an integer of 1 to 5. R ¹³ represents 5-
Indicates a tetrazolyl group. ) Is shown.

-A = B- is -N = N-, -C (R ²⁷ ) =
N- or -C (R ²⁷⁾ = CH- (wherein, R ²⁷ is hydrogen,
Halogen, alkyl having 1 to 5 carbons, alkyl having 1 to 5 carbons substituted with 1 to 3 hydroxyl groups, 2 to carbons
Alkanoyl having 5 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, haloalkyl having 1 to 2 carbon atoms, alkenyl, alkynyl,
Cycloalkylalkyl, aryl, heteroaryl,
Aralkyl, heteroarylalkyl, aryloxyalkyl, adamantyl, adamantylmethyl, formula ^{_{- (CH 2) n 8 COOR}} 14 ( wherein, .R ¹⁴ n ⁸ is showing an integer of 0 or 1 to 5 hydrogen, C 1 -C . for 5 represents an alkyl or aralkyl) with a group represented the formula ^{_{- (CH 2) n 9 CON}} (R 15) (R 16) ( wherein, n ⁹ is an integer of 0 or 1-5. R ¹⁵ , R ¹⁶
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, R ¹⁵ and R ¹⁶ may combine with adjacent nitrogen atoms to form a heterocycle. ) Groups represented by or ^{_{formula, - (CH 2) n 10}} N (R 17) (R 18) ( wherein, n ¹⁰ represents an integer of 0 or 1 to 5 .R ^17, R
¹⁸ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ¹⁷ and R ¹⁸ may combine with adjacent nitrogen atoms to form a heterocycle. ) Is shown. ).

Z ¹ is aryl, heteroaryl, or a group represented by the formula —CH═CH—R ¹⁹ (wherein R ¹⁹ represents cycloalkyl, aryl or heteroaryl having 3 to 7 carbon atoms). Shown on these rings are halogen, hydroxyl group, amino, nitro, alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups, and alkanoyl having 2 to 5 carbon atoms. , Haloalkyl having 1 to 2 carbons, 1 carbon
5 alkoxy, alkylthio having 1 to 5 carbon atoms, aryloxy of the formula ^{_{- (CH 2) n 11 COOR}} 20 ( wherein, n ¹¹ .R ²⁰ is showing an integer of 0 or 1 to 5 hydrogen, carbon atoms groups represented by) shows a 1-5 alkyl or aralkyl, wherein ^{_{-. (CH 2) n 12}} CON (R 21) (R 22) ( wherein, n ¹² represents an integer of 0 or 1 to 5 . R ²¹ , R
²² is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ²¹ and R ²² may combine with adjacent nitrogen atoms to form a heterocycle. Group represented by the formula:-(CH ₂ ) n ¹³ N (R ²³ ) (R ²⁴ ) (In the formula, n ¹³ represents 0 or an integer of 1 to 5. R ²³ , R
²⁴ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ²³ and R ²⁴ may combine with an adjacent nitrogen atom to form a heterocycle. And a group represented by the formula: — (CH ₂ ) n ¹⁴ R ²⁵ (wherein n ¹⁴ is 0 or an integer of 1 to 5. R ²⁵ is 5
-Indicates a tetrazolyl group. May have an arbitrary number of substituents selected from the groups represented by

Y ¹ is --NHCO--, --NHCONH--,
_{-NHCSNH -, - NHSO 2 -,} - NHCOO-,
-OCONH-, -OCO-, -NHCONHCO-,
_{-NHCSNHCO -, - NHCONHSO 2 -,} - N
HCSNHSO ₂ — or —NHCOCONH—. Ar ¹ is phenyl, pyridyl, thienyl or halogen on the ring, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons, 1 to 5 carbons.
Alkylthio, carboxyl, carboxyalkyl,
At least 1 selected from nitro, amino and hydroxyl group
Represents phenyl, pyridyl, and thienyl having 3 substituents. ] The phenylazole compound represented by or its pharmaceutically acceptable salt, and general formula

[0015]

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[In the formula, R ³¹ and R ³² are the same or different and each is hydrogen, halogen, cyano, nitro, a hydroxyl group, or a carbon number of 1 to 1.
5 alkyls, 1 to 5 carbons alkoxy, 1 to 1 carbons
A haloalkyl of 2 and a formula — (CH ₂ ) n ²¹ COOR ³⁵ (in the formula, n ²¹ represents 0 or an integer of 1 to 5. R ³⁵ is hydrogen, alkyl having 1 to 5 carbons, or 3 to 7 carbons. A group represented by cycloalkyl or aralkyl).
Formula ^{_{- (CH 2) n 22 R}} 36 (.R 36 shown wherein, n ²² represents an integer of 0 or 1 to 5 5
-Indicates a tetrazolyl group. ) Groups represented by or ^{_{formula, - (CH 2) n 23}} N (R 37) (R 38) (.R 37 shown wherein, n ²³ represents an integer of 0 or 1 to 5, R
³⁸ are the same or different and each represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ³⁷ and R ³⁸ may combine with an adjacent nitrogen atom to form a heterocycle. ) Is shown.

R ³³ is hydrogen, alkyl having 1 to 5 carbon atoms, 1
~ Alkyl having 1 to 5 carbon atoms substituted with 3 hydroxyl groups, cycloalkyl having 3 to 7 carbon atoms, 1 to 3 on the aromatic ring
Number of aralkyl hydroxyl groups are substituted, heteroarylalkyl, formula ^{_{- (CH 2) n 24 COOR}} 39 ( wherein, n ²⁴ is .R ³⁹ represents an integer of 0 or 1 to 5 hydrogen, 1 to carbon atoms 5 represents alkyl, aralkyl or cycloalkyl having 3 to 7 carbon atoms),
Formula ^{_{- (CH 2) n 25 N}} (R 40) (R 41) ( wherein, n ²⁵ is .R ⁴⁰ represents an integer of 0 or 1 to 5, R
⁴¹ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁴⁰ and R ⁴¹ may be bonded to adjacent nitrogen atoms to form a heterocycle. Group represented by the formula:-(CH ₂ ) n ²⁶ CON (R ⁴² ) (R ⁴³ ) (In the formula, n ²⁶ represents 0 or an integer of 1 to 5. R ⁴² , R
⁴³ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁴² and R ⁴³ may combine with an adjacent nitrogen atom to form a heterocycle. Or a group represented by the formula: — (CH ₂ ) n ²⁷ R ⁴⁴ (wherein n ²⁷ is 0 or an integer of 1 to 5. R ⁴⁴ is 5
-Indicates a tetrazolyl group. ) Is shown.

R ³⁴ is hydrogen, alkyl having 1 to 5 carbons, and the formula-(CH ₂ ) n ²⁸ COOR ⁴⁵ (wherein n ²⁸ is 0 or an integer of 1 to 5. R ⁴⁵ is hydrogen or carbon number. . group represented by showing a 1-5 alkyl or aralkyl), or the formula - a ^{_{(CH 2) n 29 n (}} R 46) (R 47) ( wherein integer n ²⁹ is 0 or 1-5 Shown R ⁴⁶ , R
⁴⁷ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁴⁶ and R ⁴⁷ may combine with adjacent nitrogen atoms to form a heterocycle. ) Is shown.

M represents 0 or an integer of 1 to 5. Y ² is -NHCO-, -NHCONH-, -NHCSNH-,
_{-NHSO 2 -, - NHCOO -,} - OCONH -, -
OCO-, -NHCONHCO-, -NHCSNHCO
_{-, - NHCONHSO 2 -, -} NHCSNHSO 2 -
Or -NHCOCONH- is shown.

Z ² is represented by aralkyl, aryl, heteroaryl, or the formula —CH═CH—R ⁴⁸ (wherein R ⁴⁸ represents cycloalkyl, aryl or heteroaryl having 3 to 7 carbon atoms). Represents a group, on these rings, halogen, hydroxyl group, amino, nitro, alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups, and 2 to 5 carbon atoms. Alkanoyl, C 1-2 haloalkyl, C 1
5 alkoxy, alkylthio having 1 to 5 carbon atoms, aryloxy of the formula ^{_{- (CH 2) n 30 COOR}} 49 ( wherein, n ³⁰ .R ⁴⁹ is showing an integer of 0 or 1 to 5 hydrogen, carbon atoms groups represented by showing a 1-5 alkyl or aralkyl), wherein -. shows a ^{_{(CH 2) n 31 CON (}} R 50) (R 51) ( wherein, n ³¹ is 0 or an integer of 1 to 5 . R ⁵⁰ , R
⁵¹ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁵⁰ and R ⁵¹ may combine with adjacent nitrogen atoms to form a heterocycle. Groups represented by) the formula ^{_{- (CH 2) n 32 N}} (R 52) (R 53) (.R 52 shown wherein, n ³² represents an integer of 0 or 1 to 5, R
⁵³ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁵² and R ⁵³ may combine with adjacent nitrogen atoms to form a heterocycle. And a group represented by the formula: — (CH ₂ ) n ³³ R ⁵⁴ (wherein n ³³ is 0 or an integer of 1 to 5. R ⁵⁴ is 5
-Indicates a tetrazolyl group. May have an arbitrary number of substituents selected from the groups represented by

Ar ² is phenyl, pyridyl, thienyl or halogen on the ring, alkyl having 1 to 5 carbons, and 1 carbon.
~ 5 alkoxy, haloalkyl having 1 to 2 carbon atoms, alkylthio having 1 to 5 carbon atoms, phenyl, pyridyl and thienyl having at least one substituent selected from carboxyl, carboxyalkyl, nitro, amino and hydroxyl group. ] The benzotriazolodiazepine compound represented by these, or its pharmaceutically acceptable salt.

The present invention also provides a medicament comprising a phenylazole compound of the general formula (I) or a pharmaceutically acceptable salt thereof, a phenylazole compound of the general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a carrier, a pharmaceutical comprising a benzotriazolodiazepine compound of the general formula (II) or a pharmaceutically acceptable salt thereof, and a benzotriazolodiazepine compound of the general formula (II) or a pharmaceutical thereof. There is also provided a pharmaceutical composition comprising an acceptable salt and a pharmaceutically acceptable carrier.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (I), specific examples of each definition are as follows. In R ¹ and R ² , halogen is chlorine, bromine, fluorine or iodine. Carbon number 1
The alkyl of 5 represents a linear or branched alkyl and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl and the like, and methyl, ethyl, propyl and isopropyl are preferable. The alkoxy having 1 to 5 carbon atoms represents a linear or branched alkoxy, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, and isopentyloxy. Methoxy and ethoxy are preferable, and methoxy is particularly preferable. The haloalkyl having 1 to 2 carbon atoms represents chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl and the like, and trifluoromethyl is preferable.

In R ³ , alkyl having 1 to 5 carbons has the same meaning as described above. Examples of the alkyl having 1 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl, and hydroxymethyl is preferable. Examples of the cycloalkyl having 3 to 7 carbon atoms include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl, and cyclohexyl is preferable. Aralkyl substituted with 1 to 3 hydroxyl groups on the aromatic ring means 4-hydroxybenzyl, 3,4
-Dihydroxybenzyl, 2- (4-hydroxyphenyl) ethyl, 2- (3,4-dihydroxyphenyl) ethyl and the like are shown. Heteroarylalkyl includes indolylmethyl, pyridylmethyl, quinolylmethyl, thienylmethyl, furylmethyl and the like.

Examples of aryl in Z ¹ and R ¹⁹ include phenyl and naphthyl, with phenyl being preferred. Heteroaryl is pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,
Thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolinyl, benzofuranyl, 2,
3-dihydrobenzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl and the like, 3-quinolyl, 2-benzofuranyl, 2,3-dihydro-7-benzofuranyl, 2-Benzothienyl, 2-indolyl, 2-indolinyl and the like are preferable, and 2-indolyl is particularly preferable. In the substituents on the ring of aryl, heteroaryl and R ¹⁹ , halogen, alkyl having 1 to 5 carbons, alkyl having 1 to 5 carbons substituted with 1 to 3 hydroxyl groups, and 1 to 1 carbons The haloalkyl having 2 and the alkoxy having 1 to 5 carbons have the same meanings as described above. Examples of the alkanoyl having 2 to 5 carbon atoms include acetyl, propionyl, butyryl, valeryl and pivaloyl. With alkylthio having 1 to 5 carbon atoms,
It represents a linear or branched alkylthio, and includes methylthio, ethylthio, propylpyrthio, isopropylthio, butylthio, isobutylthio, tertiary butylthio, pentylthio, isopentylthio, etc., and methylthio is preferable. Examples of aryloxy include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

In Ar ¹ , halogen which is a substituent on phenyl, pyridyl and thienyl, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons and 1 to 5 carbons. Alkylthio has the same meaning as above. Carboxyalkyl means carboxymethyl, 2-
Examples thereof include carboxyethyl, and carboxymethyl is preferable.

R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,
R ¹¹ , R ¹² , R ²⁷ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R
The alkyl having 1 to 5 carbon atoms in ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ has the same meaning as described above. R ⁴ , R ⁸ , R ²⁷ , R ¹⁴ ,
Aralkyl in R ²⁰ represents benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl and the like.

Cycloalkyl having 3 to 7 carbon atoms in R ⁸ , R ²⁷ and R ¹⁹ has the same meaning as described above. R ⁶ , R ⁷ , R ⁹ ,
R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ²¹ ,
In R ²² , R ²³ and R ²⁴ , the hetero ring formed by bonding to adjacent nitrogen atoms is 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1- Piperazinyl, 1-azepinyl, morpholino, thiomorpholino, 4
-Methyl piperidino, phthalimide, succinimide and the like.

