JPH072873A - Tricyclic compound - Google Patents

Abstract

PURPOSE:To obtain a new compound having cholecystokinin antagonism and useful for preventing and treating vomiting, pancreatitis, hyperinsulinism, etc. CONSTITUTION:A compound of formula I [R<1> is (substituted)aryl; R<2> is H or acyl], e.g. (6R)-2,3,5,6-tetrahydro-6-amino-5-oxo-8-(2-fluorophenyl)-1,4-thiazino[ 2,3,4- jk] [1,4]benzodiazepin. Furthermore, the compound of formula I is obtained by reacting, e.g. a compound of formula II (R<3> is organic group) with ammonia. The compound of formula II is a new compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel tricyclic compound having a cholecystokinin (CCK) antagonistic action and is used in the medical field.

[0002]

2. Description of the Related Art Although tricyclic compounds are known, the tricyclic compounds represented by the following formula (I) of the present invention are not known.

[0003]

The present invention has been made with the intention of developing more excellent pharmaceutical products.

[0004]

The present invention relates to novel tricyclic compounds and their pharmaceutically acceptable salts. More specifically, the present invention is a cholecystokinin (CCK) antagonist, and therefore, vomiting, pancreatitis, appetite regulation system disorders, pain, insulinoma, gastroparesis, pancreatic cancer, gallbladder disease (acute cholecystitis, New tricyclic compound useful for the treatment and / or prevention of diseases such as calculi), diseases associated with intestinal smooth muscle hyperactivity (irritable bowel syndrome, sphincter spasticity, etc.), hyperinsulinemia, dyspepsia, nausea, etc. It relates to a pharmaceutically acceptable salt thereof. The tricyclic compound of this invention can be represented by the following formula (I).

[Chemical 2] [Wherein R ¹ represents aryl which may have a suitable substituent, and R ² represents hydrogen or acyl] According to the present invention, the novel tricyclic compound (I) is It can be produced by each method shown in the formula.

Method 1

[Chemical 3]

Method 2

[Chemical 4] [In the above formula, R ¹ is as defined above, R ³ represents an organic group, and R ² _a represents acyl. ] The starting compound (II) is novel and can be produced by the following method.

Method A

[Chemical 5]

[Chemical 6]

[Chemical 7] [Wherein R ¹ and R ³ are each as defined above, X ¹ is halogen, X ² is halogen, R ⁴ is mono (or di or tri) halo (lower) alkyl, X ³
Represents halogen respectively]

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts, such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt, Metal salt such as magnesium salt, ammonium salt, organic base salt (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,
N'-dibenzylethylenediamine salt, etc.), organic acid salts (eg, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), Inorganic acid salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) and the like are included. In the above and subsequent description of the present specification, preferable examples or specific examples of various definitions included in the scope of the present invention will be described below in detail. The term “lower” means having 1 to 6 carbon atoms unless otherwise specified. Unless otherwise noted, the word "luxury"
It means that the number of carbon atoms is 7 to 20. Suitable "organic groups" include lower alkyl (eg methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, tertiary butyl, pentyl, neopentyl,
Tertiary pentyl, hexyl, etc., lower alkenyl (eg vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4) Or 5-hexenyl, etc., lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1
Or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), aryl (eg, phenyl, naphthyl, etc.), phenyl (lower) alkyl (eg, benzyl, phenethyl, phenylpropyl, etc.), etc. (Lower) alkyl and the like can be mentioned. Suitable "aryl" includes phenyl, naphthyl and the like.

Suitable "substituents" in the expression "aryl optionally having suitable substituents" include halogen, amino, lower alkyl, lower alkoxy, mono (or di or tri) halo (lower). Alkyl etc. are mentioned. Suitable "halogen" as well as suitable "halogen moieties" in the expression "mono (or di or tri) halo (lower) alkyl" include chlorine, bromine, fluorine and iodine. Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, tertiary pentyloxy, hexyloxy and the like. Suitable "lower alkyl" as well as suitable "lower alkyl moiety" in the expression "mono (or di or tri) halo (lower) alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl. , Tertiary butyl, pentyl, tertiary pentyl, hexyl, etc.
6 are straight-chain or branched-chain ones, and among them, those having 1 to 4 carbon atoms are preferable. Suitable "acyl" includes carbamoyl, aliphatic acyl group,
Examples thereof include an aromatic ring-containing acyl group (referred to as aromatic acyl) and a heterocyclic ring-containing acyl group (referred to as heterocyclic acyl).

