JPH1017549A - Bicyclic aromatic amidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound shown by a specific formula, having blood coagulation factor Xa inhibitory activity, thus useful as a preventive/therapeutic agent for diseases due to thrombus, embolism, etc. SOLUTION: This new compound is shown by formula I (Ar is benzene ring or a heteroaromatic ring bearing 1 to 3 heteroatom(s); Q is a 3-7C alkylene, alkenylene or alkynylene; Y is a 5- to 10-membered monocyclic or bicyclic heterocyclic group bearing at least one N (atom), e.g. (E)-2-(7-amidino-2- naphthyl)-5-(isoindolin-5-yl)-4-pentenonic ethyl ester dihydrochloride. This compound of formula I is obtained, pref., for example, by reaction of a compound of formula II with hydrogen chloride directly in an alcohol solvent. The compound of formula II is prepared, pref. by uncleophilic substitution reaction between a compound of formula III and a compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention is useful in the field of medicine, and more specifically, a bicyclic aromatic amidine derivative having a blood clot inhibiting or thromboembolic dissolving action, a process for producing the same, and a method for producing the same. It is about its use.

[0002]

2. Description of the Related Art When a blood clot or embolus is formed in a blood vessel, normal blood flow cannot be maintained, and transient cerebral ischemia attacks, cerebral infarction, angina, myocardial infarction, thrombophlebitis, chronic artery Various diseases such as obstruction develop. Conventionally, an antithrombin agent has been developed as a thrombus formation inhibitor, but it is known that this antithrombin agent causes a bleeding tendency together with a thrombus formation inhibitory effect, and it cannot easily control the coagulation ability. Was. Therefore, development of an anticoagulant with a low risk of causing a bleeding tendency based on a new mechanism of action has been desired. Therefore, an anticoagulant based on an action mechanism other than the thrombin inhibitory action has been developed.
Anticoagulants based on an inhibitory effect have been found to have less tendency to bleed. However, a drug sufficient for clinical use has not been developed, and development of a drug having a stronger FXa inhibitory activity and high specificity has been clinically desired.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel anticoagulant which overcomes the drawbacks of existing anticoagulants.

[0004]

Means for Solving the Problems The present inventors have found that the compound represented by the general formula [I] exhibits an excellent anticoagulant action, and completed the present invention.

That is, the present invention provides a new general formula

[0006]

Embedded image [Wherein, Ar represents a benzene ring or a heteroaromatic ring having 1 to 3 heteroatoms selected from the group consisting of O, N and S, and Q represents an alkylene group, an alkenylene group or an alkylene group having 3 to 7 carbon atoms. alkynylene group (the alkylene group, a hydrogen atom a lower alkyl group in the alkenylene group, or alkynylene group, an aralkyl group, a carboxyl group, an alkoxycarbonyl group, may be substituted by a hydroxyalkyl group or carboxyalkyl group, also CH ₂ is O may be substituted with O, NH or S), and Y represents a monocyclic or bicyclic heterocyclic group having at least one 5 to 10-membered nitrogen atom. Or a pharmaceutically acceptable salt thereof, its production method and use.

The meaning of the terms used in the present specification will be explained.

[0008] 1 selected from the group consisting of O, N and S
The “heteroaromatic ring having 3 to 3 heteroatoms” means, for example, furan, thiophene, pyrrole, pyridine, oxazole, thiazole ring and the like.

The alkylene group having 3 to 7 carbon atoms means an alkylene group having 3 to 7 carbon atoms bonded on a straight chain, for example,-(CH ₂ ) ₃ -,-(CH ₂ ) ₄ -,-(C
_{H 2) 5 -, - (} CH 2) 6 -, - (CH 2) 7 - , and the like.

The alkenylene group having 3 to 7 carbon atoms means an alkenylene group in which 3 to 7 carbon atoms are bonded on a straight chain, for example, -CH ₂ CH = CH-, -CH = CH
_{CH 2 -, - (CH 2} ) 2 CH = CH -, - (CH 2) 3 C
H = CH -, - (CH 2) 4 CH = CH -, - (CH 2) 5
CH = CH -, - CH = CH (CH 2) 2 -, - CH = C
_{H (CH 2) 3 -,} - CH = CH (CH 2) 4 -, - CH 2
CH = CHCH _2- and the like.

An alkynylene group having 3 to 7 carbon atoms refers to an alkynylene group having 3 to 7 carbon atoms bonded in a straight chain, for example, -CH ₂ C≡C-, -C≡CCH ₂ −,
-(CH ₂ ) ₂ C≡C-,-(CH ₂ ) ₃ C≡C-,-(C
H ₂ ) ₄ CH≡CH-,-(CH ₂ ) ₅ C≡C-, -C≡C
(CH ₂ ) _2- , -C≡C (CH ₂ ) _3- , -C≡C (CH
_{2) 4 -, - CH 2} C≡CCH 2 - and the like.

The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec- Examples thereof include a butyl group, a pentyl group, an isopentyl group, a sec-pentyl group, a hexyl group, and a pentyl group.

The aralkyl group means an aralkyl group having 7 to 12 carbon atoms, such as benzyl, phenethyl, phenylpropyl and naphthylmethyl.

An alkoxycarbonyl group is a compound having 2 to 2 carbon atoms.
It means seven alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like.

A hydroxyalkyl group is a group having 1 to 6 carbon atoms.
And a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, and the like.

A carboxyalkyl group is one having 2 to 7 carbon atoms.
Carboxyalkyl groups, such as carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, and carboxypentyl.

"A monocyclic or bicyclic heterocyclic group having at least one 5- to 10-membered nitrogen atom" means a pyrrolidinyl group, a pyrrolinyl group, a pyronyl group, a pyrazolyl group, a dihydroindolyl group, a dihydroisodolyl group. Examples include an indolyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, an indolyl group, and the like.

Next, the meaning of the symbols used in the general formula [I] will be explained.

Ar represents a benzene ring or a heteroaromatic ring having 1 to 3 heteroatoms selected from the group consisting of O, N and S, such as a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyridine ring, An oxazole ring, a thiazole ring and the like can be mentioned.

