JP2953045B2 - Thienodiazepine compounds - Google Patents

Description

The present invention relates to cholecystokinin and gastrin,
The present invention relates to a novel thienodiazepine compound having an excellent antagonism or a salt thereof.

[Problems to be solved by conventional technologies and inventions]

WO 89/05812 discloses a thienodiazepine compound having a cholecystokinin and gastrin antagonistic action.

By the way, cholecystokinin (also called CCK) is a neuropeptide consisting of 33 amino acids, and CCK-8 consisting of 8 amino acids on the C-terminal side is also active. Gastrin also has activity with pentagastrin consisting of 34 amino acids and 5 amino acids on the C-terminal side, and the amino acid sequence of pentagastrin is the same as that on the CCK terminal side.
Both are present in the gastrointestinal tissues and central nervous system and are involved in the regulation of pancreatic enzyme secretion and gastric acid secretion.

Numerous antagonists have been studied to date as being effective in preventing or treating diseases such as pancreatic disorders and gastrointestinal ulcers, because these substances have an antagonistic effect on CCK and gastrin. Recently, it has been reported that CCK antagonism is related to anti-dementia activity.

CCK antagonists include benzotrypto [Floodings of National Academy of Science of USA (Proc. Natl. Acad. Sci.
USA (Vol. 78, pp. 6304 (1981)), and as a gastrin antagonist, proglumide [Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 27, No. 1,
597 (1984)]. However, these effects are relatively weak, and compounds having higher activity are desired.

In addition, peptide antagonists are not always satisfactory in terms of short duration of action, instability, and poor absorption.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve such problems, and as a result, have found that a certain thienodiazepine compound achieves the object, and have completed the present invention.

That is, the present invention relates to the general formula [In the formula, R ¹ and R ² are the same or different and hydrogen, halogen,
It represents alkyl or aralkyl, or R ¹ and R ² are bonded to each other to form a ring. R ³ represents oxygen, R ⁴ is hydrogen, alkyl, alkenyl or a formula: — (CH ₂ ) _m COOR
⁶ (where R ⁶ represents hydrogen, alkyl, alkenyl or aralkyl, and m represents an integer of 1 to 6), or R ³ and R ⁴ are bonded to each other to form N-N
ＣC (R ⁵ ) — (where R ⁵ represents hydrogen, alkyl, alkenyl or aralkyl or has the formula: — (CH ₂ ) _n COOR
⁷ (where R ⁷ represents hydrogen, alkyl, alkenyl or aralkyl, and n represents an integer of 1 to 6). ) Is shown. Ar and X are the same or different and represent aryl, aralkyl or heteroaryl. ] It relates to the thienodiazepine compound represented by these, or its salt.

In the above definition and the present specification, halogen is chlorine, bromine, fluorine, iodine, and alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Tertiary butyl, pentyl, isopentyl, tertiary pentyl, hexyl, octyl, 2-ethylhexyl, 1,1,3,
3-tetramethylbutyl, nonyl, decyl, dodecyl,
Alkyl having 1 to 20 carbon atoms, such as tetradecyl, octadecyl and eicosyl, and alkenyl are vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl, 2
Alkenyl having 2 to 8 carbon atoms such as -pentenyl, 3-hexenyl and 6-octenyl; alkoxy is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
Hexyloxy, octyloxy, decyloxy, dodecyloxy, octacdecyloxy, alkoxy having 1 to 20 carbon atoms such as eicosyloxy, aralkyl is halogen, alkyl, alkyl, trifluoromethyl, nitro, Benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl which may have 1 to 3 substituents selected from amino, cyano and hydroxyl groups; -Naphthylmethyl, diphenylmethyl and the like;
Aryl is phenyl, 1-naphthyl, 2-phenyl which may have 1 to 3 substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, nitro, amino, cyano and hydroxyl groups on the aromatic ring. Such as naphthyl, heteroaryl is halogen, alkyl,
Pyridyl optionally having 1 to 3 substituents selected from alkoxy, trifluoromethyl, nitro, amino, cyano and hydroxyl (2-pyridyl, 3-pyridyl,
4-pyridyl), quinolyl (eg, 2-quinolyl, 3-quinolyl), indolyl (eg, 2-indolyl, 3-indolyl), thienyl (2-thienyl, 3-thienyl),
Furyl (2-furyl, 3-furyl), benzofuranyl (2-benzofuranyl, 3-benzofuranyl, etc.), 1H
-Benzimitazol-2-yl, 2-benzothiazolyl and the like, a ring formed by combining R ¹ and R ² with each other is a cyclopentene ring, a cyclopentadiene ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring, It means a cycloheptene ring, a cycloheptadiene ring, a cycloheptatriene ring and the like.