Suitable examples of the acyl are as follows: carbamoyl; lower or higher alkanoyl (eg formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2).
-Dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, nonadecanoyl, etc., lower or higher alkoxy (For example, methoxycarbonyl, ethoxycarbonyl,
Tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, heptyloxycarbonyl, etc.), lower or higher alkylsulfonyl (eg methylsulfonyl,
Aliphatic acyl such as ethylsulfonyl), lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.); aroyl (eg, benzoyl, toluoyl, naphthoyl, etc.), ar (lower) alkanoyl [eg, phenyl (lower) alkanoyl (eg, Phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyryl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) alkanoyl (eg naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.)
Etc.], al (lower) alkenoyl [eg phenyl (lower) alkenoyl (eg phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl etc.), naphthyl (lower) alkenoyl (eg naphthylpropenoyl) , Naphthylbutenoyl, naphthylpentenoyl, etc.], al (lower) alkoxycarbonyl [eg phenyl (lower) alkoxycarbonyl (eg benzyloxycarbonyl etc.)], aryloxycarbonyl (eg phenoxycarbonyl, naphthyloxycarbonyl etc.) ), Aryloxy (lower) alkanoyl (eg, phenoxyacetyl, phenoxypropionyl, etc.), arylcarbamoyl (eg, phenylcarbamoyl). , Such as naphthylcarbamoyl),
Aromatic acyl such as arylthiocarbamoyl (eg, phenylthiocarbamoyl), arylglyoxyloyl (eg, phenylglyoxyloyl, naphthylglyoxyloyl), arenesulfonyl (eg, benzenesulfonyl, p-toluenesulfonyl); heterocycle Carbonyl, heterocyclic (lower) alkanoyl (eg thienylacetyl, thienylpropanoyl,
(Thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.), heterocycle (lower)
Heterocyclic acyl such as alkenoyl (eg, heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.), heterocyclic glyoxyloyl (eg, thiazolyl glyoxyloyl, thienyl glyoxyloyl, etc.) and the like can be mentioned. "Heterocycle carbonyl", "heterocycle (lower) alkanoyl", "heterocycle (lower) alkenoyl" and "heterocycle glyoxyloyl"
A preferred heterocycle moiety in the expression
It means a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as an oxygen atom, a sulfur atom or a nitrogen atom.

Particularly preferred heterocyclic groups are 1 to 4
3 to 8 membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic groups containing 4 nitrogen atoms, eg pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N.
-Oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,
2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), etc.
3-8 member containing 4 nitrogen atoms (more preferably 5
Or 6-membered) saturated heteromonocyclic groups such as pyrrolidinyl,
Imidazolidinyl, piperidino, piperazinyl, etc. 1
Unsaturated fused heterocyclic groups containing ~ 4 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, cinnolinyl, quinoxalinyl, etc. 1-2 oxygen atoms And 1-3
3 to 8 members (more preferably 5
Or a 6-membered) unsaturated heteromonocyclic group such as oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.),
A 3 to 8-membered (more preferably 5 or 6-membered) saturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, 1 to 2 oxygens such as morpholinyl and sydnonyl. Unsaturated fused heterocyclic group containing 1 to 3 nitrogen atoms, such as benzoxazolyl, benzooxadiazolyl, containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group such as thiazolyl, isothiazolyl, thiadiazolyl (for example, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4)
-Thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc., containing 3 to 8 members (more preferably 5 or 6 members) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. Heteromonocyclic groups, such as thiazolidinyl, 3-8 membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic groups containing 1-2 sulfur atoms, such as thienyl, dihydrodithynyl, dihydrodithionyl. Etc., such as unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom and 1 to 3 nitrogen atom, for example, benzothiazolyl, benzothiadiazolyl, 3 to 8 member containing 1 oxygen atom ( More preferably 5 or 6 membered) unsaturated heteromonocyclic groups, such as furyl, one oxygen atom and 1
Unsaturated condensation containing 1 to 2 sulfur atoms, such as 3-8 membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic groups containing 2 to 2 sulfur atoms, eg dihydrooxathinyl. Heterocyclic groups such as benzothienyl, benzothiynyl, and the like, and unsaturated condensed heterocyclic groups containing one oxygen atom and 1 to 2 sulfur atoms, such as benzoxathiynyl, and the like.