In R ²⁷ , halogen, alkyl having 1 to 5 carbon atoms, and 1 carbon atom substituted with 1 to 3 hydroxyl groups
The alkyl having 5 to 5, the alkanoyl having 2 to 5 carbons and the cycloalkyl having 3 to 7 carbons have the same meanings as described above. Alkenyl means alkenyl having 2 to 6 carbon atoms, such as vinyl, propenyl, 2-methyl-1-propenyl, 1-butenyl,
3-butenyl, 3-hexenyl and the like can be mentioned. Alkynyl is ethynyl, 1-propynyl, propargyl,
3-hexynyl etc. are mentioned. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like. Aryl includes phenyl and naphthyl, with phenyl being preferred. Heteroaryl is pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, benzoxazolyl, benz. Imidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl and the like, 3
-Quinolyl, 2-benzofuranyl, 2,3-dihydro-
7-benzofuranyl, 2-benzothienyl, 2-indolyl, 2-indolinyl and the like are preferable, and 2-indolyl is particularly preferable. Aralkyl means benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl and the like. Heteroarylalkyl includes indolylmethyl, pyridylmethyl, quinolylmethyl, thienylmethyl, furylmethyl and the like. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, and 4-phenoxybutyl.

In the general formula (I), preferred ranges are as follows. R ¹ and R ² are the same or different and are hydrogen,
Represented by alkyl having 1 to 2 carbons or by the formula — (CH ₂ ) n ¹ COOR ⁴ (wherein n ¹ represents 0 or 1; R ⁴ represents hydrogen or alkyl having 1 to 4 carbons). Is shown as a group.

R ³ represents hydrogen or a group represented by the formula — (CH ₂ ) n ⁴ COOR ⁸ (wherein n ⁴ represents 1 or 2. R ⁸ represents hydrogen, benzyl or cyclohexyl). . -A = B- is -N = N -, - C ( R 27) = N- or -CH = CH- (wherein, R ²⁷ is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, one hydroxyl group in alkyl having 1 to 2 carbon atoms which is substituted, cyclohexyl, trifluoromethyl, formula ^{_{- (CH 2) n 8 COOR}} 14 ( wherein, .R ¹⁴ n ⁸ is showing 0, 1 or 2 is hydrogen or a carbon A group represented by the formula 1 to 2 alkyl),
Or the formula ^{_{- (CH 2) n 10 N}} (R 17) (R 18) ( wherein, n ¹⁰ represents a 1 .R ^17, R ¹⁸ is an alkyl having 1 to 2 carbon atoms.) Are represented by Indicates a group. ).

Z ¹ represents aryl, heteroaryl or a group represented by the formula —CH═CH—R ¹⁹ (in the formula, R ¹⁹ represents phenyl), and halogen, amino or nitro is present on these rings. , Methyl, methoxy, 1H-tetrazol-5-ylmethyl and the formula — (CH ₂ ) n ¹¹ COOR ²⁰ (wherein n ¹¹ is 0 or an integer of 1 to 4. R ²⁰ is hydrogen or 1 to 4 carbon atoms. The alkyl group may have 1 to 2 substituents selected from the groups represented by.

Y ¹ is --NHCO--, --NHCONH--,
_{-NHCSNH -, - NHSO 2 -,} - OCONH- or an -OCO-. Ar ¹ represents phenyl or phenyl having a halogen on the ring. The following are mentioned as the heteroaryl in Z ¹ .

[0034]

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(In the formula, Hal represents halogen, and other symbols have the same meanings as described above.) In the general formula (II), specific examples of each definition are as follows. Halogen in R ³¹ and R ³² is chlorine, bromine, fluorine or iodine. The alkyl having 1 to 5 carbon atoms represents a linear or branched alkyl, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, and the like. Propyl and isopropyl are preferred. The alkoxy having 1 to 5 carbon atoms represents a linear or branched alkoxy, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy,
Pentyloxy, isopentyloxy and the like,
Methoxy and ethoxy are preferable, and methoxy is particularly preferable. The haloalkyl having 1 to 2 carbon atoms represents chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl and the like, and trifluoromethyl is preferable.

In R ³³ , alkyl having 1 to 5 carbons has the same meaning as defined above. Examples of the alkyl having 1 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl, and hydroxymethyl is preferable. Examples of the cycloalkyl having 3 to 7 carbon atoms include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl, and cyclohexyl is preferable. Aralkyl substituted with 1 to 3 hydroxyl groups on the aromatic ring means 4-hydroxybenzyl, 3,4
-Dihydroxybenzyl, 2- (4-hydroxyphenyl) ethyl, 2- (3,4-dihydroxyphenyl) ethyl and the like are shown. Heteroarylalkyl includes indolylmethyl, pyridylmethyl, quinolylmethyl, thienylmethyl, furylmethyl and the like.

The alkyl having 1 to 5 carbon atoms in R ³⁴ has the same meaning as described above. Examples of aryl in Z ² and R ⁴⁸ include phenyl and naphthyl, with phenyl being preferred.
Heteroaryl is pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolinyl, benzofuranyl,
2,3-dihydrobenzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl and the like, 3-quinolyl, 2-benzofuranyl, 2,3-dihydro-7- Benzofuranyl, 2-
Benzothienyl, 2-indolyl, 2-indolinyl and the like are preferable, and 2-indolyl is particularly preferable. Also,
Aryl, heteroaryl, R ⁴⁸ in the substituent on the ring, halogen, alkyl having 1 to 5 carbons, alkyl having 1 to 5 carbons substituted with 1 to 3 hydroxyl groups, and having 1 to 2 carbons Haloalkyl and alkoxy having 1 to 5 carbons have the same meanings as described above. Examples of the alkanoyl having 2 to 5 carbon atoms include acetyl, propionyl, butyryl, valeryl and pivaloyl. With alkylthio having 1 to 5 carbon atoms,
It represents a linear or branched alkylthio, and includes methylthio, ethylthio, propylpyrthio, isopropylthio, butylthio, isobutylthio, tertiary butylthio, pentylthio, isopentylthio, etc., and methylthio is preferable. Examples of aryloxy include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

In Ar ² , halogen which is a substituent on phenyl, pyridyl or thienyl, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons, or alkyl having 1 to 5 carbons. Alkylthio has the same meaning as above. Carboxyalkyl means carboxymethyl, 2-
Examples thereof include carboxyethyl, and carboxymethyl is preferable.

R ³⁵ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R
⁴² , R ⁴³ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁹ , R ⁵⁰ , R ⁵¹ ,
The alkyl having 1 to 5 carbon atoms in R ⁵² and R ⁵³ has the same meaning as described above. The aralkyl in R ³⁵ , R ³⁹ , R ⁴⁵ and R ⁴⁹ is benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl and the like.

Cycloalkyl having 3 to 7 carbon atoms in R ³⁵ and R ³⁹ has the same meaning as described above. R ³⁷ , R ³⁸ , R ⁴⁰ ,
R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁶ , R ⁴⁷ , R ⁵⁰ , R ⁵¹ , R ⁵² , R
^{In 53} , 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 1-azepinyl, as a heterocycle formed by bonding to adjacent nitrogen atoms.
Morpholino, thiomorpholino, 4-methylpiperidino,
Examples thereof include phthalimide and succinimide.

In the general formula (II), preferred ranges are as follows. R ³¹ and R ³² are the same or different and each is hydrogen, alkyl having 1 to 2 carbons or a formula — (CH ₂ ) n ²¹ COOR ³⁵ (wherein n ²¹ is 0 or 1; R ³⁵ is hydrogen or carbon Represents a group of 1 to 4).

R ³³ is hydrogen or a group represented by the formula — (CH ₂ ) n ²⁴ COOR ³⁹ (wherein n ²⁴ is 1, 2 or 3; R ³⁹ is hydrogen, benzyl or cyclohexyl). Indicates. R ³⁴ represents hydrogen.

M represents 0. Y ² is -NHCO-, -N
HCONH- or -NHCSNH- is shown. Z ² represents aryl, heteroaryl or the formula —CH═CH—R ⁴⁸ (wherein R ⁴⁸ represents phenyl), and halogen, methyl, methoxy and formula — (CH ₂ ) n are present on these rings. ³⁰ COOR ⁴⁹ (in the formula, n ³⁰ represents 1 or 2; R ⁴⁹ represents hydrogen or alkyl having 1 to 4 carbon atoms) and has 1 to 2 substituents. May be.

Ar ² represents phenyl or phenyl having a halogen on the ring. The following are mentioned as the heteroaryl in Z ² .

[0045]

[Chemical 6]

(In the formula, Hal represents halogen.) The pharmaceutically acceptable salts of the compounds of the general formula (I) and the general formula (II) include all salts, preferably hydrochloric acid, sulfuric acid, Salts with inorganic acids such as nitric acid, phosphoric acid, hydrobromic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, methanesulfonic acid, Salts with organic acids such as benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid, salts with alkaline metals such as lithium, sodium, potassium, calcium, magnesium and aluminum, piperidine, pyrrolidine, piperazine, morpholine, guanidine and dicyclohexyl. Amine, salts with organic bases such as N-methylglucamine, aspartic acid, glutamic acid, lysine, arginine And the like salts with amino acids is.

When the compound of the present invention has asymmetry in its molecule, it includes any form of optical isomers, diastereomers and mixtures thereof. The present invention also includes hydrates of the compounds of the present invention and solvates of methanol, ethanol, ethyl acetate and the like. Method I-1 The compound of the general formula (I) in which Y ¹ is —NHCO— has the general formula

[0048]

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(Wherein each symbol has the same meaning as described above) and an amino compound or acid addition salt thereof represented by the general formula HOOC-Z ¹ (2) (wherein each symbol has the same meaning as described above). ) And a reactive derivative thereof are condensed.

For the above condensation reaction, a known amidation method or peptide synthesis method can be applied correspondingly. For example, when the reactive derivative of carboxylic acid is an acid halide (acid chloride, acid bromide, etc.) or an acid anhydride (symmetric acid anhydride, lower alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride, etc.), The reaction is usually carried out in an inert solvent or without solvent, preferably an organic base such as triethylamine, N-methylmorpholine, pyridine or dimethylaniline or an inorganic base deoxidizing agent such as alkali hydrogen carbonate, alkali carbonate or alkali hydroxide. In the presence of -20 ° C to 80 ° C. Furthermore, as a reactive derivative, lower alkyl ester (methyl ester, ethyl ester, etc.) or so-called active ester (4-nitrophenyl ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, succinimide ester, benzotriazole ester, 4 -Dimethylsulfonium phenyl ester, etc.), the reaction is usually carried out in an inert solvent or without solvent at -20 ° C to the reflux temperature of the solvent. In addition, the amidation reaction of free carboxylic acid is performed by carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, etc.), diphenylphosphoryl azide, carbonyldiimidazole, 1-benzo In the presence of a condensing agent such as triazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) and 2-chloro-N-methylpyridinium iodide-tributylamine system (Mukoyama method) in an inert solvent or It is carried out without a solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are completed within 24 hours. Examples of the inert solvent used in the amidation reaction described above include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran and dioxane, and acetic acid esters. Such as esters, ketones such as acetone and methyl ethyl ketone,
Alcohols such as methanol, ethanol and isopropyl alcohol, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, water and mixed solvents thereof, and the like,
It can be appropriately selected depending on the reaction.

Method I-2 In the compound of the general formula (I), Y ¹ is --NHCONH--, and the compound of the general formula (1) is an amino compound or an acid addition salt thereof and a compound of the general formula O = C = N-Z ¹ (3 (In the formula, Z ¹ has the same meaning as described above.) Or an isocyanate represented by the formula: H ₂ N—Z ¹ (4) (wherein Z ¹ has the same meaning as described above). ) To phosgenes (trichloromethyl chloroformate, bis (trichloromethyl) carbonate, etc.)
Alternatively, it is synthesized by reacting carbonyldiimidazole and then reacting with the amino compound of the general formula (1) or an acid addition salt thereof.

The reaction is carried out in the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline, or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide), if necessary. In a solvent-free or inert solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are completed within 24 hours. The inert solvent used is hexane,
Hydrocarbons such as benzene and toluene, chloroform,
Halogenated hydrocarbons such as dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, esters such as acetic acid ester, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide. Examples thereof include acetonitrile, acetonitrile, dimethylsulfoxide, and a mixed solvent thereof, which can be appropriately selected depending on the reaction.

Method I-3 In the general formula (I), Y ¹ is-
The compound which is NHCSNH- is represented by the amino compound of the general formula (1) or an acid addition salt thereof and the general formula S = C = N-Z ¹ (5) (wherein Z ¹ has the same meaning as described above). It is synthesized by reacting the obtained isothiocyanate.
The reaction proceeds under the same conditions as in Method I-2.

Method I-4 In the general formula (I), Y ¹ is —NHSO ₂ —, and the amino compound of the general formula (1) or an acid addition salt thereof and the general formula Z ¹ —SO ₂ —X (6 (In the formula, X represents halogen such as chlorine and bromine, and Z ¹ has the same meaning as described above.), Or a sulfonic acid halide represented by the general formula (Z ¹ -SO ₂ ) ₂ O (7) ( In the formula, Z ¹ has the same meaning as described above.) And is synthesized.