Q is an alkylene group, alkenylene group or alkynylene group having 3 to 7 carbon atoms, wherein the hydrogen atom in the alkylene group, alkenylene group or alkynylene group is a lower alkyl group, an aralkyl group, a carboxyl group, an alkoxycarbonyl group, May be substituted with an alkyl group or a carboxyalkyl group, and CH ₂ is O, NH
Or may be substituted with S), wherein the alkylene group having 3 to 7 carbon atoms has 3 to 7 carbon atoms in a linear form.
Means an alkylene group having seven bonds, for example,-(C
_{H 2) 3 -, - (} CH 2) 4 -, - (CH 2) 5 -, - (CH
_{2) 6 -, - (CH} 2) 7 - , etc. can be mentioned, and the number 3-7 alkenylene carbon, 3 carbon atoms in a linear
Means an alkenylene group having up to 7 bonds, for example,-
_{CH 2 CH = CH -, -} CH = CHCH 2 -, - (C
_{H 2) 2 CH = CH -} , - (CH 2) 3 CH = CH -, -
_{(CH 2) 4 CH = CH} -, - (CH 2) 5 CH = CH-,
_{-CH = CH (CH 2) 2} -, - CH = CH (CH 2)
_{3 -, - CH = CH (} CH 2) 4 -, - CH 2 CH = CHC
H _2- and the like can be mentioned, and the alkynylene group having 3 to 7 carbon atoms means an alkynylene group in which 3 to 7 carbon atoms are bonded on a straight chain, for example, -CH ₂ C≡C −,
-C≡CCH ₂ -,-(CH ₂ ) ₂ C≡C-,-(CH ₂ )
₃ C≡C-,-(CH ₂ ) ₄ CH≡CH-,-(CH ₂ ) ₅
C≡C—, —C≡C (CH ₂ ) ₂ —, —C≡C (CH ₂ ) ₃
—, —C≡C (CH ₂ ) ₄ —, —CH ₂ C≡CCH ₂ — and the like.

A hydrogen atom in the alkylene group, alkenylene group or alkynylene group is a lower alkyl group, an aralkyl group, a carboxyl group, an alkoxycarbonyl group,
It may be substituted with a hydroxyalkyl group or a carboxyalkyl group, and CH ₂ may be substituted with O, NH or S, wherein the lower alkyl group is a straight-chain having 1 to 6 carbon atoms. Or a branched alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, pentyl group, isopentyl group, sec-pentyl group, hexyl group, pentyl group And the like, and an aralkyl group means an aralkyl group having 7 to 12 carbon atoms, such as a benzyl group, a phenethyl group, a phenylpropyl group, and a naphthylmethyl group. Represents an alkoxycarbonyl group having 2 to 7 carbon atoms, for example, a methoxycarbonyl group, an ethoxycarbonyl group, Examples thereof include a carbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and the like. The hydroxyalkyl group means a hydroxyalkyl group having 1 to 6 carbon atoms, such as a hydroxymethyl group, a hydroxyethyl group, and a hydroxypropyl group. A carboxyalkyl group means a carboxyalkyl group having 2 to 7 carbon atoms, such as a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, and a carboxyalkyl group. Examples thereof include a butyl group and a carboxypentyl group.

Examples of such groups include-(CH ₂ ) ₂
CH (Me) -, - ( CH 2) 3 CH (Me) -, - (C
_{H 2) 2 CH (Et)} -, - (CH 2) 3 CH (Et) -,
_{- (CH 2) 4 CH (} Me) -, - (CH 2) 5 CH (M
_{e) -, - CH 2 CH} (Me) CH 2 -, - (CH 2) 2 C
_{H (Me) CH 2 -,} - (CH 2) 3 CH (Me) CH
_{2 -, - (CH 2)} 4 CH (Me) CH 2 -, - (CH 2) 5
_{CH (Me) CH 2 -,} - (CH 2) 2 CH (CH 2 Ph)
_{-, - (CH 2) 3} CH (CH 2 Ph) -, - (CH 2) 4
_{CH (CH 2 Ph) -,} - (CH 2) 5 CH (CH 2 Ph)
_{-, - CH 2 CH (CH} 2 Ph) CH 2 -, - (CH 2) 2
_{CH (CH 2 Ph) CH 2} -, - (CH 2) 3 CH (CH 2
_{Ph) CH 2 -, - (} CH 2) 4 CH (CH 2 Ph) CH 2
_{-, - (CH 2) 5} CH (CH 2 Ph) CH 2 -, - (CH
₂ ) ₂ CH (CO ₂ H)-,-(CH ₂ ) ₃ CH (CO ₂ H)
_{-, - (CH 2) 4} CH (CO 2 H) -, - (CH 2) 5 C
_{H (CO 2 H) -,} - CH 2 CH (CO 2 H) CH 2 -, -
_{(CH 2) 2 CH (CO} 2 H) CH 2 -, - (CH 2) 3 CH
_{(CO 2 H) CH 2 -} , - (CH 2) 4 CH (CO 2 H) C
_{H 2 -, - (CH 2} ) 5 CH (CO 2 H) CH 2 -, - (C
_{H 2) 2 CH (CO 2} Me) -, - (CH 2) 3 CH (CO 2
_{Et) -, - (CH 2} ) 4 CH (CO 2 Et) -, - (C
_{H 2) 4 CH (CO 2} Et) -, - (CH 2) 5 CH (CO 2
_{Et) -, - CH 2 CH} (CO 2 Et) CH 2 -, - (C
_{H 2) 2 CH (CO 2} Et) CH 2 -, - (CH 2) 3 CH
_{(CO 2 Et) CH 2 -} , - (CH 2) 4 CH (CO 2 E
_{t) CH 2 -, - (} CH) 5 CH (CO 2 Et) CH 2 -,
_{- (CH 2) 2 CH (} CH 2 OH) -, - (CH 2) 3 CH
_{(CH 2 OH) -, -} (CH 2) 4 CH (CH 2 OH) -,
_{- (CH 2) 5 CH (} CH 2 OH) -, - CH 2 CH (CH
_{2 OH) CH 2 -, -} (CH 2) 2 CH (CH 2 OH) CH 2
_{-, - (CH 2) 3} CH (CH 2 OH) CH 2 -, - (CH
_{2) 4 CH (CH 2 OH} ) CH 2 -, - (CH 2) 5 CH (C
_{H 2 OH) CH 2 -,} - (CH 2) 2 CH (CH 2 CH 2 O
_{H) -, - (CH 2} ) 3 CH (CH 2 CH 2 OH) -, -
_{(CH 2) 4 CH (CH} 2 CH 2 OH) -, - (CH 2) 2 C
_{H (CH 2 CO 2 H)} -, - (CH 2) 3 CH (CH 2 CO 2
_{H) -, - (CH 2} ) 4 CH (CH 2 CO 2 H) -, - (C
_{H 2) 5 CH (CH 2} CO 2 H) -, - CH 2 CH (CH 2 C
_{O 2 H) CH 2 -,} - (CH 2) 2 CH (CH 2 CO 2 H) C
_{H 2 -, - (CH 2} ) 3 CH (CH 2 CO 2 H) CH 2 -, -
_{(CH 2) 4 CH (CH} 2 CO 2 H) CH 2 -, - (CH 2)
_{5 CH (CH 2 CO 2 H} ) CH 2 -, - (CH 2) 2 CH (C
_{H 2 CH 2 CO 2 H)} -, - (CH 2) 3 CH (CH 2 CH 2
_{CO 2 H) -, - (} CH 2) 4 CH (CH 2 CH 2 CO 2 H)
_{-, - NH (CH 2)} 2 -, - NH (CH 2) 3 -, - NH
_{(CH 2) 4 -, -} NH (CH 2) 2 O -, - NH (C
_{H 2) 3 O -, -} NH (CH 2) 4 O -, - NH (CH 2) 2
_{S -, - NH (CH 2} ) 3 S -, - NH (CH 2) 4 S
_{-, - CH 2 CH = C} (CO 2 H) -, - CH = C (CO
_{2 H) CH 2 -, -} (CH 2) 2 CH = C (CO 2 H) -,
_{- (CH 2) 3 CH =} C (CO 2 H) -, - (CH 2) 4 C
_{H = C (CO 2 H)} -, - (CH 2) 5 CH = C (CO
_{2 H) -, - CH =} C (CO 2 H) (CH 2) 2 -, - CH
ＣC (CO ₂ H) (CH ₂ ) ₃ —, —CH ＝ C (CO ₂ H)
_{(CH 2) 4 -, -} CH 2 CH = C (CO 2 H) CH 2 -,
_{-CH = CHCH (CO 2 H)} -, - CH = CHCH
_{(CO 2 H) CH 2 -} , - OCH 2 CH = CH -, - NH
_{CH 2 CH = CH -, -} SCH 2 CH = CH -, - CH =
_{CHCH 2 O -, - (CH} 2) 2 CH = CHCH 2 S -, -
_{(CH 2) 3 CH = CHCH} 2 O -, - NH (CH 2) 2 C
_{H = C (CO 2 H)} - ,, - NH (CH 2) 2 CH = C
(CO ₂ H), —OCH ₂ C≡C—, —NHCH ₂ C≡C
-, -SCH ₂ C≡C- and the like.