The acyl moieties as described above include 1 to 10 identical or different suitable substituents such as halogen (eg fluorine, chlorine, bromine or iodine), hydroxy, nitro, lower alkyl (eg methyl, ethyl, propyl). , Isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl etc.), amino, protected amino, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy etc.), Lower alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tertiary butylthio, pentylthio, hexylthio, etc.), carboxy, protected carboxy, N, N-di (lower) alkylamino (lower) Alkyl (e.g. N, N-dimethylaminomethyl, N, N-diethylaminomethyl,
N, N-dimethylaminoethyl, N, N-diethylaminoethyl, N, N-dipropylaminoethyl, N, N-
Dimethylaminopropyl, N, N-diethylaminopropyl, N, N-dipropylaminopropyl, N, N-dibutylaminomethyl, N, N-dipentylaminomethyl, N, N-dihexylaminomethyl, etc., hydroxyimino (lower) ) Alkyl (eg hydroxyiminomethyl, hydroxyiminoethyl, hydroxyiminopropyl, hydroxyiminobutyl, hydroxyiminopentyl, hydroxyiminohexyl etc.), arylimino (lower) alkyl [eg phenylimino (lower) alkyl (eg phenyliminomethyl, Phenyliminoethyl, phenyliminopropyl, phenyliminobutyl, phenyliminopentyl, phenyliminohexyl, etc.), lower alkanoyl (eg formyl, acetyl, phenyliminohexyl). Panoiru, butanoyl, pentanoyl, acyl such as hexanoyl, etc.), mono (or di or tri) halo (lower) alkyl which may have a like arylamino (e.g., phenylamino). Suitable "protected amino" includes acylamino and the like. Suitable "acyl moieties" in the term "acylamino" include those mentioned above. Suitable "protected carboxy" includes esterified carboxy and the like.

Suitable examples of esterified carboxy ester moieties include lower alkyl esters (eg methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, Hexyl ester, etc.), lower alkyl ester having at least one suitable substituent, such as lower alkanoyloxy (lower) alkyl ester [eg, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, etc. , Pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1 (or 2) -acetoxyethyl ester, 1 (or 2 or 3) -acetoxypropyl Stell, 1 (or 2 or 3 or 4) -acetoxybutyl ester, 1 (or 2) -propionyloxyethyl ester, 1 (or 2 or 3) -propionyloxypropyl ester, 1 (or 2) -butyryloxyethyl ester ester,
1 (or 2) -isobutyryloxyethyl ester,
1 (or 2) -pivaloyloxyethyl ester, 1
(Or 2) -hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2) -pentanoyloxyethyl ester, etc. ], Lower alkanesulfonyl (lower) alkyl ester (eg 2-mesylethyl ester), mono (or di or tri) halo (lower)
Alkyl ester (for example, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl ester (for example, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxy) Ethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene (lower) alkyl ester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) )
(Lower) alkyl ester [eg (5-methyl-2
-Oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2
-Oxo-1,3-dioxol-4-yl) ethyl ester etc.]; lower alkenyl ester (eg vinyl ester, allyl ester etc.); lower alkynyl ester (eg ethynyl ester, propargyl ester etc.); at least one suitable An optionally substituted ar (lower) alkyl ester, such as an optionally substituted mono (or di or tri) phenyl (lower) alkyl ester (eg, a benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary Butylben Aryl ester), which may have at least one suitable substituent (eg, phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl) Ester etc.); phthalidyl ester; and the like. Preferred specific examples of the object compound (I) are as follows: R ¹ is aryl (more preferably phenyl) which may have ¹ to 3 appropriate substituents [more preferably, halogen is Phenyl which may have, particularly preferably halophenyl], R ² is hydrogen, heterocyclic carbonyl [more preferably, unsaturated condensed heterocyclic carbonyl in which the heterocycle contains 1 to 4 nitrogen atoms, particularly Preferably indolylcarbonyl], or arylcarbamoyl (more preferably phenylcarbamoyl) which may have 1 to 3 appropriate substituents [more preferably,
Phenylcarbamoyl optionally having lower alkylthio, particularly preferably lower alkylthiophenylcarbamoyl].