Salts of the compounds of general formula (I) include acid addition salts with inorganic or organic acids and salts with inorganic bases, organic bases or amino acids, which are non-toxic for the purposes of the present invention. Is desirable.

Further, since the compound of the general formula (I) has at least one chiral carbon atom, all racemic forms, optically active forms, diastereomers and the like based on the compound are included in the present invention. .

The compound of the general formula (I) of the present invention is, for example, a compound of the general formula (Wherein each symbol is as defined above) and an isocyanate represented by the general formula X-NCO (III) (where X is as defined above) Can be manufactured.

The condensation reaction between the compound of the general formula (II) and the compound of the general formula (III) is performed in a suitable solvent that does not inhibit the reaction. As the solvent, for example, tetrahydroxyfuran,
Organic solvents such as diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, ethyl acetate, benzene, toluene, xylene, dimethylformamide, and dimethylacetamide can be used.

The temperature of the condensation reaction varies depending on the reagents and solvent used, but generally the boiling point of the solvent is preferably from -20 ° C.

Further, R ³ and R ⁴ are bonded to each other to form = N−N = C (R ⁵ )
The compound (I) representing a group forming-is a compound (I) wherein R ³ is oxygen and R ⁴ is hydrogen, that is, a compound represented by the general formula (Wherein the symbols have the same meanings as described above). (Wherein each symbol has the same meaning as described above). A compound represented by the general formula (V) and a general formula R ⁵ CONHNH ₂ (VI) (wherein R ⁵ has the same meaning as described above) Or a compound represented by the general formula (V) obtained by reacting a compound of the general formula (V) with hydrazine hydrate. (Wherein each symbol is as defined above) and a compound represented by the general formula R ⁵ COOH (VIII) (where R ⁵ is as defined above) or a reactive derivative thereof. or the general formula ^{R 5 C (oR 3) 3} (IX) ( wherein,, R ⁸ is an alkyl such as methyl, ethyl, R ⁵
Is as defined above. ) Is produced by reacting a compound represented by the following formula:

In the above method, phosphorus pentasulfide, Lawe
sson reagent [2,4-bis (4-methoxyphenyl) -1,3,
2,4-dithiadiphosphetane-2,4-disulfide], and examples of the reactive derivative of the compound represented by the general formula (VIII) include acid halides, acid anhydrides, mixed acid anhydrides, and carbon atoms of 1 And 5 alkyl esters, benzyl esters and the like.

The reaction between the compound of the general formula (IV) and the thionation reagent is usually carried out in an inert solvent (pyridyl, dimethylaniline,
Benzene, toluene, xylene, tetrahydrofuran,
Chloroform, dioxane, etc., or a mixed solvent thereof)
It proceeds at 30 to 100 ° C for 30 minutes to 5 hours.

The reaction between the compound of the general formula (V) and the compound of the general formula (VI) is usually carried out in an inert solvent (benzene, toluene,
In the presence of an organic acid (acetic acid, propionic acid, etc.), an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or silica gel in xylene, tetrahydrofuran, dioxane, or a mixed solvent thereof, used at room temperature and at a solvent reflux temperature of 30 minutes to 5 hours. Proceed with.

The reaction of the compound of general formula (V) with hydrazine hydrate is usually carried out in a solvent inert to the reaction (methanol, ethanol, propanol, isopropyl alcohol, butanol, etc.) at 0 to 40 ° C. for about 5 minutes to 3 hours. proceed.