Y represents a monocyclic or bicyclic heterocyclic group having at least one 5- to 10-membered nitrogen atom which may be substituted by a lower alkyl group; "A monocyclic or bicyclic heterocyclic group having at least one" is a pyrrolidinyl group, a pyrrolinyl group, a pyronyl group,
Examples include a pyrazolyl group, a dihydroindolyl group, a dihydroisoindolyl, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, and an indolyl group. The compound of the present invention can be produced, for example, by the following route 1.

[0024]

Embedded image Wherein Ar has the same meaning as above, Q ¹ is the same as Q or a group in which a functional group present in Q is protected, and Y ′ is Y
Or a functional group present in Y represents a protected group. The compound [II] in the above formula can be produced, for example, by the following routes 2 to 6.

[0025]

Embedded image [Wherein, Ar and Y ′ have the above-mentioned meanings, R ¹ represents a lower alkyl group, R ² represents an aryl group, L represents a leaving group, and X ¹ and X ² represent a halogen atom. M represents a hydrogen atom or a trialkylstannyl group, Q ² represents a bond,
Q ³ represents an alkylene group having 1 to 5 carbon atoms, alkenylene group or alkynylene group, Q ³ represents a bond, O, NH, S, an alkylene group having 1 to 5 carbon atoms, alkenylene group or alkynylene group, Q ⁴ A bond, an alkylene group which may have an alkoxycarbonyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group, wherein Q ⁵ is a bond,
An alkylene group, an alkenylene group or an alkynylene group which may have an alkoxycarbonyl group or an alkoxycarbonylalkyl group having 1 to 5 carbon atoms, wherein Q ⁶ is a bond, an alkoxycarbonyl group having 1 to 5 carbon atoms or an alkoxycarbonyl group; An alkylene group which may have a carbonylalkyl group, an alkenylene group or an alkynylene group,
Q ⁷ represents a bond, an alkyl group having 1 to 5 carbon atoms, and V represents O, NH, a protecting group —N or S. Next, the synthesis route will be described in detail. The reaction for converting the route 1 cyano compound [II] to the bicyclic aromatic amidino compound [I] of the present invention is a well-known reaction, and usually involves directly reacting hydrogen chloride in an alcoholic solvent. Alternatively, it can be produced by reacting hydrogen chloride dissolved in a suitable solvent and then reacting with ammonia gas.

When the thus obtained compound has an alkoxycarbonyl group, an alkoxyalkyl group, an unsaturated bond, or the like, the compound may be prepared by a known method such as hydrolysis, reduction using an alkali metal hydride, or catalytic reduction. It can be converted into a carboxyl group, a carboxyalkyl group, a hydroxyalkyl group, a single bond or the like. When a protecting group is present, it can be removed by a usual method. Routes 2 to 4 The reactions of Routes 2 to 4 can be carried out by reacting a compound having a leaving group represented by the formula [V] or [IX] with an appropriate base to obtain a compound of the formula [VI], “VII” or [VIII] ], A so-called nucleophilic substitution reaction. Examples of the solvent used in this case include ether solvents such as ethyl ether, tetrahydrofuran, and dioxane; aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and hexamethylphosphorylamide; and alcohol solvents such as ethyl alcohol. Is done. The reaction temperature is usually in the range of -78 ° C to the boiling point of the solvent, but the reaction can be carried out outside this range if necessary. Examples of usable bases include alkaline carbonates such as sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate, alkali hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal alkoxides such as sodium ethoxide and hydrogen. Bases such as sodium chloride and lithium hexamethyldisilazane can be used. The reaction time is usually 30 minutes to 4 days. Further, as the leaving group, a chlorine atom,
Examples thereof include a halogen atom such as a bromine atom and an iodine atom, and an alkyl or arylsulfonyloxy group such as a mesyl group and a tosyl group. Route 5 Route 5 is a so-called Wittig reaction in which an appropriate base is added in the presence of the compound [X] and the compound [XI], or the compound [XI] is reacted with the base to form an ylide compound. The reaction can be carried out by reacting compound [X]. The reaction is usually carried out using an ethereal solvent such as ethyl ether, tetrahydrofuran or dioxane, or a solvent such as methylene chloride, the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent, and the reaction time is usually 30 minutes to 24 hours. However, if necessary, it can be performed outside this range. Route 6 Route 6 is a coupling reaction between an acetylene compound [XII] and a halogenated aromatic compound [XIII],
It is carried out in the presence of a suitable palladium catalyst. Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, and the reaction is preferably performed using a base such as copper lead such as cuprous iodide or diethylamine.