The method for producing the object compound (I) of the present invention will be described in detail below. Method 1 Compound (Ia) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof. Suitable salts of the compounds (Ia) and (II) may be those exemplified for the compound (I). Suitable salt of the compound (III) may be the acid addition salt exemplified for the compound (I). This reaction usually involves water, alcohol (eg methanol, ethanol, etc.), benzene,
N, N-dimethylformamide, tetrahydrofuran,
It is carried out in a solvent such as methylene chloride, ethylene chloride, chloroform, diethyl ether, acetonitonyl, or any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Method 2 Compound (Ib) or a salt thereof can be prepared by subjecting compound (Ia) or a reactive derivative of the amino group or a salt thereof to an acylation reaction. Suitable acylating agent to be used in the present acylation reaction, wherein: R ² _a -OH (XV) compound or its reactive derivative (as defined above is R ² _a in the formula.) Alternatively, salts thereof can be mentioned. Suitable reactive derivative at the amino group of compound (Ia) is a Schiff base type imino compound produced by the reaction of compound (Ia) with a carbonyl compound such as aldehyde or ketone, or an enamine type isomer which is a tautomer thereof. Body; a silyl derivative produced by the reaction of a compound (Ia) with a silyl compound such as N, O-bis (trimethylsilyl) acetamide or N-trimethylsilylacetamide; a silyl derivative produced by the reaction of the compound (Ia) with phosphorus trichloride or phosgene Examples thereof include derivatives. Suitable salts of the compounds (Ia) and (XV) may be the same as those exemplified for the compound (I). Suitable reactive derivative of the compound (XV) includes acid halide, acid anhydride, active amide, active ester, isocyanate and the like. Suitable examples include acid chlorides and acid azides; substituted phosphoric acids (for example, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, Alkanesulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (eg, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid ( Mixed acid anhydrides with acids such as benzoic acid); symmetrical acid anhydrides; imidazole, 4-substituted imidazole, dimethylpyrazole,
Active amides with triazoles or tetrazoles; active esters (eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺
= CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl Thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,
8-quinolyl thioester, etc. or N-hydroxy compound (for example, N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole and the like); a substituted or unsubstituted aryl isocyanate; a substituted or unsubstituted aryl isothiocyanate; and the like. These reactive derivatives can be appropriately selected from among them according to the kind of the compound (XV) used. The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide,
It is carried out in pyridine or any other solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water. When compound (XV) is used in the reaction in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '.
-(4-Diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3
-Dimethylaminopropyl) carbodiimide, N, N-
Carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, 1-alkoxy-
1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7
-Hydroxybenzisoxazolium salt, 2-hydroxy hydroxide
Ethyl-5- (m-sulfophenyl) isoxazolium inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, N, N
It is preferred to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like. The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N-lower alkylmorpholine, N, N-di (lower) alkylbenzylamine. it can.

A method for producing the starting compound (II) will be described below. Method A-Compound (VI) or a salt thereof can be prepared by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof according to the method disclosed in Preparation Example 1 below or a method similar thereto. Method A-Compound (VIII) or a salt thereof can be prepared by reacting compound (VI) or a salt thereof with compound (VII). This reaction can be carried out by the method disclosed in Preparation Example 2 below or a method similar thereto. Method A-Compound (X) or a salt thereof can be prepared by reacting compound (VIII) or a salt thereof with compound (IX) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation Example 3 below or a method similar thereto. Method A-Compound (XII) or a salt thereof can be prepared by reacting compound (X) or a salt thereof with compound (XI). This reaction can be carried out in the presence or absence of a conventional solvent. The reaction temperature is not particularly limited, but usually the reaction is carried out under heating or heating.