The reaction of the compound of the general formula (VII) with the compound of the general formula (VIII) or a reactive derivative thereof or the compound of the general formula (IX) is carried out in a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran, dioxane Such,
Or a mixed solvent thereof) in the presence of an organic acid (such as acetic acid or propionic acid), an inorganic acid (such as hydrochloric acid or sulfuric acid) or silica gel at room temperature to the reflux temperature of the solvent used for 30 minutes to 6 hours.

The compound of the general formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, column chromatography and the like.

Compounds of the general formula (I) can be prepared by a conventional method using inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), organic acids (acetic acid,
Propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc., inorganic bases (sodium hydroxide, potassium hydroxide) , Calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonium hydroxide, etc.), organic bases (methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethylaminomethane, quinine,
Salts can be obtained by treating with guanidine, cinchonine, etc.) or amino acids (lysine, ornithine, arginine, alanine, etc.).

When the compound of the present invention has a chiral carbon atom, it is usually obtained as a racemic form. The racemate can be separated into optical isomers by a conventional method. Such optical isomers can also be prepared by using optically active starting materials. Individual diastereomers can be purified by fractional crystallization or chromatography.

Examples of the compounds included in the present invention are as follows.

[Actions and Effects of the Invention] The compounds of the present invention and salts thereof have excellent cholecystokinin and gastrin antagonism, and exhibit potent and long-lasting pancreatic enzymes and gastric acid secretion inhibitory action. It is useful as a drug acting on peripheral nerves and as a preventive or therapeutic drug for pancreatic disorders and gastrointestinal ulcers.
Further, the compound of the present invention can be expected to have an anti-dementia effect based on cholecystokinin antagonism, and is also useful as an anti-dementia drug.

 Next, the pharmacological action of the compound of the present invention will be described.

 The compounds of the present invention used in the test are as follows.

Compound A: 4- (2-chlorophenyl) -2-ethyl-8
-Methyl-6- (3- (3-tolyl) ureido) -8H-
6,7-dihydro-thieno [3,2-f] [1,4] diazepin-7-one Compound B: 4- (2-chlorophenyl) -2-ethyl-9
-Methyl-6- (3-tolyl) ureido) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine -8, CCK-4 and the following compounds were also tested.

L-364718: N- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3
-Yl) -1H-indole-2-carboxamide Experimental example 1: CCK receptor binding Whole pancreas was removed from adult male mongrel dogs to remove adipose tissue
Homogenized (Brinkman Polytron PT20) in 50 mM Tris-HCl (pH 7.5). After filtration with a nylon cloth (120 mesh), centrifugation (50,000 × g, 12 minutes) was performed, and the obtained precipitate was homogenized and centrifuged in a Tris buffer solution in the same manner as described above. The precipitate was subjected to binding assay buffer (5 mM magnesium chloride, 5 mM dithiothreitol, 2 mg /
ml bovine serum albumin, 0.1 mg / ml bacitracin, 0.14 mg
50mM Tris-HCl, pH / ml trypsin inhibitor (soybean), pH
7.2) and used as a receptor source for peripheral tissues. In the case of central tissue, it is adjusted using guinea pig cerebral cortex, 5 mM magnesium chloride, 1 mM EGTA [ethylene glycol bis (2-aminoethyl ether) tetraacetic acid], 360 m
M sodium chloride, 15 mM potassium chloride, 20 mM HEPES (N
-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), 0.25 mg / ml balatrasin pH 6.5.

Binding assays consisted of 50 μl buffer (for total binding), 1 μM final concentration of unlabeled CCK-8 sulfate (non-specific binding) or test compound (for determination of ¹²⁵ I-CCK binding inhibitory ability) and ¹²⁵ I
-CCK-8 (63-67 TB _q / mmol, 40,000-50,000 cpm)
Was added to 450 μm of the membrane suspension (containing 100 μm as protein). Incubate the reaction mixture at 20 ° C. for 30 minutes,
Immediately after suction filtration with a glass fiber filter paper (Whatman G / FB), the plate was washed three times with 2.5 ml of ice-cooled Tris buffer, and the radioactivity concentration on the filter paper was measured.