The compound of the present invention has the general formula

[0028]

Embedded image After converting the halogen atom represented by X of the compound represented by the formula (where necessary to protect the existing functional group) into a cyano group by a usual method, the cyano group is converted into an amidino group, and The compound can also be produced by removing the protecting group. Pharmacological Test (1) Measurement of Human Activated Blood Coagulation Factor X (f.Xa) Inhibitory Activity 3 μL of dimethyl sulfoxide solution of specimen adjusted to each concentration
1 at 0.16 μg / ml human activated blood coagulation factor X (American DiagnosticaInc.)
c. ), 150 μl of Hepes-sodium hydroxide buffered saline (HBS), pH 7.4, and incubated at 37 ° C. for 3 minutes. 0.4 mM synthetic substrate S-276
The reaction was started by adding 150 μl of HBS solution of No. 5 (first chemical) and incubated at 37 ° C. for 5 minutes. 50μ
The enzymatic reaction was stopped by adding 1
The absorbance at m was measured. The sample concentration (IC ₅₀ ) at which the enzyme reaction was inhibited by 50% was determined and used as an index of the human activated blood coagulation factor X inhibitory activity. Table 1 shows the human activated blood coagulation factor X (f.Xa) inhibitory activity of the compound of the present invention.
It was shown to. (2) Measurement of human thrombin inhibitory activity 3 μl of a dimethyl sulfoxide solution of a sample adjusted to each concentration
1 to 0.0067 μg / ml human thrombin (Sigma
A) was mixed with 150 μl of Hepes-sodium hydroxide buffered saline (HBS) having a pH of 7.4 and incubated at 37 ° C. for 3 minutes. 0.2 mM synthetic substrate S-2238
Add 150 μl of HBS solution (1st chemical) and add 37
Incubated at 15 ° C for 15 minutes. The enzyme reaction was stopped by adding 50 μl of 50% acetic acid, and the absorbance at 405 nm was measured. The sample concentration (IC ₅₀ ) at which the enzyme reaction was inhibited by 50% was determined, and this was used as an index of the human thrombin inhibitory activity. Table 1 shows the human thrombin inhibitory activity of the compound of the present invention.
It was shown to.

[0029]

[Table 1] As described above, the compound of the present invention has an excellent blood coagulation factor Xa inhibitory action, and thus can be used as a prophylactic / therapeutic agent for various diseases caused by thrombus, embolus and the like.

When the compound of the present invention is used as a medicament, it may be mixed with a solid or liquid excipient carrier known in the art, and may be in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration. Can be used. Such pharmaceutical preparations include, for example, injections, inhalants, syrups,
Liquid preparations such as emulsions, for example, solid preparations such as tablets, capsules and granules, and the like can be mentioned. In addition, these preparations may contain, if necessary, a commonly used dropping agent such as an auxiliary agent, a stabilizer, a wetting agent, an emulsifier, an absorbent or a surfactant. Examples of the additives include distilled water for injection, Ringer's solution, glucose, sucrose, corn starch, magnesium stearate, and talc.

The dose of the compound of the present invention as a blood coagulation inhibitor varies depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, and the like. Parenteral administration, 0.1 to 100 mg / K per day when administered to adult patients
g body weight and 0.01% per day for parenteral administration.
〜１０10 mg / Kg body weight. EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION

[0033]

EXAMPLES Example 1 (E) -2- (7-amidino-2naphthyl) -5-
(Isoindoline-5-yl) -4-ethyl pentenoate
Ester dihydrochloride (1) (E) -5- (Nt-butyloxycarbonyl
Isoindoline-5-yl) -2- (7-cyano 2-
Synthesis of ethyl naphthyl) -4-pentenoate In an argon atmosphere, hexamethylphosphorylamide (1.1 ml), hexamethyldisilazane lithium amide (0.1 ml) and tetrahydrafuran (0.9 ml)
The solution was added at -78 ° C with 7-cyano-2-naphthylacetic acid ethyl ester (263 mg) in tetrahydrofuran (2.
0 ml) solution was added dropwise and stirred for 30 minutes. Then (E)
-1-Bromo-3- (Nt-butyloxycarbonylisoindoline-5-yl) -2-propene (375
mg) in tetrahydrofuran (2.0 ml). After stirring at −78 ° C. for 1 hour, the mixture was slowly raised to room temperature and stirred overnight. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The obtained residue was separated and purified by silica gel column chromatography, and (E) -5- (N-butyloxycarbonylisoindoline-5-yl) -2- (7-cyano-2-naphthyl) -4-pentenoic acid ethyl ester (360m
g) was obtained. (2) (E) -5- (Nt-butyloxycarbonylisoindoline-5-yl) -2- (7-cyano-2-naphthyl) -4-pentenoic acid ethyl ester (180 m
To a solution of g) in ethanol (2.0 ml) was added 4N hydrochloric acid-dioxane (8.0 ml), and the mixture was stirred at room temperature overnight. The residue obtained by distilling off the solvent was dissolved in ethanol (7.0 ml), and the ammonia gas was saturated under ice-cooling, followed by stirring at room temperature overnight. The residue obtained by evaporating the solvent was purified by reverse-layer column chromatography (water-tetrahydrofuran), and a small amount of dilute hydrochloric acid was added to the portion containing the desired product, followed by concentration to dryness to obtain the title compound (139 mg). Was.

¹ H-NMR (300 MHz, δ ppm,
CD ₃ OD): 1.16 (3H, t, J = 7.1H)
z), 2.80 (1H, m), 3.05 (1H, m),
4.03 (1H, t, J = 7.6 Hz), 4.13 (2
H, m), 4.55 (4H, s), 6.28 (1H,
m), 6.50 (1H, d, J = 15.8 Hz),
7.25-7.38 (3H, m), 7.70-7.80
(2H, m), 7.98-8.10 (3H, m), 8.
41 (1H, s), 8.86 (brs), 9.37 (b
rs) Example 2 2- (7-amidino-2-naphthyl) -5- (isoin
Dryin-5-yl) pentanoic acid ethyl ester dihydrochloride
Salt (E) -2- (7-amidino-2-naphthyl) -5- (isoindoline-5-yl) -4-pentenoic acid ethyl ester dihydrochloride (13 mg) in ethanol (2.0
10% palladium-carbon catalyst (10 mg)
Was added and stirred vigorously in a hydrogen stream at room temperature under normal pressure for 6 hours. The catalyst was filtered off from the reaction solution, and a small amount of dilute hydrochloric acid was added to the filtrate, followed by drying under reduced pressure to obtain the title compound (11 mg).