Method A-Compound (XIII) or a salt thereof can be prepared by subjecting compound (XII) or a salt thereof to hydrolysis. The hydrolysis can be carried out in the presence of a base. Suitable bases include alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide). Etc.), alkali metal carbonates (eg sodium carbonate,
Examples thereof include inorganic bases such as potassium carbonate), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate etc.). This reaction is
Usually, water, alcohol (eg, methanol, ethanol, etc.), benzene, N, N-dimethylformamide,
It is carried out in a solvent such as tetrahydrofuran, diethyl ether or any other solvent which does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. Method A-Compound (II) or a salt thereof can be prepared by reacting compound (XIII) or a salt thereof with compound (XIV). This reaction is usually performed in the presence of a base such as tri (lower) alkylamine (eg trimethylamine, triethylamine, diisopropylethylamine etc.), di (lower) alkylaniline (eg dimethylaniline etc.). This reaction is usually carried out in a solvent such as benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. The object compound (I) and its pharmaceutically acceptable salts are CCK antagonists, and are therefore useful as therapeutic agents for vomiting, pancreatitis and the like. Further, the target compound (I)
And its pharmaceutically acceptable salts are expected to have gastrin antagonism, ulcer, gastric hypersecretion, Zol
Treatment and / or treatment of Linger-Ellison syndrome
It is also expected to be useful as a preventive drug.

In order to clarify the usefulness of the target compound (I), the pharmacological activity of typical compounds is shown below. [I] Test compound (6RS) -2,3,5,6-tetrahydro-6- (2
-Indolylcarbonylamino) -5-oxo-8-
(2-Fluorophenyl) -1,4-thiazino [2,2
3,4-jk] [1,4] benzodiazepine [II] test: [ ¹²⁵ I] CCK-8 binding to rat pancreatic membrane (i) Membrane production Rats were decapitated to kill the entire pancreas (approximately 0. 7 g) and remove a small amount of 50 mM Tris-HCl buffer (pH 7.4).
The mixture was put into a flask and chopped into pieces, and then put into 30 volumes of a buffer solution and homogenized with a Polytron homogenizer.
Homogenized for 10 minutes at 30,000 xg (16
It was centrifuged at 000 rpm). The pellet was again suspended in the same buffer by a glass-Teflon homogenizer and centrifuged at 30,000 xg for 10 minutes. This procedure (wash) was repeated twice more. The final pellet (membrane) was suspended in an incubation solution (see below) so that the final protein concentration was 2 mg / ml.
All operations were performed at 0-4 ° C. (Ii) Receptor binding assay The composition of the incubation solution is as follows: 50m
M Tris-HCl (pH 7.4), 5 mM MgCl ₂ , 5
mM dithiothreitol (DTT), 0.14 mg / m
1 bacitracin, and 0.2% bovine serum albumin (B
SA). Freshly prepared membranes (200 μg protein) were 500 μl containing 50 pM ¹²⁵ I-CCK-8 with or without test compound (1 × 10 ^-8 M).
Incubation was carried out for 30 minutes at 37 ° C. with shaking in a plastic test tube containing the above incubation solution.
To measure non-specific binding, 1 μM CCK-8 was added. Each measurement was performed in duplicate. The reaction was stopped by filtering the reaction mixture through a Whatman GF / B glass filter. Filter with 0.1% BS
After washing with a 50 mM Tris-HCl (pH 7.4) buffer containing A, the radioactivity of the filter was counted. The specific binding amount was determined by subtracting the non-specific binding amount from the total binding amount. The effect of the test compound is specific to ¹²⁵ I-CCK-
It was expressed as the inhibition rate (%) of 8 bonds.