The effect of the test compound on CCK receptor binding is determined by the following formula, and the concentration (IC
₅₀ , nM).

The results are summarized in Table 1.

When the compound of the present invention and a pharmaceutically acceptable salt thereof are used as a medicament, usually, pharmaceutically acceptable additives such as carriers, excipients, diluents, and solubilizing agents (lactose, corn starch, talc, kaolin, Saline, sterile water, etc.)
Mixed with tablets (including sugar-coated tablets and film-coated tablets),
It can be administered to patients in the form of capsules, powders, injections, drops, suppositories, cataplasms and the like.

The dose may vary depending on the patient's sex, age, weight or symptoms, etc., and is usually about 1 to 50 per day for oral administration per adult.
A range of 0 mg is preferred.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to Examples, but it is needless to say that the present invention is not limited thereto.

Example 1 6-Amino-4- (2-chlorophenyl) -2-ethyl-8-methyl-8H-6,7- in 10 ml of tetrahydrofuran.
Dihydro-thieno [3,2-f] [1,4] diazepine-7-
Dissolve 610 mg of ON, and add 277 mg of 3-tolyl isocyanate. After leaving for 30 minutes, the solvent is distilled off under reduced pressure, and the residue is washed with diisopropyl ether. Ethyl acetate was added, and the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to give 4- (2) having a melting point of 226 to 227 ° C.
-Chlorophenyl) -2-ethyl-8-methyl-6-
(3- (3-tolyl) ureido) -8H-6,7-dihydro-thieno [3,2-f] [1,4] diazepin-7-one 470 m
get g.

Example 2 6-amino-4- (2-chlorophenyl) -2-ethyl-9-methyl-6H-thieno [3,
2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 1.04 g and 3-tolyl isocyanate from 250 to 25
4- (2-chlorophenyl) -2-ethyl-9- at 2 ° C
Methyl-6- (3- (3-tolyl) ureido) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,
4] Obtain 850 mg of diazepine.

Example 3 6- (R, S) -4- (2-chlorophenyl) -2-ethyl-9-methyl-6- (3- (3-tolyl) ureido) -6H-thieno [3,2-f] (1,2,4) triazolo (4,
3-a] [1,4] Diazepine 1.12 g was chromatographed using an optically active column (Chiraspher, Merck) (hexane: dioxane: isopropyl alcohol = 60: 40: 1).
Was used for optical resolution. Optical purity is determined by HPLC under similar conditions
6- (R) -form and 6- (S) -form were 380 mg and 270 mg each.
mg was obtained.

The absolute configuration was determined by X-ray structural analysis.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/55 601 A61K 31/55 601 31/645 31/645 (56) References JP-A-61-15875 (JP, A) J. Med. Chem. , 31 (1), p. 176-181 (1988) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 495 / 04,495 / 14 A61K 31 / 55,31 / 645 REGISTRY (STN) CA (STN)

Claims (1)

(57) [Claims] (1) General formula [In the formula, R ¹ and R ² are the same or different and hydrogen, halogen,
It represents alkyl or aralkyl, or R ¹ and R ² are bonded to each other to form a ring. R ³ represents oxygen, R ⁴ is hydrogen, alkyl, alkenyl or a formula: — (CH ₂ ) _m COOR
⁶ (where R ⁶ represents hydrogen, alkyl, alkenyl or aralkyl, and m represents an integer of 1 to 6), or R ³ and R ⁴ are bonded to each other to form ＝ N −N =
C (R ⁵⁾ - (wherein, R ⁵ is hydrogen, alkyl, or an alkenyl or aralkyl, wherein :-( CH ₂₎ in _n COOR ⁷ (wherein, R ⁷ is hydrogen, alkyl, alkenyl or aralkyl, and n represents an integer of 1 to 6), and represents a group represented by the following formula: Ar and X are the same or different and represent aryl, aralkyl or heteroaryl. ] The thienodiazepine compound represented by these, or its salt.