¹ H-NMR (300 MHz, δ ppm,
CD ₃ OD): 1.16 (3H, t, J = 7.4H
z), 1.50-1.75 (2H, m), 1.80-
1.95 (1H, m), 2.10-2.25 (1H,
m), 2.69 (2H, t, J = 7.4 Hz), 3.8
5 (1H, t, J = 7.7 Hz), 4.11 (2H,
m), 4.56 (4H, s), 7.16-7.20 (2
H, m), 7.29 (1H, d, J = 7.5 Hz),
7.64 (1H, dd, J = 1.6 Hz, J = 8.5H
z), 7.78 (1H, dd, J = 1.6 Hz, J =
8.5 Hz), 7.96 (1H, s), 7.98 (1
H, d, J = 8.5 Hz), 8.07 (1H, d, J =
8.5 Hz), 8.40 (1H, d, J = 1.6 Hz) Example 3 (E) -2- (7-Amidino 2 naphthyl) -5-
(Isoindoline-5-yl) -4-pentenoic acid disalt
Acid salt (E) -2- (7-amidino-2-naphthyl) -5- (isoindoline-5-yl) -4-pentenoic acid ethyl ester dihydrochloride (70 mg) in 6N HCl (2.0 mg)
ml) solution was stirred overnight at room temperature. The residue obtained by distilling off the solvent was separated and purified by HP-20 column chromatography (water-acetonitrile), followed by Sephadex LH-20 column chromatography (ethanol), and a small amount of dilute hydrochloric acid was added to the portion containing the target compound. In addition, the mixture was concentrated to dryness to give the title compound (139 mg).

¹ H-NMR (300 MHz, δ ppm,
CD ₃ OD): 2.72-2.85 (1H, m);
00-3.12 (1H, m), 3.98 (1H, t, J
= 7.5 Hz), 4.55 (4H, s), 6.27 (1
H, dt), 6.48 (1H, d, J = 15.8H)
z), 7.28-7.34 (3H, m), 7.73-
7.79 (2H, m), 7.95-8.10 (3H,
m), 8.42 (1H, d, J = 1.8 Hz) Example 4 2- (7-amidino 2-naphthyl) -5- (isoin
Dolin-5-yl) pentanoic acid dihydrochloride 2- (7-amidino-2-naphthyl) -5- (isoindoline-5-yl) pentanoic acid ethyl ester dihydrochloride (9.9 mg) in 6N HCl (2.0 ml) was added at room temperature to 1 ml. The mixture was stirred at 50 ° C. for 5 hours. The residue obtained by evaporating the solvent was separated and purified by reverse-layer column chromatography (water-methanol), a small amount of dilute hydrochloric acid was added to the portion containing the target compound, and the mixture was concentrated to dryness to give the title compound (5.2 m
g) was obtained.

¹ H-NMR (300 MHz, δ ppm,
CD ₃ OD): 1.50-1.90 (3H, m);
10-2.25 (1H, m), 2.69 (2H, t, J
= 7.4 Hz), 3.73 (1H, bt), 4.54
(4H, s), 7.15-7.28 (3H, m), 7.
68-7.76 (2H, m), 7.92-8.00 (2
H, m), 8.05 (1H, d, J = 8.8 Hz),
8.37 (1H, d, J = 1.6 Hz) Low resolution FAB-MS [M + H] ⁺ : 3
88 Example 5 (E) -2- (5-amidinobenzofuran-2-yl)
-5- (isoindoline-5-yl) -4-pentenoic acid
Ethyl ester dihydrochloride (1) (E) -5- (Nt-butyloxycarbonyl
Isoindoline-5-yl) -2- (5-cyanobenzo
Furan-2-yl) -4-pentenoic acid ethyl ester
Synthesis (E) -3- (Nt-butyloxycarbonylisoindolin-5-yl) -1-bromo-2-propene (7
0 mg) and ethyl 2- (5-cyanobenzofuran-2)
(E) -5- (Nt-butyloxycarbonylisoindolin-5-yl) -2-yl- (yl) acetate (107 mg) in the same manner as described in Example 1.
(5-Cyanobenzofuran-2-yl) -4-pentenoic acid ethyl ester (60 mg) was obtained. (2) Using (E) -5- (Nt-butyloxycarbonylisoindoline-5-yl) -2- (5-cyanobenzofuran-2-yl) -4-pentenoic acid ethyl ester (48 mg), (E) -2- (5-Amidinobenzofuran-2-yl) -5- (isoindoline-5-yl) -4-pentenoic acid ethyl ester dihydrochloride (E) was prepared in the same manner as described in Example 1. 29 mg).

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 1.13 (} 3H, t, J = 7.1
Hz), 2.92 (2H, m), 4.13 (2H,
q, J = 7.1 Hz), 4.27 (1H, t, J = 7.
4Hz), 4.43 (4H, t, J = 5.6Hz),
6.27 (1H, dt, J = 16 Hz, 7.0 Hz),
6.53 (1H, d, J = 16 Hz), 7.04 (1
H, s), 7.30 (2H, s), 7.36 (1H,
s), 7.70 (1H, d, J = 8.7 Hz), 7.8
1 (1H, d, J = 8.6 Hz), 8.10 (1H,
s), 9.05 (2H, brs), 9.33 (2H, b
rs), 9.8 (2H, brs). Low resolution FAB-MS [M + H] ⁺ : 4
04 Example 6 (E) -2- (5-amidinobenzofuran-2-yl)
-5- (isoindoline-5-yl) -4-pentenoic acid
Dihydrochloride (E) -2- (5-amidinobenzofuran-2-yl)
The title compound (13 mg) was obtained in the same manner as in Example 3 using -5- (isoindoline-5-yl) -4-pentenoic acid ethyl ester dihydrochloride (15 mg).