Test results Inhibition rate (%): 92.5 The target compound (I) or a pharmaceutically acceptable salt thereof is generally administered to mammals including humans in capsules, microcapsules, tablets, granules, powders, troches, and It can be administered in the form of conventional pharmaceutical compositions such as syrups, aerosols, inhalants, solutions, injections, suspensions, emulsions and the like.
The pharmaceutical composition of the present invention includes, for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, excipients such as calcium carbonate, for example, cellulose, methyl cellulose, hydroxypropyl cellulose, polypropylpyrrolidone, Gelatin, gum arabic, polyethylene glycol, sucrose,
Binders such as starch, such as starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium hydrogen carbonate, calcium phosphate,
Disintegrating agents such as calcium citrate, for example magnesium stearate, talc, lubricants such as sodium lauryl sulphate, fragrances such as citric acid, menthol, glycine, orange powder, such as sodium benzoate, sodium bisulfite, methylparaben, propyl. Preservatives such as parabens, eg stabilizers such as citric acid, sodium citrate, acetic acid, etc., suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate, etc., dispersing agents, eg aqueous diluents such as water, eg cocoa butter. It may contain various organic or inorganic carrier substances commonly used for medicinal purposes such as base waxes of polyethylene glycol, white kerosene and the like. The active ingredient may be usually administered in a unit dose of 0.01 mg / kg to 50 mg / kg once to four times a day. However, the dose may be increased or decreased depending on the age, weight, condition of the patient or administration method. The following preparations and examples are given solely for the purpose of illustrating the invention in more detail.

Preparation Example 1 3,4-dihydro-2H-1,4-benzothiazine (3
0.2 g) and 2-fluorobenzonitrile (24.2)
g) in a solution of toluene (250 ml) with stirring at 5 ° C.
While cooling to room temperature, a solution of boron trichloride in toluene (1.9
1M, 110 ml) is added dropwise. After the addition is complete, the mixture is stirred at room temperature for 1 hour. The mixture is cooled again in the ice bath. To the cooled mixture was added aluminum chloride (28.0
g) is added in small portions. Warm the mixture to 1
Heat under reflux for 3 hours. The reaction mixture was stirred and cooled in an ice bath with 6N hydrochloric acid (65 ml) and water (1
30 ml) is added dropwise. The mixture is heated under reflux for 2 hours and left at room temperature overnight. The separated organic layer and the ethyl acetate extract from the aqueous layer are combined and washed 3 times with 6N hydrochloric acid and 2 times with water. After drying over magnesium sulfate, the solvent is removed under reduced pressure to give an oil (32.6 g). The oil is subjected to silica gel chromatography. As the eluent,
n-Hexane is used, followed by a mixture of n-hexane, ethyl acetate and chloroform. The desired fractions were combined and the solvent was evaporated under reduced pressure to give 5- (2-fluorobenzoyl) -3,4-dihydro-2H-1,4-benzothiazine (9.90 g) as a red oil. IR (Film): 3275, 1610, 1505, 1270, 1245, 1211, 11
35, 1100, 985,828, 745 cm ^-1 NMR (CDCl ₃ , δ): 2.99-3.04 (2H, m), 3.64-3.90 (2H,
m), 6.42 (1H, t, J = 10.0Hz), 7.08-7.43 (7H, m), 9.40
(1H, br s)

Preparation Example 2 5- (2-Fluorobenzoyl) -3,4-dihydro-
Bromoacetyl bromide was added to a solution of 2H-1,4-benzothiazine (9.90 g) and dry pyridine (3.6 g) in methylene chloride (200 ml) while stirring and cooling to 0 to 5 ° C in an ice bath. (3.78 ml) is added dropwise. After the addition is complete, the mixture is stirred at room temperature for 2 hours and heated at reflux for 1.5 hours. The reaction mixture is left at room temperature and washed twice with water.
After drying over magnesium sulfate, the solvent is removed under reduced pressure to give an oil (17.6 g). This is subjected to silica gel chromatography and eluted with chloroform. The desired fractions are combined and evaporated under reduced pressure. The residue was triturated in diisopropyl ether, collected by filtration and 5- (2-
Fluorobenzoyl) -3,4-dihydro-4-bromoacetyl-2H-1,4-benzothiazine (9.86
g) is obtained as a yellow powder. mp: 106-108 ° C IR (nujol): 1662, 1604, 950, 749 cm ^-1 NMR (CDCl ₃ , δ): 2.69-2.84 (1H, m), 2.99-3.09 (1H,
m), 3.33-3.47 (1H, m), 3.73 (2H, ABq, J = 11.5Hz, 20.6H
z), 4.65-4.76 (1H, m), 7.04-7.81 (7H, m)