The amidation reaction is preferably carried out in the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline, or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide). Furthermore, it is carried out in a solvent-free or inert solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are completed within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. , Ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, and mixed solvents thereof, which can be appropriately selected according to the reaction.

Method I-5 In the general formula (I), the compound in which Y ¹ is --NHCOO-- is an amino compound of the general formula (1) or an acid addition salt thereof and a general formula Z ¹ --OCO--X (8) ( In the formula, each symbol has the same meaning as described above.) Or a compound represented by the general formula (Z ¹ -OCO) ₂ O (9) (wherein Z ¹ has the same meaning as described above). It is synthesized by reacting with a compound. This amidation reaction is preferably performed with a deoxidizing agent (triethylamine, N-
Organic bases such as methylmorpholine, pyridine and dimethylaniline, or alkali hydrogen carbonate, alkali carbonate,
In the presence of (inorganic base such as alkali hydroxide), it is carried out in a solvent-free or inert solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are complete within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. , Ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, and mixed solvents thereof, which can be appropriately selected according to the reaction.

Method I-6 The amino compound represented by the general formula (1) can be obtained by the method described in Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 14,
General formula described on page 1078, 1971

[0058]

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(In the formula, each symbol has the same meaning as defined above.) The benzodiazepine compound is easily synthesized by hydrolyzing it in an acidic aqueous solution. The reaction is usually carried out in the presence of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, etc.
It proceeds easily in an aqueous solution or a water-containing organic solvent. Examples of the organic solvent used here include alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, and dimethyl sulfoxide. The concentration of the acid and the reaction temperature depend on the stability of the diazepine ring of the compound of the general formula (10) to be used, but it is generally carried out at room temperature to reflux the solvent for 30 minutes to several hours at pH 5 or less. . The obtained amino compound can be isolated as a suitable acid addition salt and used as a starting compound, or can be subjected to the next production step without isolation.

Method I-7 In the general formula (1), -A = B- is -C (R ²⁷ ) = N-
Is the general formula

[0061]

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(Wherein each symbol has the same meaning as defined above), the compound is represented by Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 25, 1466.
It can be synthesized according to the method described on page 1982. For example, the general formula

[0063]

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(Wherein each symbol has the same meaning as defined above), by reacting the compound represented by the general formula with triethyl orthoacetate and hydrazine in the presence of an acid catalyst.

[0065]

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(Wherein each symbol has the same meaning as defined above), the compound represented by the formula is obtained. Then, the compound of the general formula (13)

[0067]

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(Wherein R ³ has the same meaning as defined above) and the compound represented by the general formula

[0069]

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(Wherein each symbol has the same meaning as defined above), the compound represented by the formula is obtained. The amino compound of the general formula (11) can be synthesized by heating the compound of the general formula (15) in the presence of an acid catalyst and then deprotecting it. Alternatively, the compound represented by the general formula (12) is added to the compound represented by the general formula in the presence of an acid catalyst.

[0071]

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(In the formula, R ³ has the same meaning as described above) and a compound represented by the general formula R ²⁷ —CONHNH ₂ (17) (wherein each symbol has the same meaning as described above). By reacting the compound with

[0073]

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(Wherein each symbol has the same meaning as defined above), the compound represented by the formula is obtained. Then, the compound of general formula (18) is heated in the presence of an acid catalyst and then deprotected to synthesize an amino compound of general formula (11). METHOD I-8 formula (I), compound Y ¹ is -OOCNH- the general formula

[0075]

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(Wherein each symbol has the same meaning as described above), the hydroxy compound represented by the general formula (3) is reacted with the hydroxy compound represented by the general formula (3), or the phosgene compound is added to the amino compound of the general formula (4). Trichloromethyl chloroformate, bis (trichloromethyl) carbonate, etc.] or carbonyldiimidazole, followed by reaction with a hydroxy compound of the general formula (19) or an acid addition salt thereof. In this case, the reaction is carried out in the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline or an inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide), if necessary. It is carried out in a solvent-free or inert solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are complete within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. , Acetone, ketones such as methyl ethyl ketone,
Examples thereof include amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, and mixed solvents thereof, which can be appropriately selected depending on the reaction.

Method I-9 In the general formula (I), Y ¹ is —OOC—, and the known esterification with the carboxylic acid of the general formula (2) or an acid halide thereof and the hydroxy compound of the general formula (19). It can be easily synthesized by the reaction. When the acid halide (acid chloride, acid bromide, etc.) of the compound of the general formula (2) is used, the esterification reaction is carried out in an inert solvent or without solvent, preferably in the range of -20 ° C to the boiling point of the solvent used. Done. When the free carboxylic acid of the general formula (2) is used, its esterification reaction is carried out by carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl)).
-Carbodiimide, etc.), carbonyldiimidazole and the like in the presence of a condensing agent, preferably at -20 ° C to 80 ° C. Alternatively, the reaction can be carried out in an inert solvent, preferably in the presence of an acid catalyst (hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, etc.), but the reaction temperature is raised to the boiling point of the solvent and the produced water is distilled off. In some cases, the reaction may proceed remarkably fast. As the inert solvent used in the esterification reaction described above, hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, etc. Ethers, esters such as acetate, ketones such as acetone,
Examples thereof include dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixed solvent thereof, which can be appropriately selected depending on the reaction.

Method I-10 The hydroxy compound of the general formula (19) can be obtained by subjecting the thienodiazepine compound of the general formula (10) to a hydrolysis reaction and subsequently reacting it with an alkali metal nitrite.
The hydrolysis reaction of the compound of the general formula (10) is usually hydrochloric acid,
It easily proceeds in an aqueous solution in the presence of sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid and the like. The concentration of the acid and the reaction temperature depend on the stability of the diazepine ring of the compound of the general formula (10) used, but the pH is generally 5
The reaction is carried out at room temperature to reflux of the solvent for 30 minutes to several hours. Then, an alkali metal nitrite (for example, sodium nitrite, potassium nitrite) is added to this reaction solution, and the reaction is carried out at room temperature for several minutes while heating.

Method I-11 In the general formula (I), -A = B- is -C (R ²⁷ ) = N.
A compound represented by-and R ²⁷ is 1-hydroxyalkyl can also be synthesized from the compound of the general formula (II) which is the compound of the present invention. For example,

[0080]

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(In the formula, R ⁶⁰ represents lower alkyl, and other symbols have the same meanings as described above.)

[0082]

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It can also be obtained by subjecting a compound represented by the formula (wherein each symbol has the same meaning as described above) to a hydrolysis reaction, and subsequently acting an alkali metal nitrite.
The hydrolysis reaction of the compound of the general formula (20) is usually hydrochloric acid,
It easily proceeds in an aqueous solution in the presence of sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid and the like. The concentration of the acid and the reaction temperature depend on the stability of the diazepine ring of the compound of the general formula (20) used, but generally the pH is 5
The reaction is carried out at room temperature to reflux of the solvent for 30 minutes to several hours. Then, an alkali metal nitrite (for example, sodium nitrite, potassium nitrite) is added to this reaction solution, and the reaction is carried out at room temperature for several minutes while heating.

Method I-12 In the general formula (I), -A = B is -C (R ²⁷ ) = N-
A compound in which R ²⁷ is a dimethylaminomethyl group can also be synthesized from the compound of the general formula (II) which is the compound of the present invention. For example, the general formula

[0085]

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(Wherein each symbol has the same meaning as defined above), in the general formula (II), m is 0, R is
General formula where ³⁴ is equivalent to hydrogen

[0087]

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(In the formula, each symbol has the same meaning as above.)
Formic acid and formaldehyde to the compounds represented by
It is also synthesized by using it. Formic acid used is
60 to 90% of which is industrially easily available, but
Of course, even if it is less than this, or even more than this
It doesn't matter. In addition, formaldehyde is also aqueous
However, solid ones such as paraformaldehyde are also acceptable.
No. The starting compound (21) was once hydrolyzed with formic acid.
Understood R ²⁷Produces a compound in which is 1-aminoalkyl
Then, formic acid and formaldehyde react with it, and 1-dim
A tylaminoalkyl compound is obtained. The reaction is with formic acid
It is preferable to use a solution of formaldehyde as the solvent.
However, various inert solvents (methanol, ethanol,
Tetrahydrofuran, dioxane, benzene, dimethyl
Formamide). Usually 1-2
It is most advantageous to heat and reflux for 4 hours, but
It can also be carried out at low temperatures.

[0089] Compound Y ¹ is -NHCONHCO- in process I-13 formula (I) has the general formula (1) an amino compound or an acid addition salt with a general formula O = C = N-CO- Z 1 of (22) (wherein Z ¹ has the same meaning as described above), and is synthesized by reacting an isocyanate represented by the formula. The reaction proceeds under the same conditions as in Method I-2.

Method I-14 A compound of the general formula (I) in which Y ¹ is —NHCSNHCO— is a compound of the general formula (I) or an acid addition salt thereof with the general formula S═C═N—CO—Z ¹ (23) (wherein Z ¹ has the same meaning as defined above) and is synthesized by reacting an isothiocyanate.
The reaction proceeds under the same conditions as in Method I-2.

Method I-15 In the compound of the general formula (I), Y ¹ is --NHCONHSO _2- , the amino compound of the general formula (1) or an acid addition salt thereof and a compound of the general formula O═C═N—SO ₂ — It is synthesized by reacting an isocyanate represented by Z ¹ (24) (wherein Z ¹ has the same meaning as described above). The reaction proceeds under the same conditions as in Method I-2.

Method I-16 In the compound of the general formula (I), Y ¹ is —NHCSNHSO ₂ —, the amino compound of the general formula (1) or an acid addition salt thereof and a compound of the general formula S═C═N—SO ₂ — It is synthesized by reacting an isothiocyanate represented by Z ¹ (25) (wherein Z ¹ has the same meaning as described above).
The reaction proceeds under the same conditions as in Method I-2.

Method I-17 In the compound of the general formula (I), Y ¹ is —NHCOCONH—, the amino compound of the general formula (4) or an acid addition salt thereof can be cooled at room temperature or with ice in a solvent inert to the reaction. Under the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide), oxalyl chloride is reacted with It is synthesized by reacting the amino compound (1) preferably at −20 ° C. at room temperature. Usually these reactions are complete within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. Examples thereof include acetones, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, and mixed solvents thereof, which can be appropriately selected according to the reaction.

Method II-1 The compound of the general formula (II) can be obtained by the method of Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 14, 107.
General formula synthesized according to the method described on page 8, 1971

[0095]

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(Wherein each symbol has the same meaning as defined above), 1,3-dihydro-5-phenyl-2H-
In 1,4-benzodiazepin-2-thione compound with the general formula _{H 2 NNHCO- (CH 2) m} -CH (R 33) -Y 2 -Z 2 (32) ( wherein each symbol is as defined above. ) Can be synthesized by reacting the acid hydrazide compound.

The reaction is usually carried out in a solvent inert to the reaction (benzene, toluene, xylene, dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, etc.), an organic acid (acetic acid, propionic acid, trifluoroacetic acid, etc.), an inorganic acid. The reaction proceeds from room temperature to the reflux temperature of the solvent used in the presence of (hydrochloric acid, sulfuric acid, etc.) or silica gel.

Method II-2 The compound of the general formula (II) can be obtained by reacting the compound of the general formula (31) with hydrazine or a hydrate thereof.

[0099]

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(Wherein each symbol has the same meaning as defined above) and a compound represented by the general formula HOOC- (CH ₂ ) m-CH (R ³³ ) -Y ² -Z ² (34) (wherein , Each symbol has the same meaning as defined above.) A general formula obtained by reacting a carboxylic acid represented by

[0101]

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(In the formula, each symbol has the same meaning as defined above.) The compound can be synthesized by subjecting it to a ring-closing reaction to form a triazole ring. The reaction of the compound of the general formula (31) with hydrazine or a hydrate thereof is carried out in a solvent (dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, butanol, etc.) usually inert to the reaction, at -20 ° C to 50 ° C.
Proceed with.

The compound of the general formula (33) and the general formula (34)
In the reaction of the compound of formula (34), the carboxylic acid derivative of the general formula (34) is an acid halide (acid chloride, acid bromide, etc.) or an acid anhydride (symmetric acid anhydride, lower alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride). Object)
The reaction is carried out in an inert solvent or without solvent, if necessary, with the removal of an organic base such as triethylamine, N-methylmorpholine, pyridine or dimethylaniline or an inorganic base such as an alkali hydrogen carbonate, an alkali carbonate or an alkali hydroxide. It is carried out under cooling to warming in the presence of an acid agent. Further, as a reactive derivative of the general formula (34), lower alkyl ester (methyl ester, ethyl ester, etc.) or so-called active ester (4-nitrophenyl ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, succinimide ester) , Benzotriazole ester, 4-dimethylsulfonium phenyl ester, etc.), the reaction is carried out in an inert solvent or without solvent at room temperature to under heating.
When the general formula (34) is a free carboxylic acid, the amidation reaction can be carried out by carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, etc.) and diphenylphosphoryl. Azide, carbonyldiimidazole, 1-
In the presence of a condensing agent such as benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) and 2-chloro-N-methylpyridinium iodide-tributylamine system (Mukoyama method) in an inert solvent Alternatively, without a solvent, preferably -20
It is carried out at 80 to 80 ° C. Usually these reactions are completed within 24 hours. As the inert solvent used in the reaction, hydrocarbons such as hexane, benzene and toluene, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and butanol, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, tetrahydrofuran , Dioxane,
Examples thereof include ethers such as diethyl ether and diisopropyl ether, esters such as acetic acid ester, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, and mixed solvents thereof.