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 2.75-3.0 (} 2H, m),
4.13 (1H, t, J = 7.1 Hz), 4.43 (4
H, brs), 6.27 (1H, dt, J = 15 Hz,
7.7 Hz), 6.50 (1H, d, J = 15H)
z), 7.00 (1H, s), 7.30 (2H,
s), 7.36 (1H, s), 7.69 (1H, d, J
= 8.9 Hz), 7.81 (1H, d, J = 8.7H)
z), 8.08 (1H, s), 8.92 (2H,
s), 9.28 (2H, s), 9.5 (2H, brs) Low resolution FAB-MS [M + H] ⁺ : 3
76 Example 7 2- (5-amidinobenzofuran-2-yl) -5
Ethyl (isoindoline-5-yl) -4-pentanoate
Ester dihydrochloride (1) 5- (Nt-butyloxycarbonylisoin
Dolin-5-yl) -2- (5-cyanobenzofuran-
Synthesis of ethyl 2-yl) -4-pentanoate (E) -5- (Nt-butyloxycarbonylisoindolin-5-yl) -2- (5-cyanobenzofuran-2-yl) -4- Pentenic acid ethyl ester (92m
g) and reduced in the same manner as in Example 2 to give 5- (N-
Ethyl tert-butyloxycarbonylisoindoline-5-yl) -2- (5-cyanobenzofuran-2-yl) pentanoate (92 mg) was obtained. (2) 2- (5-cyanobenzofuran-2-yl) -5
Using 2- (isoamido-5-yl) -4-pentanoic acid ethyl ester (91 mg) as in Example 1, 2- (5-amidinobenzofuran-2-yl) -5-yl.
(Isoindolin-5-yl) pentanoic acid ethyl ester dihydrochloride (61 mg) was obtained.

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 1.13 (} 3H, t, J = 7.1
Hz), 1.55 (2H, m), 1.98 (2H,
m), 2.64 (2H, t, J = 7.4 Hz), 4.1
1 (3H, q, J = 7.1 Hz), 4.43 (4H, b
rs), 6.99 (1H, s), 7.15 (1H,
d, J = 8.3 Hz), 7.18 (1H, s), 7.2
8 (1H, d, J = 8.3 Hz), 7.70 (1H,
dd, J = 8.6 Hz, 2.1 Hz), 7.80 (1
H, d, J = 8.6 Hz), 8.09 (1H, s),
8.96 (2H, brs), 9.31 (2H, br)
s), 9.58 (2H, brs) Low resolution FAB-MS [M + H] ⁺ : 40
6 Example 8 2- (5-amidinobenzofuran-2-yl) -5
(Isoindoline-5-yl) pentanoic acid dihydrochloride 2- (5-amidinobenzofuran-2-yl) -5
Using (isoindolin-5-yl) -4-pentanoic acid ethyl ester dihydrochloride (45 mg), the title compound (14 mg) was obtained in the same manner as in Example 3.

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 1.54 (} 2H, m), 1.91
(2H, m), 2.64 (2H, t, J = 7.5H
z), 3.97 (1H, t, J = 7.0 Hz), 4.4
3 (4H, brt, J = 5.3 Hz), 6.95 (1
H, s), 7.15 (1H, dd, J = 7.9 Hz,
1.3 Hz), 7.19 (1H, s), 7.28 (1
H, d, J = 7.9 Hz), 7.69 (1H, dd,
J = 7.7 Hz, 1.7 Hz), 7.79 (1H, d,
J = 7.7 Hz), 8.09 (1H, s), 8.99
(2H, brs), 9.32 (2H, brs), 9.6
7 (2H, brs) Low resolution FAB-MS [M + H] ⁺ : 37
8 Example 9 2- (5-amidinobenzofuran-2-yl) -5
Ethyl (isoindoline-5-yl) -4-pentate
Ester dihydrochloride (1) 5- (Nt-butyloxycarbonylisoin
Dolin-5-yl) -2- (5-cyanobenzofuran-
Synthesis of 2-yl) -4-pentynoic acid ethyl ester 3- (Nt-butyloxycarbonylisoindolin-5-yl) -1-bromo-2-propyne (103 m
g) and ethyl 2- (5-cyanobenzofuran-2-yl) acetate (204 mg) in the same manner as in Example 1 to obtain 5- (Nt-butyloxycarbonylisoindolin-5-yl) -2. -(5-cyanobenzofuran-2-yl) -4-pentynoic acid ethyl ester (92 m
g) was obtained. (2) 5- (Nt-butyloxycarbonylisoindoline-5-yl) -2- (5-cyanobenzofuran-
2-yl) -4-pentynoic acid ethyl ester (188 m
g) and in the same manner as in Example 1, the title compound (13
2 mg).

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 1.16 (} 3H, t, J = 7.1
Hz), 3.19 (2H, m), 4.17 (2H,
q, J = 7.1 Hz), 4.44 (5H, brm),
7.13 (1H, s), 7.27 (1H, d, J =
8.1 Hz), 7.33 (1H, s), 7.35 (1
H, d, J = 8.1 Hz), 7.72 (1H, dd, J)
= 8.6 Hz, 1.8 Hz), 7.84 (1H, d,
J = 8.6 Hz), 8.13 (1H, s), 8.95
(2H, brs), 9.31 (2H, brs), 9.6
2 (2H, brs). Low resolution FAB-MS [M + H] ⁺ : 40
2 Example 10 2- (5-amidinobenzofuran-2-yl) -5
(Isoindolin-5-yl) -4-pentinoic acid disalt
2- (5-amidinobenzofuran-2-yl) -5- acid salt
The title compound (36 mg) was obtained in the same manner as in Example 3 using (isoindolin-5-yl) -4-pentynoic acid ethyl ester dihydrochloride (131 mg).

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 3.14 (} 2H, m), 4.29
(1H, t, J = 7.1 Hz), 4.44 (4H, b
rm), 7.09 (1H, s), 7.25 (1H, d,
J = 7.7 Hz), 7.31 (1H, s), 7.34
(1H, d, J = 7.7 Hz), 7.72 (1H, d
d, J = 8.8 Hz, 2.0 Hz), 7.83 (1H,
d, J = 8.8 Hz), 8.13 (1H, s), 9.0
3 (2H, brs), 9.34 (2H, brs),
9.8 (2H, brs) Low resolution FAB-MS [M + H] ⁺ : 37
4 Example 11 (E) -2- (5-amidinobenzo [b] thiophene-
2-yl) -5- (isoindoline-5-yl) -4-
Pentenic acid ethyl ester dihydrochloride (1) (E) -5- (Nt-butyloxycarbonyl
Isoindoline-5-yl) -2- (5-cyanobenzo
[B] ethyl thiophen-2-yl) -4-pentenoate
Synthesis of ester 3- (Nt-butyloxycarbonylisoindolin-5-yl) -1-bromo-2-propene (77 mg)
And ethyl 2- (5-cyanobenzo [b] thiophene-
Using (2-yl) acetate (80 mg) and in the same manner as in Example 1, (E) -5- (Nt-butyloxycarbonylisoindoline-5-yl) -2- (5-cyanobenzo [b] Thiophen-2-yl) -4-pentenoic acid ethyl ester (111 mg) was obtained. (2) (E) -5- (Nt-butyloxycarbonylisoindoline-5-yl) -2- (5-cyanobenzo [b] thiophen-2-yl) -4-pentenoic acid ethyl ester (50 mg) Was used to obtain the title compound (27 mg) in the same manner as in Example 1. ¹ H-NMR (30
0 MHz, δ ppm, CD ₃ OD): 1.21 (3H,
t, J = 7.2 Hz), 2.87 (1H, quinte)
t, J = 7.2 Hz), 3.03 (1H, quinte)
t, J = 7.2 Hz), 4.18 (2H, q, J = 7.
2Hz), 4.28 (1H, t, J = 7.2Hz),
4.57 (4H, s), 6.29 (1H, dt, J = 1
5.6, 7.2 Hz), 6.53 (1H, d, J = 1)
5.6 Hz), 7.33 (2H, m), 7.39 (1
H, s), 7.48 (1H, s), 7.68 (1H,
d, J = 8.6 Hz), 8.08 (1H, d, J = 8.
6Hz), 8.25 (1H, s), 8.78 (2H, b
rs), 9.25 (2H, brs) Low resolution FAB-MS [M + H] ⁺ : 4
20 Example 12 (E) -2- (5-Amidinobenzo [b] thiophene-
2-yl) -5- (isoindoline-5-yl) -4-
Pentenic acid dihydrochloride (E) -2- (5-amidinobenzo [b] thiophene-
2-yl) -5- (isoindoline-5-yl) -4-
The title compound (16 mg) was obtained in the same manner as in Example 3 using pentenoic acid ethyl ester (24 mg).