Preparation Example 3 Sodium hydride (4.57 g) and hydroxylamine hydrochloride (9.09 g) in ethanol-water mixed solvent (1:
1, 100 ml) solution with stirring at 65-70 ° C. while stirring 5- (2-fluorobenzoyl) -3,4-dihydro-4-bromoacetyl-2H-1,4-benzothiazine (10 g) in ethanol (30 ml). ) Medium suspension is added in small portions. The mixture is stirred under the same conditions for 2.5 hours. The ethanol is removed under reduced pressure to give an aqueous residue. The residue is extracted twice with ethyl acetate, the extract is washed with water and dried over magnesium sulphate. The solvent is removed under reduced pressure to give an oil. This is triturated in a mixture of ethanol and diisopropyl ether, filtered, washed with diisopropyl ether, dried and
3,5,6-Tetrahydro-5-oxo-8- (2-fluorophenyl) -1,4-thiazino [2,3,4-j
k] [1,4] benzodiazepine-7-oxide (2.
21 g) are obtained as a yellow powder. mp: 206-206.5 ° C IR (nujol): 1670, 1372, 753 cm ^-1 NMR (CDCl ₃ , δ): 3.05 (1H, dt, J = 2.8Hz, 12Hz), 3.24
(1H, td, J = 2.8Hz, 12Hz), 3.44 (1H, dt, J = 4Hz, 12Hz), 4.
76 (2H, ABq, J = 12.6Hz, 17.4Hz), 5.18 (1H, td, J = 4Hz, 12
Hz), 6.79-7.51 (8H, m)

Preparation Example 4 2,3,5,6-tetrahydro-5-oxo-8- (2
-Fluorophenyl) -1,4-thiazino [2,3,4
-Jk] [1,4] Benzodiazepine-7-oxide (2.16g) in methylene chloride (25ml) while stirring and cooling trifluoroacetic anhydride (4.15g) in an ice bath while cooling. Methylene (3 ml) solution is added dropwise. The mixture is stirred under the same conditions for 2 hours and at room temperature for 4 hours. The mixture is evaporated under reduced pressure below 20 ° C. Ethanol (50 ml) is added to the residue and the mixture is neutralized with saturated aqueous sodium bicarbonate solution. The resulting mixture is stirred at room temperature overnight. The ethanol is removed to give an aqueous residue. The residue is extracted 3 times with ethyl acetate, the extracts are combined and washed twice with water. After drying the extract over magnesium sulfate, the solvent is removed under reduced pressure. The residue was triturated in diisopropyl ether, filtered off, and (6RS) -2,
3,5,6-Tetrahydro-6-hydroxy-5-oxo-8- (2-fluorophenyl) -1,4-thiazino [2,3,4-jk] [1,4] benzodiazepine (1.95 g) As a white powder. mp: 195 ℃ (decomposition) IR (nujol): 3240, 1690, 1610, 1600, 1370, 13
08, 1210, 1158, 1136, 1020, 770, 745 cm ^-1 NMR (DMSO-d ₆ , δ): 2.87-3.01 (1H, m), 3.26-3.36 (2
H, m), 4.89 (1H, s), 5.00 (1H, td, J = 3.4Hz, 13.2Hz), 6.
57 (1H, br s), 6.89-7.64 (8H, m)

Example 1 (6RS) -2,3,5,6-tetrahydro-6-hydroxy-5-oxo-8- (2-fluorophenyl)-
A solution of 1,4-thiazino [2,3,4-jk] [1,4] benzodiazepine (1.90 g) and diisopropylethylamine (1.13 g) in methylene chloride (30 ml) was stirred in an ice bath. A solution of methanesulfonyl chloride (0.995 g) in methylene chloride (2 ml) is added dropwise with cooling. The mixture is stirred under the same conditions for 1 hour and at room temperature for 0.5 hour. (6RS) -2,3,5,6-Tetrahydro-6-mesyloxy-5-oxo-8- (2-fluorophenyl) -1,4-thiazino [2,3,4-jk]
A reaction mixture containing [1,4] benzodiazepine,
28% aqueous ammonia (15 ml) and acetonitrile (3
0 ml) at 30 ° C. with vigorous stirring. The resulting mixture is stirred for 4 hours. The separated organic layer and the chloroform extract from the aqueous layer are combined and washed twice with water. After drying over magnesium sulfate, the solvent is removed under reduced pressure to give an oil. It is chromatographed on silica gel, eluting with chloroform and then with a chloroform-methanol (50: 1) mixture. The desired fractions are combined and evaporated under reduced pressure. The residue was triturated in diisopropyl ether, filtered off, and (6RS)-
2,3,5,6-Tetrahydro-6-amino-5-oxo-8- (2-fluorophenyl) -1,4-thiazino [2,3,4-jk] [1,4] benzodiazepine (0. 79 g) are obtained as yellow crystals. mp: 162-164 ℃ (decomposition) IR (nujol): 3370, 3300, 1685, 1606, 1595, 14
82, 1356, 1310, 1210, 1015, 815, 750 cm ^-1 NMR (CDCl ₃ , δ): 2.22 (2H, br s), 3.01 (1H, dt, J = 3H
z, 12Hz), 3.19 (1H, td, J = 3Hz, 12Hz), 3.41 (1H, dt, J =
4Hz, 12Hz), 4.57 (1H, s), 5.20 (1H, td, J = 4Hz, 12Hz),
6.9-7.7 (8H, m)