The compound of the general formula (35) can be isolated by the above reaction, but it can be directly led to the compound of the general formula (II) without isolation. In this case, the reaction is carried out in the above-mentioned inert solvent using an organic acid (acetic acid,
The reaction proceeds from room temperature to the reflux temperature of the solvent used in the presence of propionic acid, trifluoroacetic acid, etc.), inorganic acid (hydrochloric acid, sulfuric acid, etc.) or silica gel.

Method II-3 The compound of the general formula (II) is the compound of the general formula (33) and the compound of the general formula (R ⁶¹ O) ₃ C- (CH ₂ ) m-CH (R ³³ ) -Y ² -Z. ² (36) (in the formula, R ⁶¹ represents alkyl having 1 to 5 carbon atoms and other symbols have the same meanings as described above), and can be synthesized by reacting the orthoester derivative. .

The reaction is usually an inert solvent (benzene, toluene, xylene, dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, etc.).
In the presence of an organic acid (acetic acid, propionic acid, trifluoroacetic acid, etc.), an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or silica gel, the reaction proceeds from room temperature to the reflux temperature of the solvent used. Method II-4 The compound of the general formula (II) in which Y ² is —NHCO— has the general formula

[0107]

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(Wherein each symbol has the same meaning as described above) and an amino compound or acid addition salt thereof represented by the general formula HOOC-Z ² (38) (wherein Z ² has the same meaning as described above). ) And a reactive derivative thereof are condensed.

For the above condensation reaction, a known amidation method or peptide synthesis method can be applied correspondingly. For example, when the reactive derivative of carboxylic acid is an acid halide (acid chloride, acid bromide, etc.) or an acid anhydride (symmetric acid anhydride, lower alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride, etc.), The reaction is usually carried out in an inert solvent or without solvent, preferably an organic base such as triethylamine, N-methylmorpholine, pyridine or dimethylaniline or an inorganic base deoxidizing agent such as alkali hydrogen carbonate, alkali carbonate or alkali hydroxide. In the presence of -20 ° C to 80 ° C. Furthermore, as a reactive derivative, lower alkyl ester (methyl ester, ethyl ester, etc.) or so-called active ester (4-nitrophenyl ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, succinimide ester, benzotriazole ester, 4 -Dimethylsulfonium phenyl ester, etc.), the reaction is usually carried out in an inert solvent or without solvent at -20 ° C to the reflux temperature of the solvent. In addition, the amidation reaction of free carboxylic acid is performed by carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, etc.), diphenylphosphoryl azide, carbonyldiimidazole, 1-benzo In the presence of a condensing agent such as triazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) and 2-chloro-N-methylpyridinium iodide-tributylamine system (Mukoyama method) in an inert solvent or It is carried out without a solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are completed within 24 hours. Examples of the inert solvent used in the amidation reaction described above include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether. Ethers, esters such as acetic acid esters, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and isopropyl alcohol, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, water and these The mixed solvent may be mentioned and can be appropriately selected according to the reaction.

Method II-5 In the general formula (II), the compound in which Y ² is —NHCONH— is the amino compound of the general formula (37) or an acid addition salt thereof and the general formula O═C═N—Z ² ( 39) by reacting an isocyanate represented by the formula (wherein Z ² has the same meaning as described above), or a general formula H ₂ NZ ² (40) (wherein Z ² has the same meaning as described above). .) To phosgene [trichloromethyl chloroformate, bis (trichloromethyl) carbonate, etc.]
Alternatively, it is synthesized by reacting carbonyldiimidazole and then reacting with the amino compound of the general formula (37) or an acid addition salt thereof.

The reaction is carried out in the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline, or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide), if necessary. In a solvent-free or inert solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are completed within 24 hours. The inert solvent used is hexane,
Hydrocarbons such as benzene and toluene, chloroform,
Halogenated hydrocarbons such as dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, esters such as acetic acid ester, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide. Examples thereof include acetonitrile, acetonitrile, dimethylsulfoxide, and a mixed solvent thereof, which can be appropriately selected according to the reaction.

Method II-6 In the general formula (II), the compound in which Y ² is —NHCSNH— is the amino compound of the general formula (37) or an acid addition salt thereof with the general formula S═C═N—Z ² ( 41) Synthesized by reacting an isothiocyanate represented by the formula (wherein Z ² has the same meaning as described above).
The reaction proceeds under the same conditions as in Method II-5.

Method II-7 In the general formula (II), the compound in which Y ² is —NHSO ₂ — is the amino compound of the general formula (37) or an acid addition salt thereof and the general formula Z ² —SO ₂ —X ( 42) (In the formula, X represents halogen such as chlorine and bromine, and Z ² has the same meaning as described above.), Or a sulfonic acid halide represented by the general formula (Z ² —SO ₂ ) ₂ O (43) (In the formula, Z ² has the same meaning as described above.) It is synthesized by reacting with a sulfonic acid anhydride.

This amidation reaction is preferably carried out in the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline, or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide). Furthermore, it is carried out in a solvent-free or inert solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are completed within 24 hours. As the inert solvent used, hydrocarbons such as hexane, benzene, and toluene,
Halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, esters such as acetic acid ester, ketones such as acetone and methyl ethyl ketone, dimethylformamide, dimethylacetamide, etc. Amides, acetonitrile, dimethylsulfoxide, and a mixed solvent thereof can be used and can be appropriately selected depending on the reaction.

Method II-8 In the general formula (II), the compound in which Y ² is —NHCOO— is the amino compound of the general formula (37) or an acid addition salt thereof and the general formula Z ² —OCO-X (44). (Wherein each symbol has the same meaning as described above) or a compound represented by the general formula (Z ² —OCO) ₂ O (45) (wherein Z ² has the same meaning as described above). It is synthesized by reacting with a compound. This amidation reaction is preferably carried out in the presence of a deoxidizing agent (for example, an organic base such as triethylamine, N-methylmorpholine, pyridine or dimethylaniline, or an inorganic base such as alkali hydrogen carbonate, alkali carbonate or alkali hydroxide).
In a solvent-free or inert solvent, preferably from -20 ° C to 8
It is performed at 0 ° C. Usually these reactions are completed within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. Examples thereof include acetones, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, and mixed solvents thereof, which can be appropriately selected according to the reaction.

Method II-9 The amino compound represented by the general formula (37) is described in JP-A-48-9239.
According to the method described in Japanese Patent Publication No. 9

[0117]

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(In the formula, Am represents a protected amino group, and other symbols have the same meanings as described above.) The compound represented by the above formula can be synthesized by deprotecting the amino group. Examples of the amino protecting group include tertiary butyloxycarbonyl group, phthaloyl group, (substituted) benzoyl group, acetyl group, trifluoroacetyl group, and benzyloxycarbonyl group, which are commonly used in organic chemistry. Deprotection groups include deprotection with acids (hydrofluoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, formic acid, etc.), alkali metal hydroxides (sodium hydroxide, hydroxide). It can be easily carried out by deprotection using a base such as potassium and barium hydroxide) or hydrazine and its hydrate, and hydrogenolysis using a metal catalyst (palladium, Raney nickel, etc.).

Method II-10 In the general formula (II), the compound of the general formula (II) in which Y ² is —OOCNH— is

[0120]

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(Wherein each symbol has the same meaning as defined above), the hydroxy compound represented by the general formula (39) is reacted with the hydroxy compound or the amino compound represented by the general formula (40) is reacted with phosgene [trichloro. Methyl chloroformate, bis (trichloromethyl) carbonate, etc.]
Alternatively, it is synthesized by reacting carbonyldiimidazole and then reacting with the hydroxy compound of the general formula (47) or an acid addition salt thereof. The reaction in this case is
If necessary, in the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide), a solvent-free or inert solvent is used. Medium, preferably at -20 ° C to 80 ° C.
Usually these reactions are completed within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. , Acetone, ketones such as methyl ethyl ketone,
Examples thereof include amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, and mixed solvents thereof, which can be appropriately selected depending on the reaction.

Method II-11 The compound of the general formula (II) in which Y ² is —OOC— is a known esterification compound of the carboxylic acid of the general formula (38) or an acid halide thereof with a hydroxy compound of the general formula (47). It can be easily synthesized by the reaction. When an acid halide (acid chloride, acid bromide, etc.) of the compound of the general formula (38) is used, the esterification reaction is carried out in an inert solvent or without solvent, preferably from -20 ° C to the boiling point of the solvent used. Done in. In addition, the general formula (3
When the free carboxylic acid of 8) is used, the esterification reaction is performed by condensation of carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, etc.), carbonyldiimidazole, etc. It is carried out in the presence of an agent, preferably at -20 ° C to 80 ° C. Alternatively, the reaction can be carried out in an inert solvent, preferably in the presence of an acid catalyst (hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, etc.), but the reaction temperature is raised to the boiling point of the solvent and the produced water is distilled off. In some cases, the reaction may proceed remarkably fast. As the inert solvent used in the esterification reaction described above, hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, etc. Examples thereof include ethers, esters such as acetic acid esters, ketones such as acetone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and mixed solvents thereof, which can be appropriately selected depending on the reaction.

Method II-12 The hydroxy compound of the general formula (47) can be easily synthesized according to a known method, for example, the method described in JP-A-48-92399. Method II-13 A compound of the general formula (II) in which Y ² is —NHCONHCO— is the amino compound of the general formula (37) or an acid addition salt thereof, and a compound of the general formula O═C═N—CO—Z ² (48). (In the formula, Z ² has the same meaning as described above.) It is synthesized by reacting an isocyanate. The reaction proceeds under the same conditions as in Method II-5.

Method II-14 The compound of the general formula (II) in which Y ² is —NHCSNHCO— is the amino compound of the general formula (37) or an acid addition salt thereof and the general formula S═C═N—CO—Z ² (49) It is synthesized by reacting an isothiocyanate represented by the formula (wherein Z ² has the same meaning as described above).
The reaction proceeds under the same conditions as in Method II-5.

Method II-15 The compound of the general formula (II) in which Y ² is —NHCONHSO ₂ — is the amino compound of the general formula (37) or an acid addition salt thereof and the general formula O═C═N—SO ₂ —. It is synthesized by reacting an isocyanate represented by Z ² (50) (wherein Z ² has the same meaning as described above). The reaction proceeds under the same conditions as in Method II-5.

Method II-16 The compound of the general formula (II) in which Y ² is —NHCSNHSO ₂ — is the amino compound of the general formula (37) or an acid addition salt thereof and the general formula S═C═N—SO ₂ —. It is synthesized by reacting an isothiocyanate represented by Z ² (51) (wherein Z ² has the same meaning as described above).
The reaction proceeds under the same conditions as in Method II-5.

Method II-17 A compound of the general formula (II) in which Y ² is —NHCOCONH— is a compound inert to the amino compound of the general formula (40) or an acid addition salt thereof at room temperature or ice-cooled. Under the presence of a deoxidizing agent (organic base such as triethylamine, N-methylmorpholine, pyridine and dimethylaniline or inorganic base such as alkali hydrogen carbonate, alkali carbonate and alkali hydroxide), oxalyl chloride is reacted with The amino compound of (37) is preferably -20 ° C.
Is synthesized by reacting from room temperature to room temperature. Normal,
These reactions are complete within 24 hours. Examples of the inert solvent used include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, and esters such as acetic acid ester. Examples thereof include acetones, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, and mixed solvents thereof, which can be appropriately selected according to the reaction.

General formula (I) and general formula (II) of the present invention
In the compound of_Two) n⁶CON (R¹¹)
(R¹²),-(CH_Two) n⁹CON (R^Fifteen) (R¹⁶),-(C
H_Two) n¹²CON (R^{twenty one}) (R^{twenty two}),-(CH_Two) n²⁶CON
(R⁴²) (R⁴³) Or-(CH_Two) n³¹CON (R⁵⁰) (R
⁵¹The compound having an acid amide structure represented by
The corresponding carboxylic acid or its reactive derivative and the general formula HN (Ra) (Rb) (52) (wherein Ra and Rb are each R¹¹, R¹², R^Fifteen,
R¹⁶, R^{twenty one}, R^{twenty two}, R⁴², R ⁴³, R⁵⁰Or R⁵¹The table
You. Also by condensation with an amino compound represented by
Synthesized.

For the above-mentioned amidation reaction, a known amidation method or peptide synthesis method can be applied correspondingly. For example,
The reactive derivative of carboxylic acid is an acid halide (acid chloride,
Acid bromide) or acid anhydride (symmetrical acid anhydride, lower alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride, etc.), the reaction is usually carried out in an inert solvent or without solvent, preferably In the presence of an organic base such as triethylamine, N-methylmorpholine, pyridine, dimethylaniline or an inorganic base such as an alkali hydrogen carbonate, an alkali carbonate or an alkali hydroxide, a -20
It is carried out at 80 to 80 ° C. Furthermore, as a reactive derivative, a lower alkyl ester (methyl ester, ethyl ester, etc.) or so-called active ester (4-nitrophenyl ester, 4-chlorobenzyl ester, 4
-Chlorophenyl ester, succinimide ester,
(Benzotriazole ester, 4-dimethylsulfonium phenyl ester, etc.), the reaction is usually
It is carried out in an inert solvent or without a solvent at -20 ° C to the reflux temperature of the solvent. In addition, the amidation reaction of free carboxylic acid is performed by carbodiimides (N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, etc.), diphenylphosphoryl azide, carbonyldiimidazole, 1-benzo Triazolyloxy tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), 2-
In the presence of a condensing agent such as chloro-N-methylpyridinium iodide-tributylamine (Mukoyama method), in an inert solvent or without a solvent, preferably -20 ° C to 80 ° C.
It is performed in. Usually these reactions are complete within 24 hours. As the inert solvent used in the above amidation reaction, hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether. , Esters such as acetate, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and isopropyl alcohol, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl sulfoxide, water and mixed solvents thereof And the like, and can be appropriately selected according to the reaction.