¹ H-NMR (300 MHz, δ ppm,
CD ₃ OD): 2.75 (1H, quintet, J =
7.2 Hz), 2.97 (1H, quintet, J =
7.2 Hz), 3.96 (1H, t, J = 7.2H)
z), 4.55 (4H, s), 6.32 (1H, dt,
J = 16.1, 7.2 Hz), 6.50 (1H, d, J)
= 16.1 Hz), 7.25-7.38 (4H, m),
7.62 (1H, d, J = 8.5 Hz), 8.01 (1
H, d, J = 8.5 Hz), 8.15 (1 H, s) Low resolution FAB-MS [M + H] ⁺ : 39
2 Example 13 1- [N- (4-pyridyl) amino] -4- (7-amido
Zinault 2 naphthyl) methyloxy-2-butyne disalt
Acid salt (1) 1- [Nt-butyloxycarbonyl-N-
(4-pyridyl) amino] -4- (7-cyano 2na
Synthesis of 1- (7-cyano-2-naphthyl) methyloxy-4-hydroxy-2-butyne (136 mg) in ethyl acetate (5 ml) under ice-cooling with a solution of triethylamine (107 μl)
l) then methanesulfonyl chloride (60 μl)
Was added and stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and evaporated to give a mesyl compound. In a separate reaction vessel, under argon atmosphere, 4-t-butoxycarbonylaminopyridine (150 mg) in dimethylformamide (3 ml)
60% oily sodium hydride was added to the solution at room temperature for 1.5 hours.
Stirred for hours. To this was added a dimethylformamide solution (7 ml) of the mesyl compound synthesized above and potassium iodide (20 ml).
0 mg), and the mixture was further stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and evaporated. The obtained residue was separated and purified by silica gel column chromatography,
1- [Nt-butyloxycarbonyl-N- (4-pyridyl) amino] -4- (7-cyano-2-naphthyl)
Methyloxy-2-butyne (137 mg) was obtained. (2) 1- [Nt-butyloxycarbonyl-N- (4-pyridyl) amino] -4- (7-cyano-2-naphthyl) methyloxy-2-butyne ethanol (2 m
1) 4N hydrochloric acid-dioxane (20 ml) was added to the solution,
The mixture was stirred at room temperature for one day. The residue obtained by distilling off the solvent was dissolved in ethanol (20 ml), and the ammonia gas was saturated under ice-cooling, followed by stirring at room temperature for 2 days. The residue obtained by evaporating the solvent was separated and purified by HP-20 column chromatography (water-methanol), and the title compound (115
mg).

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6, 80 ℃)} : 4.25 (2H, m),
4.31 (2H, t, J = 2.4 Hz), 4.74 (2
H, s), 6.97 (2H, m), 7.63 (1H,
m), 7.84 (1H, m), 7.95 (1H,
s), 8.02 (1H, d, J = 9.0 Hz), 8.1
0 (1H, d, J = 9.0 Hz), 8.18 (2H,
m), 8.53 (1H, m), 8.98 (1H, br)
s), 9.25 (4H, brs) Low resolution FAB-MS [M + H] ⁺ : 34
5 Example 14 4- (7-amidino-2-naphthyl) -1- [N- (4
-Pyridyl) amino] -2-butyne (1) 4- (7-cyano 2 naphthyl) -1- [N-
t-butyloxycarbonyl-N- (4-pyridyl) a
Synthesis of mino] -2-butyne Under argon atmosphere, 4- [Nt-butoxycarbonyl-N- (2-propynyl) amino] pyridine (150 m
g) in a solution of tetrahydrofuran (2 ml) at -78 ° C at 1.6 M in butyllithium tetrahydrofuran (0.
33 ml), and the mixture was stirred at -78 ° C for 5 minutes and at 0 ° C for 20 minutes. The reaction solution was cooled again to -78 ° C, tributyltin chloride (0.14 ml) was added, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 150 ml of ethyl acetate-hexane (2: 1), filtered through celite, and the solvent was distilled off. Tetrakis (triphenylphosphine) palladium (30 mg) was added to a solution of the obtained residue and 7-cyano 2-bromomethylnaphthalene (106 mg) in toluene (4 ml), and the mixture was refluxed for 1 hour under an argon atmosphere. The reaction solution was returned to room temperature, a saturated potassium fluoride solution was added, and the mixture was stirred for 30 minutes. The insolubles were filtered through celite, and the filtrate was washed with a saturated potassium fluoride solution, water and saturated saline, dried, and evaporated. The obtained residue was separated and purified by silica gel column chromatography,
4- (7-cyano-2-naphthyl) -1- [Nt-butyloxycarbonyl-N- (4-pyridyl) amino]
-2-butyne (62 mg) was obtained. (2) 4- (7-cyano-2-naphthyl) -1- [Nt-butyloxycarbonyl-N- (4-pyridyl) amino] -2-butyne (60 mg) in ethanol (1 m
l) 4N hydrochloric acid-dioxane (10 ml) was added to the solution,
The mixture was stirred at room temperature for 4 days. The residue obtained by evaporating the solvent was dissolved in ethanol (10 ml), and the ammonia gas was saturated under ice-cooling, followed by stirring at room temperature for 3 days. The residue obtained by evaporating the solvent was separated and purified by HP-20 column chromatography (water-methanol), followed by Sephadex LH-20 column chromatography (methanol) to obtain the title compound (14 mg).