Example 2

[Chemical 8] (6RS) -2,3,5,6-tetrahydro-6-amino-5-oxo-8- (2-fluorophenyl) -1,
A solution of 4-thiazino [2,3,4-jk] [1,4] benzodiazepine (163.5 mg) and indole-2-carboxylic acid (80.6 mg) in N, N-dimethylformamide (3 ml) was added at room temperature. While stirring at 1-hydroxybenzotriazole (67.6 mg), N-ethyl-
N '-(3-dimethylaminopropyl) carbodiimide hydrochloride (95.6 mg) and triethylamine (5
0.6 mg) are added sequentially. The mixture is stirred under the same conditions for 7 hours. The reaction mixture is poured into water and adjusted to pH 8 with aqueous sodium bicarbonate solution. The resulting precipitate was collected by filtration, washed with water and dried to give (6RS) -2,3,5,6-tetrahydro-6- (2-indolylcarbonylamino) -5.
-Oxo-8- (2-fluorophenyl) -1,4-thiazino [2,3,4-jk] [1,4] benzodiazepine (195.7 mg) is obtained as a yellow powder. mp: 245-250 ℃ (decomposition) IR (nujol): 3390, 3270, 1678, 1645, 1530, 13
72, 1208, 746 cm ^-1 NMR (DMSO-d ₆ , δ): 2.98-3.09 (1
H, m), 3.20-3.40 (2H, m), 5.0-5.06 (1H, m), 5.70 (1H,
d, J = 8.6Hz), 6.9-7.7 (12H, m), 9.63 (1H, d, J = 8.6Hz), 1
1.7 (1H, s)

Example 3 (6RS) -2,3,5,6-tetrahydro-6-amino-5-oxo-8- (2-fluorophenyl) -1,
4-Thiazino [2,3,4-jk] [1,4] benzodiazepine (100 mg) in tetrahydrofuran (1 m
l) To the solution is added 3-methylthiophenyl isocyanate (50.5 mg) with stirring at room temperature. The mixture is stirred under the same conditions for 4 hours. To this reaction mixture was added diisopropyl ether (4 ml) and the resulting mixture was left for 0.5 hour. The resulting precipitate was collected by filtration, washed with diisopropyl ether, dried under reduced pressure, and then (6RS)-
2,3,5,6-Tetrahydro-6- [N '-(3-methylthiophenyl) ureido] -5-oxo-8- (2
-Fluorophenyl) -1,4-thiazino [2,3,4
-Jk] [1,4] benzodiazepine (110.8m
g) is obtained. mp: 253−255 ℃ IR (nujor): 3380, 1675, 1640, 1603, 1545, 13
72, 1310 cm ^-1 NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 2.96-3.05 (1H, m),
3.32-3.35 (2H, m), 4.98-5.05 (1H, m), 5.34 (1H, d, J = 8.
4Hz), 6.80-7.62 (12H, m), 9.12 (1H, s)

Claims (1)

[Claims] 1. The formula: [Wherein, R ¹ represents aryl which may have an appropriate substituent, and R ² represents hydrogen or acyl], and a pharmaceutically acceptable salt thereof.