In the compounds of the general formulas (I) and (II), the compound having a free carboxyl group should be synthesized by protecting the carboxyl group with an ester and deprotecting in the final step. Is also synthesized by. The deprotection reaction in this case is performed by a deprotection reaction known in organic chemistry (hydrolysis reaction with acid or base, catalytic reduction reaction using metal catalyst, etc.). Also, a compound having a hydroxyl group is similarly synthesized by protecting the hydroxyl group during the synthesis and deprotecting in the final step.
Examples of the protecting group in this case include a (substituted) acetyl group, a (substituted) benzoyl group, a (substituted) benzyl group, a tertiary butyl group, a tetrahydropyranyl group, a trimethylsilyl group, and a tertiary butyldimethylsilyl group. The deprotection reaction thereof can be easily performed by a known method.

General formula (I) and general formula (II) of the present invention
In the compound of 1, the compound having a free 5-tetrazolyl group is synthesized by protecting the toterazole ring with a trityl group or a (substituted) benzyl group and deprotecting in the final step, or a cyano group or-(CH ₂ ) A compound having an amide structure represented by n CONH ₂ is subjected to dehydration reaction to give-(C
H ₂₎ was converted into represented cyanoalkyl in n CN, it can be synthesized by converting them cyano group into tetrazolyl group. This tetrazolylation reaction can be produced by reacting a cyano compound with sodium azide or trimethylsilyl azide, and the reaction conditions are benzene, toluene, xylene, dimethylformamide, pyridine, chloroform, dichloromethane, 1,2-dichloroethane, methanol, It is carried out in an inert solvent such as ethanol at a temperature of 0 to 250 ° C.

In the compounds of the general formulas (I) and (II), Z ¹ and Z ² are 2-indole and the 3-position of the indole ring is substituted with halogen. It can also be synthesized by directly halogenating a hydrogen compound. For example, fluorine gas,
Transition metal fluorides (cobalt fluoride, silver fluoride, cesium fluoride, etc.) or fluorinating reagents (1-fluoro-
2,6-dichloropyridine, 1-fluoro-3,5-dichloropyridine, 1-fluoropyridine, etc.) for fluorination, and chlorine, sulfuryl chloride, phosphorus pentachloride, cupric chloride, etc. Chlorination can be carried out by using bromine. These halogenation reactions are carried out in an inert solvent or without solvent, preferably at -20 ° C to 80 ° C. Usually these reactions are complete within 24 hours. As the inert solvent used in the above halogenation reaction, hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether. , Esters such as acetic acid ester, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and isopropyl alcohol, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, water and mixed solvents thereof And the like, and can be appropriately selected according to the reaction.

The compounds of the general formula (I) and the general formula (II) thus obtained are inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and hydrobromic acid, acetic acid, propionic acid and succinic acid by a conventional method. , Glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, organic acids such as pamoic acid, lithium, sodium, potassium, They are treated by treating with an alkali metal such as calcium, magnesium and aluminum, an organic base such as piperidine, pyrrolidine, piperazine, morpholine, guanidine, dicyclohexylamine and N-methylglucamine, and an amino acid such as aspartic acid, glutamic acid, lysine and arginine. Can be salt.

When the compound of the present invention has an asymmetric center in the molecule, it is usually obtained as a racemate. The racemate can be resolved into optical isomers by a conventional method such as chromatography using a column having an optically active carrier. Such optical isomers can also be produced by using an optically active starting material compound. Individual diastereomers can be purified by fractional crystallization or chromatography using optically active acids and bases.

General formula (I) and general formula (II) of the present invention
CC or a pharmaceutically acceptable salt thereof has excellent CC
K and gastrin antagonism, especially having a strong antagonism selectively against CCK-A receptor, and also showing potent and persistent pancreatic enzyme and gastric acid secretion inhibitory action,
Central and peripheral nervous system disorders (anxiety, schizophrenia, etc.) and digestive system disorders (pancreatitis, gallbladder disorders, gastrointestinal ulcers,
It is useful as a preventive or therapeutic drug for irritable bowel syndrome, constipation, pancreatic cancer, etc. Further, the compound of general formula (II) can also be used as a starting material for the synthesis of the compound of general formula (I).

General formula (I) or general formula (II) of the present invention
When the compound of 1) or a pharmaceutically acceptable salt thereof is used as a medicine, the compound of the present invention is a pharmaceutically acceptable carrier (excipient, binder, disintegrating agent, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing aid Pharmaceutical composition or formulation (tablet, pill, capsule, granule, powder, syrup, emulsion, elixir, suspension, solution, injection, drip or It can be administered orally or parenterally in the form of suppositories and the like.

The pharmaceutical composition can be formulated according to a conventional method. As used herein, parenteral refers to
It includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or infusion. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. Furthermore, aseptic non-volatile oil can also be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for rectal administration are solid at room temperature, such as the drug and a suitable nonirritating excipient, for example, cocoa butter or polyethylene glycols, but liquid at intestinal temperatures and melt in the rectum, It can be manufactured by mixing with a substance that releases a drug.
Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. In such dosage forms, the active ingredient compound is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans,
It can be mixed with pectins, gum tragacanth, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also, as usual, contain further additives, for example inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbines, ascorbic acid. , Α
-Antioxidants such as tocopherol and cysteine, disintegrants, binders, thickeners, buffers, sweetening agents, flavoring agents, perfume agents and the like. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs,
Suspensions, solutions and the like can be mentioned, which may contain an inert diluent commonly used in the art, for example, water.

Dosage is based on age, weight, general health status,
Gender, diet, time of administration, method of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated at that time may be determined in consideration of these or other factors. The compound of the present invention or a pharmaceutically acceptable salt thereof,
It has low toxicity and can be used safely, and its daily dose varies depending on the condition and weight of the patient, the type of compound, the administration route, etc.
It is administered intramuscularly or rectally at about 0.1 to 500 mg / person / day, and orally at about 0.5 to 1000 mg / person / day.

[0139]

[Examples] The present invention will be specifically described below with reference to raw material production examples, examples, pharmaceutical formulation examples and experimental examples, but the present invention is not limited thereto. Raw Material Production Example 1 2-aminobenzophenone 25.0 g, ethyl orthoacetate 25.4 ml, acetic acid 3.8 ml, and benzene 300 ml.
And refluxed for 3 hours. After the reaction solution was concentrated, the obtained residue and 3.8 ml of acetic acid were dissolved in 250 ml of ethanol, and hydrazine monohydrate 7 was stirred while cooling with ice.
ml was added dropwise and stirred overnight. The precipitated crystals were filtered to give 3-amino-4-hydroxy-2-methyl-4-phenyl-3,4-dihydroquinazoline 23.
1 g was obtained. Melting point 212 [deg.] C.

Raw Material Production Example 2 25.65 g of benzyloxycarbonylglycine was dissolved in 100 ml of hexamethylphosphoric triamide, and -15
4.61 ml of thionyl chloride was added dropwise at [deg.] C and the mixture was stirred for 3 hours, then 14.95 g of 3-amino-4-hydroxy-2-methyl-4-phenyl-3,4-dihydroquinazoline was added and the mixture was stirred overnight at room temperature. . The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over magnesium sulfate. After distilling off the solvent, it was crystallized from acetone and isopropyl ether to give 3-
((N-benzyloxycarbonyl) glycyl) amino-4-hydroxy-2-methyl-4-phenyl-3,4
12.23 g of dihydroquinazoline were obtained. Melting point 144
Raw Material Production Example 3 3-((N-benzyloxycarbonyl) glycyl) amino-4-hydroxy-2-methyl-4-phenyl-
666 mg of 3,4-dihydroquinazoline was dissolved in 6 ml of acetic acid and refluxed for 1 hour. The reaction mixture was concentrated, the residue was partitioned between ethyl acetate and water, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. After distilling off the solvent, the obtained solid was recrystallized from ethyl acetate to give 2- (3- (N-benzyloxycarbonylamino) methyl-5-methyl-1,2,4-triazol-4-yl. ) 0.38 g of benzophenone was obtained. Melting point 170-171 ° C. Example 1 2- (3- (N-benzyloxycarbonylamino) methyl-5-methyl-1,2,4-triazol-4-yl) benzophenone (340 mg) in 30% hydrogen bromide-acetic acid solution It was dissolved in 6 ml and stirred for 2 hours. Isopropyl ether was added to the reaction solution and decantation was performed 3 times to wash the precipitate. Obtained 2- (3-aminomethyl-5)
-Methyl-1,2,4-triazol-4-yl) benzophenone hydrobromide was dissolved in 15 ml of dichloroethane, and 168 mg of 3,4-dichlorobenzoyl chloride and 1.12 ml of triethylamine were added under ice cooling.
Stirred all day and night. The reaction solution was diluted with chloroform, and the organic layer was washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel chromatography using a mixed solvent of ethyl acetate: methanol = 10: 1 as an eluent, and crystallized from diethyl ether to give N- (4- (2-benzoylphenyl). ) -5-Methyl-1,2,4-triazol-3-ylmethyl) -3,4-dichlorobenzamide (50 mg) was obtained. Melting point 163-164 ° C Example 2 2.35 g of 2- (3- (N-benzyloxycarbonylamino) methyl-5-methyl-1,2,4-triazol-4-yl) benzophenone was added to 30% hydrogen bromide- It was dissolved in 20 ml of acetic acid solution and stirred for 3 hours. Isopropyl ether was added to the reaction solution and decantation was performed 3 times.
The precipitate was washed. Obtained 2- (3-aminomethyl-
5-Methyl-1,2,4-triazol-4-yl) benzophenone hydrobromide was added to dimethylformamide 20.
It was dissolved in ml, 1.0 g of indole-2-carboxylic acid chloride and 7.0 ml of triethylamine were added under ice cooling, and the mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate to give N- (4- (2-benzoylphenyl) -5-methyl-1,2,4-triazole-3-
Ilmethyl) -indole-2-carboxamide 0.3
0 g was obtained. Melting point 252 to 254 ° C. Example 3 2- (3- (N-benzyloxycarbonylamino) methyl-5-methyl-1,2,4-triazol-4-yl) benzophenone 2.13 g was added to 30% hydrogen bromide- It was dissolved in 15 ml of acetic acid solution and stirred for 3 hours. Isopropyl ether was added to the reaction solution and decantation was performed 3 times.
The precipitate was washed. Obtained 2- (3-aminomethyl-
5-Methyl-1,2,4-triazol-4-yl) benzophenone hydrobromide was added to dimethylformamide 15
The mixture was dissolved in ml, 0.52 ml of 3-methylphenyl isocyanate and 7.0 ml of triethylamine were added under ice cooling, and the mixture was stirred all day and night. The reaction solution was poured into water, and the obtained crude crystals were recrystallized from methanol to give N- (4- (2-benzoylphenyl) -5-methyl-1,2,4-triazol-3-ylmethyl) -N '. 0.60 g of-(3-methylphenyl) urea was obtained. Melting point 204-205 ° C. Example 4 Journal of Medicinal Chemistry (J. Me
d. Chem.) 14-Page, 1078, 6- (2-chlorophenyl) -8- synthesized by the method described in 1971.
Chloro-1-methyl-4H-s-triazolo [4,3-
0.5 g of a] [1,4] benzodiazepine was dissolved in 5 ml of a mixed solvent of ethanol: water = 9: 1, 0.85 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed for 3 hours. The solvent was concentrated under reduced pressure, ethyl acetate was added, the residual water was distilled off, 5 ml of dimethylformamide was added, and 0.32 g of indole-2-carboxylic acid chloride under ice cooling,
1.15 ml of triethylamine was added and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous citric acid solution, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate to give N- (4- (4-chloro-2- (2-chlorobenzoyl) phenyl) -5-methyl-1,2,4.
0.20 g of -triazol-3-ylmethyl) indole-2-carboxamide-1 / 4 ethyl acetate solvate was obtained. Melting point 154-156 ° C Example 5 Journal of Medicinal Chemistry (J. Me
d. Chem.) Vol. 14, 1078, 6- (2-chlorophenyl) -1-synthesized by the method described in 1971.
Methyl-4H-s-triazolo [4,3-a] [1,
4] 0.5 g of benzodiazepine in ethanol: water = 9:
P-toluenesulfonic acid 1 dissolved in 5 ml of a mixed solvent of 1
0.93 g of the hydrate was added, and the mixture was heated under reflux for 3 hours. The solvent was concentrated under reduced pressure, ethyl acetate was added, the remaining water was distilled off, 5 ml of dimethylformamide was added, 0.30 g of indole-2-carboxylic acid chloride and 1.1 ml of triethylamine were added under ice cooling, and the mixture was stirred for 1 hour. . The reaction mixture was partitioned between ethyl acetate and 5% aqueous citric acid solution, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate to give N-
(4- (2- (2-chlorobenzoyl) phenyl) -5
0.34 g of -methyl-1,2,4-triazol-3-ylmethyl) indole-2-carboxamide was obtained. Melting point 230-232 ° C Example 6 6- (2-chlorophenyl) -1-methyl-4H-s-
0.5 g of triazolo [4,3-a] [1,4] benzodiazepine was dissolved in 5 ml of a mixed solvent of ethanol: water = 9: 1, 0.93 g of p-toluenesulfonic acid monohydrate was added, and refluxed for 3 hours. Heated. The solvent was concentrated under reduced pressure, ethyl acetate was added, and the remaining water was distilled off, followed by dimethylformamide 5
Then, under ice-cooling, 0.27 g of 2-amino-4-chlorobenzoic acid, 0.71 g of 1-benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate (Bop reagent) and triethylamine. 90 ml was added and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous citric acid solution, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give 2-amino-4-chloro-N- (4- (2-
(2-chlorobenzoyl) phenyl) -5-methyl-
0.18 g of 1,2,4-triazol-3-ylmethyl) benzamide was obtained. Melting point 226-229 [deg.] C. Example 7 6- (2-chlorophenyl) -1-methyl-4H-s-
0.5 g of triazolo [4,3-a] [1,4] benzodiazepine was dissolved in 5 ml of a mixed solvent of ethanol: water = 9: 1, 0.93 g of p-toluenesulfonic acid monohydrate was added, and refluxed for 3 hours. Heated. The solvent was concentrated under reduced pressure, ethyl acetate was added, and the remaining water was distilled off, followed by dimethylformamide 5
ml was added, 0.23 ml of 3-methoxyphenyl isocyanate and 1.15 ml of triethylamine were added under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous citric acid solution, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give N- (4
-(2- (2-chlorobenzoyl) phenyl) -5-methyl-1,2,4-triazol-3-ylmethyl)-
0.40 g of N '-(3-methoxyphenyl) urea was obtained. Melting point 177 to 179 ° C. Raw material production example 4 5- (2-chlorophenyl) -1,3-dihydro-2H
2.0 g of -1,4-benzodiazepine-2-thione was dissolved in 40 ml of toluene, 1.59 g of N-α-tertiary butoxycarbonylglycine hydrazine was added, and the mixture was heated at 80 ° C. for 2 hours and further 0.5 ml of acetic acid. Was added and refluxed for 2 hours. Ethyl acetate was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized with ethyl acetate to give 1-tertiary butoxycarbonylaminomethyl-6.
0.95 g of-(2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine was obtained. Melting point 198-199 ° C. Obtained 1-tertiary butoxycarbonylaminomethyl-
0.95 g of 6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine was dissolved in 10 ml of trifluoroacetic acid and stirred for 30 minutes under ice cooling. did. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from ethyl acetate to give 1-aminomethyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-].
0.36 g of a] [1,4] benzodiazepine was obtained. Melting point 172-174 ° C Example 8 1-Aminomethyl-6- (2-chlorophenyl) -4H
-[1,2,4] triazolo [4,3-a] [1,4]
Benzodiazepine 0.12g was added to dimethylformamide 1
Dissolve in 0 ml, 0.10 ml of triethylamine, 1
-Benzotriazolyloxytris (dimethylamino)
Phosphonium hexafluorophosphate (BOP reagent) 0.18 g, indole-2-carboxylic acid 0.06
6 g was added, and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried with magnesium sulfate. The solvent was distilled off, and the residue was crystallized from ethyl acetate and recrystallized from methanol to give N- (6- (2-chlorophenyl) -4H-
50 mg of [1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-1-ylmethyl) indole-2-carboxamide / methanol solvate was obtained. Melting point 1
95-200 ° C. Raw Material Production Example 5 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2-thione 2.0 g was dissolved in butanol 60 ml, and N-α- Third
2.4 g of grade butoxycarbonylglycine hydrazine was added and refluxed overnight. Chloroform was added to the reaction solution, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized with a mixed solvent of ethyl acetate and hexane to give 1-tertiary butoxycarbonylaminomethyl-
8-chloro-6- (2-chlorophenyl) -4H-
0.95 g of [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine was obtained. Melting point 198-199
° C. obtained 1-tertiary butoxycarbonylaminomethyl-
8-chloro-6- (2-chlorophenyl) -4H-
0.95 g of [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine was added to 10 ml of trifluoroacetic acid.
And was stirred for 30 minutes under ice cooling. Evaporate the solvent,
Ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. Evaporate the solvent,
Crystallized from ethyl acetate to give 1-aminomethyl-8-chloro-6- (2-chlorophenyl) -4H- [1,2,
4] Triazolo [4,3-a] [1,4] benzodiazepine 0.36 g was obtained. Melting point 172-174 [deg.] C. Example 9 1-Aminomethyl-8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-
0.17 g of a] [1,4] benzodiazepine was dissolved in 10 ml of dimethylformamide, 0.073 ml of triethylamine and 0.09 g of indole-2-carboxylic acid chloride were added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over magnesium sulfate. The solvent was evaporated and recrystallized from ethyl acetate to give N- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,
4] Triazolo [4,3-a] [1,4] benzodiazepin-1-ylmethyl) indole-2-carboxamide / ethyl acetate solvate (50 mg) was obtained. Melting point 265-26
8 ° C. Example 10 1-Aminomethyl-6- (2-chlorophenyl) -4H
-[1,2,4] triazolo [4,3-a] [1,4]
0.12 g of benzodiazepine and 10 ml of dichloroethane
, Triethylamine 0.055 ml, 3,4
-0.082 g of dichlorobenzoyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Chloroform was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried with magnesium sulfate. The solvent was distilled off, crystallized with ethyl acetate, recrystallized from ethanol, and N-
(6- (2-chlorophenyl) -4H- [1,2,4]
Triazolo [4,3-a] [1,4] benzodiazepin-1-ylmethyl) -3,4-dichlorobenzamide 7
5 mg were obtained. Mp 225-227 [deg.] C. Example 11 1-Aminomethyl-8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-
a] [1,4] Benzodiazepine 0.50 g was dissolved in chloroform 10 ml to give triethylamine 0.21 m.
0.30 g of 1,3,4-dichlorobenzoyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Chloroform was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried with magnesium sulfate. Evaporate the solvent,
Crystallize with a mixed solvent of ethyl acetate and hexane, recrystallize with a mixed solvent of ethyl acetate and methanol to give N-
(8-chloro-6- (2-chlorophenyl) -4H-
0.15 g of [1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-1-ylmethyl) -3,4-dichlorobenzamide was obtained. Melting point 239-240 [deg.] C. Example 12 1-Aminomethyl-6- (2-chlorophenyl) -4H
-[1,2,4] triazolo [4,3-a] [1,4]
Benzodiazepine (0.95 g) was dissolved in chloroform (10 ml) to give 2-chlorophenylisocyanate (0.38).
ml was added, and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried with magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate to give N- (6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine-1-. Ilmethyl) -N '-(2-chlorophenyl) urea 0.1
5 g were obtained. Melting point 219 to 220 ° C Example 13 1-Aminomethyl-8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-
0.34 g of a] [1,4] benzodiazepine was dissolved in 10 ml of chloroform, 0.13 ml of 2-chlorophenyl isocyanate was added, and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried with magnesium sulfate. The solvent was distilled off, and the residue was crystallized with a mixed solvent of ethyl acetate and hexane to give N- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-].
a] [1,4] benzodiazepin-1-ylmethyl)-
0.17 g of N '-(2-chlorophenyl) urea was obtained. Melting point 224-226 ° C. Raw material Production Example 6 N-α-tertiary butoxycarbonyl-D-glutamic acid γ-benzyl ester 8.6 g was dissolved in tetrahydrofuran 66 ml, triethylamine 3.64 ml was added, and isobutyl chloroformate was added at -10 ° C. 3.55 ml was slowly added dropwise. 1 hour later dimethylformamide 5
6.6 g of 5- (2-chlorophenyl) -2-hydrazine-1,3-dihydro-2H-1,4-benzodiazepine dissolved in 0 ml was added dropwise and stirred at room temperature. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was distilled off, the residue was dissolved in 200 ml of toluene, and acetic acid 3.6 m
was added and refluxed for 2 hours. Ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography using ethyl acetate as an eluent, (R) -4- (tertiary butoxycarbonylamino).
-4- (6- (2-chlorophenyl) -4H- [1,
2,4] Triazolo [4,3-a] [1,4] benzodiazepin-1-yl) butanoic acid benzyl ester 4.8
3 g were obtained.

The obtained (R) -4- (tertiary butoxycarbonylamino) -4- (6- (2-chlorophenyl)
-4H- [1,2,4] triazolo [4,3-a]
[1,4] Benzodiazepin-1-yl) butanoic acid benzyl ester (4.83 g) was dissolved in trifluoroacetic acid (50 ml), and the mixture was stirred under ice cooling for 30 minutes. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. Evaporate the solvent,
(R) -4-Amino-4- (6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a]
1.01 g of [1,4] benzodiazepin-1-yl) butanoic acid benzyl ester was obtained.

Example 14 (R) -4-Amino-4- (6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a]
[1,4] benzodiazepin-1-yl) butanoic acid benzyl ester 1.36 g, dimethylformamide 15 m
1, triethylamine 0.43 ml, BOP reagent 1.3
6 g and 0.50 g of indole-2-carboxylic acid were added,
Stir overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel chromatography using ethyl acetate as an eluent to give (R) -4- (6- (2-chlorophenyl) -4H- [1,2,4 ] Triazolo [4,3-
a] [1,4] benzodiazepin-1-yl) -4-
0.67 g of (1H-indole-2-carboxamide) butanoic acid benzyl ester was obtained.

NMR (270 MHz, CDCl ₃ ):
2.13 to 2.85 (4H, m), 4.08 to 4.26
(1H, m), 4.93 to 5.14 (2H, m), 5.
45-5.52 (1H, m), 5.83-6.02 (1
H, m), 6.86-9.36 (20H, m) Example 15 (R) -4- (6- (2-chlorophenyl) -4H-
[1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-1-yl) -4- (1H-indole-2-carboxamido) butanoic acid benzyl ester 0.
53 g was suspended in 10 ml of methanol and alkali-hydrolyzed with 1.69 ml of 1N aqueous sodium hydroxide solution to give (R) -4- (6- (2-chlorophenyl) -4H- [1, 2,4] triazolo [4,3-
a] [1,4] benzodiazepin-1-yl) -4-
(1H-Indol-2-carboxamide) butanoic acid 1
0.14 g of / 2 hydrate was obtained. Melting point 225 to 226 ° C. Raw material Production Example 7 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2-thione 5.0 g was dissolved in butanol 150 ml, and N- 5.1 g of α-tertiary butoxycarbonyl-D-glutamic acid hydrazine γ-benzyl ester was added, and the mixture was refluxed overnight. Chloroform was added to the reaction solution, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography using ethyl acetate and methanol as a mixed solvent. (R) -4- (tertiary butoxycarbonylamino) -4- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3
1.90 g of benzyl ester of -a] [1,4] benzodiazepin-1-yl) butanoic acid was obtained.

The resulting (R) -4- (tertiary butoxycarbonylamino) -4- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,4
3-a] [1,4] benzodiazepin-1-yl) butanoic acid benzyl ester (1.90 g) was added to trifluoroacetic acid 2
It was dissolved in 0 ml and stirred under ice cooling for 30 minutes. The solvent was evaporated, chloroform was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off and (R) -4-amino-4- (8-chloro-6-
(2-Chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine-1-
1.73 g of benzyl) butanoic acid benzyl ester was obtained.

Example 16 (R) -4-Amino-4- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] ] Benzodiazepin-1-yl) butanoic acid benzyl ester 1.73 g was dissolved in dimethylformamide 20 ml and triethylamine 0.5
1 ml, BOP reagent 1.62 g, and indole-2-carboxylic acid 0.59 g were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography using a mixed solvent of ethyl acetate and methanol as an eluent,
(R) -4- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a]
[1,4] benzodiazepin-1-yl) -4- (1H
1.33 g of indole-2-carboxamide) butanoic acid benzyl ester was obtained.

NMR (270 MHz, CDCl ₃ ):
2.11 to 2.84 (4H, m), 3.94 to 4.19
(1H, m), 4.87 to 5.15 (2H, m), 5.
46 to 5.54 (1H, m), 5.74 to 5.93 (1
H, m), 6.88-9.33 (19H, m) Example 17 (R) -4- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [ 4,3-a]
[1,4] benzodiazepin-1-yl) -4- (1H
-Indol-2-carboxamido) butanoic acid benzyl ester (1.09 g) was suspended in methanol (10 ml),
By alkali hydrolysis using 3.29 ml of 1N aqueous sodium hydroxide solution, (R) -4- (8-chloro-6- (2-chlorophenyl) -4H- [1,2,
4 g of triazolo [4,3-a] [1,4] benzodiazepin-1-yl) -4- (1H-indole-2-carboxamido) butanoic acid was obtained. Melting point 270 ° C. or higher NMR (270 MHz, DMSO-d6): 1.93-
2.50 (4H, m), 4.24-4.35 (1H,
t), 5.27 to 5.31 (1H, d), 5.48 to
5.91 (1H, m), 6.94 to 11.66 (14
H, m) Example 18 (R) -4-amino-4- (6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a]
[1,4] Benzodiazepin-1-yl) butanoic acid benzyl ester (1.26 g), chloroform (15 ml), triethylamine (0.40 ml) and 3,4-dichlorobenzoyl chloride (0.60 g) were added, and the mixture was stirred at room temperature for 2 hours.
Chloroform was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried with magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography using ethyl acetate as an eluent to obtain (R) -4- (6- (2
-Chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-1-yl) -4- (3,4-dichlorobenzamido) butanoic acid benzyl ester 0.60 g Got

NMR (270 MHz, CDCl ₃ ):
2.49-2.67 (4H, m), 5.10-5.29
(3H, m), 7.33 to 7.83 (17H, m) Example 19 (R) -4- (6- (2-chlorophenyl) -4H-
0.40 g of [1,2,4] triazolo [4,3-a] [1,4] benzodiazepin-1-yl) -4- (3,4-dichlorobenzamido) butanoic acid benzyl ester was added to 10 ml of methanol. Suspension and alkaline hydrolysis with 1.21 ml of 1N aqueous sodium hydroxide solution gave (R) -4- (6- (2-chlorophenyl).
-4H- [1,2,4] triazolo [4,3-a]
[1,4] benzodiazepin-1-yl) -4- (3,3
0.19 g of 4-dichlorobenzamido) butanoic acid was obtained.

NMR (270 MHz, DMSO-d
6): 2.07 to 2.70 (4H, m), 4.08 to
4.19 (1H, m), 5.46 to 5.51 (1H,
d) 5.83 to 5.84 (1H, m), 7.10
9.32 (12H, m) The compounds obtained in the above Examples 1 to 19 and the compounds included in the present invention are shown in the following table.

[0149]

[Table 1]

[0150]

[Table 2]

[0151]

[Table 3]

[0152]

[Table 4]

[0153]

[Table 5]

[0154]

[Table 6]

[0155]

[Table 7]

[0156]

[Table 8]

[0157]

[Table 9]

[0158]

[Table 10]

[0159]

[Table 11]

[0160]

[Table 12]

[0161]

[Table 13]

[0162]

[Table 14]

[0163]

[Table 15]

[0164]

[Table 16]

[0165]

[Table 17]

[0166]

[Table 18]

[0167]

[Table 19]

[0168]

[Table 20]

[0169]

[Table 21]

Formulation Example 1 0.5 part of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch were mixed well and then kneaded well with the binder prepared in 2 parts of corn starch. The kneaded mixture is sieved through 16 mesh and placed in an oven for 5 minutes.
After drying at 0 ° C, it was sieved with 24 mesh. The kneaded powder thus obtained was mixed well with 8 parts of cornstarch, 11 parts of crystalline cellulose and 9 parts of talc, and the mixture was compressed and compressed to give 1
A tablet is obtained containing 0.5 mg of active ingredient per tablet. Formulation Example 2 1.0 mg of the compound of Example 1 and 9.0 m of sodium chloride
g in water for injection and filtered to remove pyrogens,
The filtrate is aseptically transferred to an ampoule, sterilized, and melt-sealed to give an injection containing 1.0 mg of the active ingredient.

Next, the pharmacological action of the compound of the present invention will be shown. Experimental Example 1: CCK-A receptor binding The whole pancreas was removed from a male Wistar rat and adipose tissue was collected.
10 mM MES [2- (morpholino) ethane
Sulfonic acid] buffer (0.02% bacitracin, 0.0
2% soybean trypsin inhibitor, 0.0001% pheny
Rumethanesulfonyl fluoride content, pH 6.5)
Homogenize (Brinkman Polytron PT20)
did. Centrifuge after filtering with nylon cloth (120 mesh)
Separate (40,000 xg, 15 minutes) and
Homogenize and centrifuge in the above buffer as described above.
went. The sediment is diluted with 500 times wet weight for binding assay.
Immersion solution (130 mM sodium chloride, 4.7 mM potassium chloride)
Um, 5 mM magnesium chloride, 0.02% bacitrac
0.0001% Phenylmethanesulfonyl Fluora
Id-containing 10 mM MES, pH 6.5)
Used as a source of treetop receptors. Binding assay is 10 μl
Dimethyl sulfoxide (for total binding), final concentration 1 μM
Unlabeled CCK-8 Sulfate (for non-specific binding) or test
Compound(^ThreeH-pCCK-8, 2.2-3.3TBq /
50 μl) was added to 940 μl of membrane suspension.
The reaction mixture was incubated at 22 ° C for 120 minutes and
Directly after suction filtration with lath fiber filter paper (Whatman G / FB)
Then, wash 3 times with 3 ml of ice-cooled MES buffer, and then wash on filter paper.
Was measured. Experimental Example 2: CCK-B Receptor Binding Using a male Wistar rat cerebral cortex, 0.32 M
Homogenize in callose solution (Brinkman-Politro
PT20) and then centrifuged (1,000 xg, 10 minutes
And the resulting supernatant is further centrifuged (40,000 ×).
g, 15 minutes). The obtained precipitate is 10 mM HEP
ES (N-2-hydroxyethylpiperazine-N'-2
-Ethanesulfonic acid) buffer (130 mM sodium chloride)
In 5 mM magnesium chloride, pH 7.4)
Homogenize and centrifuge (40,000 x
g, 10 minutes). Precipitate 10 mM HEPES
Homogenize and centrifuge in buffer as above.
Was. 30 times the wet weight of the obtained sediment for binding assay
Buffer solution (130 mM sodium chloride, 5 mM magnesium chloride)
Cium, 0.02% bacitracin, 0.0001% fe
Nylmethanesulfonyl fluoride containing 10 mM ME
S, pH 6.5) and used as a central receptor source
Was. Binding assay is 10 μl of dimethyl sulfoxide
(For total binding), final concentration 1 μM unlabeled CCK-8 sulfate
Salt (for non-specific binding) or test compound ( ^ThreeH-pCCK
-8, 2.2-3.3 TBq / mmol) 50 μl
The membrane suspension was added to 940 μl. Reaction mixture at 4 ° C at 4 ° C
Incubate for 0 minutes and filter on glass fiber filter (Whatman
G / FB) Suction filtered immediately after cooling with ice, MES buffer
The plate was washed 3 times with 3 ml, and the radiation density on the filter paper was measured.

The effect of the test compound on the CCK receptor binding was determined by the inhibition rate according to the following formula, and the specific binding was determined to be 50%.
The concentration was evaluated (IC ₅₀ , nM). The results of the CCK receptor binding test of the compounds according to the invention are shown in the table below. ──────────────────────────────────── Test compound CCK-A CCK-B Example No. IC ₅₀ (NM) IC ₅₀ (nM) ──────────────────────────────────── 4 4.7> 1000 5 8.1> 1000 6 9.8> 1000 7 9.4> 1000 8 3.6> 1000 9 9.8> 1000 10 8.1> 1000 15 7.2> 1000 ───────── ──────────────────────────── Experimental Example 3: Effects on anesthetized guinea pig CCK-induced pancreatic secretions Male guinea pigs weighing about 650 g were urethane ( uretha
Ne) was anesthetized with 1.6 g / kg subcutaneous administration, and a perfusion fluid injection cannula was attached to the pylorus and an outflow cannula was attached 2 cm distal to the ligament of treitz. The duodenum was perfused with a physiological saline solution at a rate of 8 ml / 15 minutes, and the amount of trypsin secretion in the perfusion effluent was measured. Na-Benzoyl-
It was measured with a spectrophotometer using arginine p-nitroanilide (BAPNA) as a synthetic substrate. 0.1 μg of CCK-8
/ Kg intravenous administration induces pancreatic juice secretion, CCK-8 is again administered 60 minutes later, and the inhibition rate of the intravenous administration of the test drug administered 5 minutes before the second CCK-8 administration is calculated by the following formula. Was calculated.

Inhibition rate (%) = {1- (trypsin secretion amount in 60 minutes induced by the second CCK administration / first secretion amount)} × 100 Experimental Example 4: Rat caerulein-induced pancreatitis model Effects on Pancreas Volume 5, 284 (1990)
Year)) was improved. 20 μg / kg of cerulein was subcutaneously administered 4 times every 1 hour to male rats weighing about 200 g, and 4 hours after the final administration, blood was collected and the pancreas was excised. Amylase activity in blood is maltopentaose
Was measured as a synthetic substrate, and the pancreas was weighed 10
% Formalin aqueous solution, hematoxylin-eosin staining was performed, and the cells were examined under a light microscope. The test drug was orally or intravenously administered 30 minutes before the first administration of cerulein. Amylase activity and pancreatic weight inhibition rate were calculated by the following formulas, and the tissue findings were set to 0 when none were observed, and scored from 1 to 4 from the smallest change to the largest change to determine the pancreas. It was defined as the degree of tissue disorder improvement.

Amylase activity inhibition rate (%) = {1- (average amylase activity of test drug administration group / average amylase activity of control group)} × 100 Pancreatic weight inhibition rate (%) = {1- (test drug (Average pancreatic weight of administration group / average pancreatic weight of control group)} × 100 Experimental Example 5: Effect on delay of gastric emptying induced by CCK in mouse Oral or intravenous administration of the test drug to male mice weighing about 20 g, 25 30 minutes after CCK-8 /
kg was administered subcutaneously. After 5 minutes, 0.1 ml of an aqueous 1.5% methyl cellulose solution containing 0.05% phenol red was orally administered. After 15 minutes, the stomach contents were collected and 10%
Was deproteinized by mixing with an aqueous solution of trichloroacetic acid. After centrifugation,
1N NaOH was added to the supernatant, the mixture was centrifuged again, and the absorbance (590 nm) of the supernatant was measured with a spectrophotometer. The improvement rate was calculated by the following formula.

Improvement rate (%) = {1- (average absorbance of test drug administration group / average absorbance of control group)} × 100

[0176]

INDUSTRIAL APPLICABILITY The general formula (I) and the general formula (I
The compound of I) has excellent CCK and gastrin antagonism, particularly strong selective antagonism of CCK-A receptor, and exhibits potent and persistent pancreatic enzyme and gastric acid secretion inhibitory action, Central and peripheral nervous system disorders (anxiety, schizophrenia, etc.) and digestive system disorders (pancreatitis, gallbladder disorders, gastrointestinal ulcers, irritable bowel syndrome, constipation,
It is useful as a preventive or therapeutic drug for pancreatic cancer. Further, the compound of the general formula (II) can also be used as a raw material for synthesizing the compound of the general formula (I).

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[Procedure amendment]

[Submission date] December 6, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0149

[Correction method] Change

[Correction contents]

[0149]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/55 ACP A61K 31/55 ACP ADU ADU C07D 249/08 535 C07D 249/08 535 257/04 257/04 C 403/12 209 403/12 209 403/14 209 403/14 209 405/12 249 405/12 249 409/12 249 409/12 249 487/04 156 487/04 156 (72) Inventor Asano Kiyoshi Fukuoka 195, Otomi-cho, Yoshitomi-cho, Yoshitomi Pharmaceutical Co., Ltd. 2nd Research Center, Yoshitomi Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Kitajima 955, Otomi-cho, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Drug Discovery No. 2 In the laboratory

Claims (19)

[Claims] 1. A compound of the general formula [In the formula, R ¹ and R ² are the same or different and each is hydrogen, halogen, cyano, nitro, a hydroxyl group, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons, formula- (CH ₂ ) n ¹ COOR ⁴ (In the formula, n ¹ represents 0 or an integer of 1 to 5. R ⁴ represents hydrogen, alkyl having 1 to 5 carbons, cycloalkyl having 3 to 7 carbons or aralkyl. .) Represented by
Formula ^{_{- (CH 2) n 2 R}} 5 (.R 5 shown in the formula, n ² is an integer of 0 or 1 to 5 5-
Indicates a tetrazolyl group. ) Groups represented by or ^{_{formula, - (CH 2) n 3}} N (R 6) (R 7) (.R 6 shown in the formula, n ³ is 0 or an integer of 1 to 5, R ⁷
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, R ⁶ and R ⁷ may combine with adjacent nitrogen atoms to form a heterocycle. ) Is shown. R ³ is hydrogen, alkyl having 1 to 5 carbon atoms,
C1-C5 alkyl substituted with 1-3 hydroxyl groups, C3-C7 cycloalkyl, 1-on the aromatic ring
Aralkyl substituted with three hydroxyl groups, heteroarylalkyl, and a formula — (CH ₂ ) n ⁴ COOR ⁸ (wherein, n ⁴ represents 0 or an integer of 1 to 5. R ⁸ represents hydrogen and 1 carbon atom). To alkyl, aralkyl or cycloalkyl having 3 to 7 carbon atoms).
Formula ^{_{- (CH 2) n 5 N}} (R 9) (R 10) ( wherein, n ⁵ is an integer of 0 or 1~5 .R ^9, R ¹⁰
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, R ⁹ and R ¹⁰ may combine with adjacent nitrogen atoms to form a heterocycle. Group represented by the formula:-(CH ₂ ) n ⁶ CON (R ¹¹ ) (R ¹² ) (In the formula, n ⁶ represents 0 or an integer of 1 to 5. R ¹¹ , R ¹²
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, ¹¹ and R ¹² may combine with an adjacent nitrogen atom to form a heterocycle. Or a group represented by the formula: — (CH ₂ ) n ⁷ R ¹³ (wherein, n ⁷ represents 0 or an integer of 1 to 5. R ¹³ represents 5-
Indicates a tetrazolyl group. ) Is shown. −
A = B- is -N = N -, - C ( R 27) = N- or -C
(R ²⁷⁾ = CH- (wherein, R ²⁷ is hydrogen, halogen, alkyl of 1 to 5 carbon atoms, 1 to 3 alkyl of 1 to 5 carbon atoms which is substituted with a hydroxyl group, a carbon number 2-5 Alkanoyl, cycloalkyl having 3 to 7 carbons, haloalkyl having 1 to 2 carbons, alkenyl, alkynyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, aryloxyalkyl, adamantyl, adamantylmethyl, formula- A group represented by (CH ₂ ) n ⁸ COOR ¹⁴ (wherein n ⁸ represents 0 or an integer of 1 to 5; R ¹⁴ represents hydrogen, alkyl having 1 to 5 carbons or aralkyl); ^{_{- (CH 2) n 9 CON}} (R 15) (R 16) (.R 15 shown wherein, n ⁹ is an integer of 0 or 1 to 5, R ¹⁶
Are the same or different and represent hydrogen or alkyl having 1 to 5 carbon atoms. Alternatively, R ¹⁵ and R ¹⁶ may combine with adjacent nitrogen atoms to form a heterocycle. ) Groups represented by or ^{_{formula, - (CH 2) n 10}} N (R 17) (R 18) ( wherein, n ¹⁰ represents an integer of 0 or 1 to 5 .R ^17, R
¹⁸ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ¹⁷ and R ¹⁸ may combine with adjacent nitrogen atoms to form a heterocycle. ) Is shown. ). Z ¹ represents aryl, heteroaryl, or a group represented by the formula —CH═CH—R ¹⁹ (wherein R ¹⁹ represents cycloalkyl, aryl, or heteroaryl having 3 to 7 carbon atoms); On the ring, halogen, hydroxyl group, amino, nitro, alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups, alkanoyl having 2 to 5 carbon atoms, carbon number 1-2 haloalkyl, 1 carbon
5 alkoxy, alkylthio having 1 to 5 carbon atoms, aryloxy of the formula ^{_{- (CH 2) n 11 COOR}} 20 ( wherein, n ¹¹ .R ²⁰ is showing an integer of 0 or 1 to 5 hydrogen, carbon atoms groups represented by) shows a 1-5 alkyl or aralkyl, wherein ^{_{-. (CH 2) n 12}} CON (R 21) (R 22) ( wherein, n ¹² represents an integer of 0 or 1 to 5 . R ²¹ , R
²² is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ²¹ and R ²² may combine with adjacent nitrogen atoms to form a heterocycle. Group represented by the formula:-(CH ₂ ) n ¹³ N (R ²³ ) (R ²⁴ ) (In the formula, n ¹³ represents 0 or an integer of 1 to 5. R ²³ , R
²⁴ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ²³ and R ²⁴ may combine with an adjacent nitrogen atom to form a heterocycle. And a group represented by the formula: — (CH ₂ ) n ¹⁴ R ²⁵ (wherein n ¹⁴ is 0 or an integer of 1 to 5. R ²⁵ is 5
-Indicates a tetrazolyl group. May have an arbitrary number of substituents selected from the groups represented by Y ¹ is -NH
CO-, -NHCONH-, -NHCSNH-, -NH
_{SO 2 -, - NHCOO -,} - OCONH -, - OCO
-, -NHCONHCO-, -NHCSNHCO-,-
NHCONHSO ₂ -, - shows or -NHCOCONH- - NHCSNHSO _2. Ar ¹ is phenyl, pyridyl, thienyl or halogen on the ring, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons, alkylthio having 1 to 5 carbons, carboxyl, carboxyalkyl. , Phenyl, pyridyl and thienyl having at least one substituent selected from nitro, amino and hydroxyl. ] The phenylazole compound represented by these, or its pharmaceutically acceptable salt. 2. R ¹ and R ² are the same or different and are hydrogen;
Tables represented by alkyl having 1 to 2 carbons or by the formula — (CH ₂ ) n ¹ COOR ⁴ (wherein n ¹ represents 0 or 1; R ⁴ represents hydrogen or alkyl having 1 to 4 carbons). The phenylazole compound or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by 3. A group in which R ³ is hydrogen or a group represented by the formula — (CH ₂ ) n ⁴ COOR ⁸ (wherein n ⁴ represents 1 or 2; R ⁸ represents hydrogen, benzyl or cyclohexyl). The phenylazole compound according to claim 1 or a pharmaceutically acceptable salt thereof. Wherein -A = B- is -N = N -, - C ( R 27)
= N- or -CH = CH- (In the formula, R ²⁷ is hydrogen, halogen, alkyl having 1 to 4 carbons, alkyl having 1 to 2 carbons substituted with one hydroxyl group, cyclohexyl, trifluoromethyl. A group represented by the formula: — (CH ₂ ) n ⁸ COOR ¹⁴ (wherein n ⁸ represents 0, 1 or 2; R ¹⁴ represents hydrogen or alkyl having 1 to 2 carbon atoms);
Or the formula ^{_{- (CH 2) n 10 N}} (R 17) (R 18) ( wherein, n ¹⁰ represents a 1 .R ^17, R ¹⁸ is an alkyl having 1 to 2 carbon atoms.) Are represented by Indicates a group. ) Is a phenylazole compound or a pharmaceutically acceptable salt thereof according to claim 1. 5. Z ¹ represents aryl, heteroaryl or a group represented by the formula —CH═CH—R ¹⁹ (wherein R ¹⁹ represents phenyl), and halogen or amino is present on these rings. , Nitro, methyl, methoxy, 1H-tetrazol-5-ylmethyl and the formula — (CH ₂ ) n ¹¹ COOR ²⁰ (wherein n ¹¹ represents 0 or an integer of 1 to 4. R ²⁰ represents hydrogen or a carbon number of 1). The phenylazole compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may have 1 to 2 substituents selected from the group represented by the formula (1) to 4). 6. Y ¹ is —NHCO—, —NHCONH
-, - NHCSNH -, - NHSO 2 -, - OCONH
-Or -OCO-, The phenylazole compound according to claim 1 or a pharmaceutically acceptable salt thereof. 7. The phenylazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar ¹ is phenyl or phenyl having a halogen on the ring. 8. A medicine comprising the phenylazole compound according to claim 1 or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising the phenylazole compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 10. A general formula: [In the formula, R ³¹ and R ³² are the same or different and are hydrogen, halogen, cyano, nitro, hydroxyl group, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons, and formula- (CH ₂ ) n ²¹ COOR ³⁵ (In the formula, n ²¹ represents 0 or an integer of 1 to 5. R ³⁵ represents hydrogen, alkyl having 1 to 5 carbons, cycloalkyl having 3 to 7 carbons or aralkyl. .) Represented by
Formula ^{_{- (CH 2) n 22 R}} 36 (.R 36 shown wherein, n ²² represents an integer of 0 or 1 to 5 5
-Indicates a tetrazolyl group. ) Groups represented by or ^{_{formula, - (CH 2) n 23}} N (R 37) (R 38) (.R 37 shown wherein, n ²³ represents an integer of 0 or 1 to 5, R
³⁸ are the same or different and each represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ³⁷ and R ³⁸ may combine with an adjacent nitrogen atom to form a heterocycle. ) Is shown. R ³³ is hydrogen, alkyl having 1 to 5 carbons, alkyl having 1 to 5 carbons substituted with 1 to 3 hydroxyl groups, cycloalkyl having 3 to 7 carbons, and 1 to 3 alkyls on the aromatic ring. aralkyl substituted with a hydroxyl group, heteroarylalkyl, formula ^{_{- (CH 2) n 24 COOR}} 39 ( wherein, .R ³⁹ n ²⁴ is showing an integer of 0 or 1 to 5 hydrogen, a 1 to 5 carbon atoms A group represented by alkyl, aralkyl or cycloalkyl having 3 to 7 carbon atoms),
Formula ^{_{- (CH 2) n 25 N}} (R 40) (R 41) ( wherein, n ²⁵ is .R ⁴⁰ represents an integer of 0 or 1 to 5, R
⁴¹ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁴⁰ and R ⁴¹ may be bonded to adjacent nitrogen atoms to form a heterocycle. Group represented by the formula:-(CH ₂ ) n ²⁶ CON (R ⁴² ) (R ⁴³ ) (In the formula, n ²⁶ represents 0 or an integer of 1 to 5. R ⁴² , R
⁴³ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁴² and R ⁴³ may combine with an adjacent nitrogen atom to form a heterocycle. Or a group represented by the formula: — (CH ₂ ) n ²⁷ R ⁴⁴ (wherein n ²⁷ is 0 or an integer of 1 to 5. R ⁴⁴ is 5
-Indicates a tetrazolyl group. ) Is shown.
R ³⁴ is hydrogen, alkyl having 1 to 5 carbons, and formula — (CH ₂ ) n ²⁸ COOR ⁴⁵ (in the formula, n ²⁸ is 0 or an integer of 1 to 5. R ⁴⁵ is hydrogen and 1 to 5 carbons . alkyl or a group represented by) an aralkyl or the ^{_{formula, - (CH 2) n 29}} n (R 46) (R 47) ( wherein, n ²⁹ represents an integer of 0 or 1 to 5 .R ⁴⁶ , R
⁴⁷ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁴⁶ and R ⁴⁷ may combine with adjacent nitrogen atoms to form a heterocycle. ) Is shown. m represents 0 or an integer of 1 to 5. Y
² is -NHCO-, -NHCONH-, -NHCSNH
_{-, - NHSO 2 -, -} NHCOO -, - OCONH
-, -OCO-, -NHCONHCO-, -NHCSN
_{HCO -, - NHCONHSO 2 -,} - NHCSNHS
O ₂ - or an -NHCOCONH-. Z ² represents an aralkyl, aryl, heteroaryl, or group represented by the formula —CH═CH—R ⁴⁸ (wherein R ⁴⁸ represents cycloalkyl, aryl, or heteroaryl having 3 to 7 carbon atoms). On these rings, halogen, hydroxyl group, amino, nitro, alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups, alkanoyl having 2 to 5 carbon atoms, C 1-2 haloalkyl, 1 carbon
5 alkoxy, alkylthio having 1 to 5 carbon atoms, aryloxy of the formula ^{_{- (CH 2) n 30 COOR}} 49 ( wherein, n ³⁰ .R ⁴⁹ is showing an integer of 0 or 1 to 5 hydrogen, carbon atoms groups represented by showing a 1-5 alkyl or aralkyl), wherein -. shows a ^{_{(CH 2) n 31 CON (}} R 50) (R 51) ( wherein, n ³¹ is 0 or an integer of 1 to 5 . R ⁵⁰ , R
⁵¹ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁵⁰ and R ⁵¹ may combine with adjacent nitrogen atoms to form a heterocycle. Groups represented by) the formula ^{_{- (CH 2) n 32 N}} (R 52) (R 53) (.R 52 shown wherein, n ³² represents an integer of 0 or 1 to 5, R
⁵³ is the same or different and represents hydrogen or alkyl having 1 to 5 carbons. Alternatively, R ⁵² and R ⁵³ may combine with adjacent nitrogen atoms to form a heterocycle. And a group represented by the formula: — (CH ₂ ) n ³³ R ⁵⁴ (wherein n ³³ is 0 or an integer of 1 to 5. R ⁵⁴ is 5
-Indicates a tetrazolyl group. May have an arbitrary number of substituents selected from the groups represented by Ar ² is phenyl, pyridyl, thienyl or halogen on the ring, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, haloalkyl having 1 to 2 carbons, alkylthio having 1 to 5 carbons,
It represents phenyl, pyridyl or thienyl having at least one substituent selected from carboxyl, carboxyalkyl, nitro, amino and hydroxyl group. ] The benzotriazolodiazepine compound represented by these, or its pharmaceutically acceptable salt. 11. R ³¹ and R ³² are the same or different and each is hydrogen, alkyl having 1 to 2 carbon atoms or the formula — (CH ₂ ) n ²¹ COOR ³⁵ (wherein n ²¹ represents 0 or 1. R ³⁵ Is hydrogen or an alkyl group having 1 to 4 carbon atoms.) The benzotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 10. 12. R ³³ is represented by hydrogen or the formula — (CH ₂ ) n ²⁴ COOR ³⁹ (wherein n ²⁴ represents 1, 2 or 3; R ³⁹ represents hydrogen, benzyl or cyclohexyl). A benzotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein 13. A benzotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein R ³⁴ is hydrogen. 14. A benzotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein m is 0. 15. Y ² is —NHCO—, —NHCONH
The benzotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 10, which is -or -NHCSNH-. 16. Z ² represents aryl, heteroaryl or the formula —CH═CH—R ⁴⁸ (wherein R ⁴⁸ represents phenyl), and on these rings halogen, methyl, methoxy and the formula — 1 to 2 groups selected from the group represented by (CH ₂ ) n ³⁰ COOR ⁴⁹ (wherein n ³⁰ represents 1 or 2; R ⁴⁹ represents hydrogen or alkyl having 1 to 4 carbon atoms); A substituent which may have a substituent.
0. The benzotriazolodiazepine compound described in 0 or a pharmaceutically acceptable salt thereof. 17. The benzotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein Ar ² is phenyl or phenyl having a halogen on the ring. 18. A medicine comprising the benzotriazolodiazepine compound according to claim 10 or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising the benzotriazolodiazepine compound or the pharmaceutically acceptable salt thereof according to claim 10 and a pharmaceutically acceptable carrier.