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6, 80 ℃)} : 3.89 (2H, m),
4.25 (2H, m), 6.99 (2H, d, J = 7.
5 Hz), 7.65 (1H, dd, J = 2.1, 7.8)
Hz), 7.83 (1H, dd, J = 2.1, 8.4H)
z), 7.98 (2H, m), 8.08 (1H, d, J
= 8.4 Hz), 8.18 (2H, m), 8.48 (1
H, m), 8.85 (1H, brs), 9.30 (4
H, brs) Low resolution FAB-MS [M + H] ⁺ : 31
5 Reference Example 1 (7-cyano-2-naphthyl) acetic acid ethyl ester 7-cyano-2-naphthalenecarboxylic acid (583 mg)
Thionyl chloride (0.64 ml) was added dropwise to a toluene (10 ml) solution of the compound under ice-cooling, and the mixture was heated under reflux for 2 hours and then the solvent was distilled off. The residue was dissolved in tetrahydrofuran, and diazomethane (352 mg) and triethylamine (0.15
ml) in an ether solution (12 ml) under ice-cooling.
After stirring for an hour, the mixture was stirred at room temperature overnight. After the precipitated crystals were removed by filtration and the solvent was distilled off, the obtained residue was dissolved in ethanol (10 ml), and silver (I) oxide (612 mg) was added little by little while heating at 65 to 85 ° C. After completion of the reaction, the reaction solution was filtered through celite, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (139 mg).

¹ H-NMR (300 MHz, δ ppm,
CDCl ₃ ): 1.27 (3H, t, J = 7.1H)
z), 3.80 (2H, s), 4.18 (2H, q, J
= 7.1 Hz), 7.57-7.61 (2H, m),
7.84-7.92 (2H, m), 7.78 (1H,
s), 8.19 (1H, s) Low resolution FAB-MS [M + H] ⁺ : 24
0 Reference Example 2 2- (5-cyanobenzo [b] thiophen-2-yl)
The title compound was obtained in the same manner as in Reference Example 1 of ethyl acetate .

¹ H-NMR (300 MHz, δ ppm,
CDCl ₃ ): 1.30 (3H, t, J = 7.2H)
z), 3.94 (2H, s), 4.23 (2H, q, J
= 7.2 Hz), 7.25 (1H, s), 7.51 (1
H, d, J = 8.4 Hz), 7.87 (1H, d, J)
= 8.4 Hz), 8.03 (1H, s) Reference Example 3 Ethyl 2- (5-cyanobenzofuran-2-yl) acetate
The title compound was obtained in the same manner as in Ester Reference Example 1.

¹ H-NMR (300 MHz, δ ppm,
CDCl ₃ ): 1.30 (3H, t, J = 7.1H)
z), 3.86 (2H, s), 4.23 (2H, q, J
= 7.1 Hz), 6.72 (1H, s), 7.50-
7.57 (2H, m), 7.87 (1H, d, J = 1.
0 Hz) Reference Example 4 3- (Nt-butyloxycarbonylisoindoline )
-5-yl) -1-bromo-2-propyne To a solution of 5-bromoisoindoline (1.1 g) in dioxane (30 ml) was added triethylamine (1.2 ml),
N, N-dimethylaminopyridine (132 mg) and di-t-butyldica-carbonate (1.84 g) are added and stirred overnight. The reaction solution is diluted with ethyl acetate and washed with 1M potassium hydrogen sulfate, water, and saturated saline. After drying the sodium sulfate,
The mixture obtained by distilling off the filtration solvent was purified by silica gel column chromatography to obtain Nt-butyloxycarbonyl-5-bromoisoindoline (1.2 g). Nt-butyloxycarbonyl-5-bromoisoindoline (410 mg) and 2-propyn-1-o-
A solution of toluene (0.16 ml) in pyrrolidine (15 ml) was degassed with nitrogen gas and heated to 85 ° C. Add tetrakistriphenylphosphine palladium (82 mg) and add 85
Stir at 17 ° C. for 17 hours. The reaction solution is diluted with ethyl acetate and washed with 1M potassium hydrogen sulfate and saturated saline.
After drying the sodium sulfate, the solvent obtained by evaporating the filtration solvent was purified by silica gel column chromatography, and 3- (Nt
-Butyloxycarbonylisoindoline-5-yl)
-2-Propin-1-ol (257 mg) was obtained. 3
-(Nt-butyloxycarbonylisoindoline-
5-yl) -2-propyn-1-ol (192 mg)
And carbon tetrabromide (469 mg) in dichloromethane (7 m
l) Cool the solution to 0 ° C and add triphenylphosphine (3
70 mg) and stirred at room temperature for 30 minutes. After adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, the mixture is extracted with ethyl acetate, and the organic layer is separated and washed with saturated saline. After drying over sodium sulfate, the filtrate was evaporated and the resulting mixture was purified by silica gel column chromatography to give 3- (Nt-butyloxycarbonylisoindolin-5-yl) -1.
-Bromo-2-propyne (228 mg) is obtained.

¹ H-NMR (300 MHz, δ ppm,
_{DMSO-d 6): 1.52 (} 9H, s), 4.16
(2H, s), 4.60-4.70 (4H, m),
7.15-7.40 (3H, m) Low resolution FAB-MS [M + Na] ⁺
358 and 360

[0051]

Industrial Applicability The compound of the present invention has a blood coagulation factor Xa inhibitory activity and is effective in preventing and preventing diseases caused by thrombus, embolism and the like.
Useful as a therapeutic.

[0052]

Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07D 405/06 209 C07D 405/06 209 409/06 209 409/06 209 // C07D 307/79 307/79 333 / 60 333/60 (72) Inventor Yoshiyuki Sato 3rd Okubo Tsukuba, Ibaraki Pref. Within Tsukuba Research Laboratories (72) Inventor Mitsuru Miyachi 3rd Okubo Tsukuba, Ibaraki Pref. In-house (72) Inventor Yoko Takaeno 3rd Okubo Tsukuba City, Ibaraki Pref.

Claims (6)

[Claims] 1. A compound of the general formula [Wherein, Ar represents a benzene ring or a heteroaromatic ring having 1 to 3 heteroatoms selected from the group consisting of O, N and S, and Q represents an alkylene group, an alkenylene group or an alkylene group having 3 to 7 carbon atoms. alkynylene group (the alkylene group, a hydrogen atom a lower alkyl group in the alkenylene group, or alkynylene group, an aralkyl group, a carboxyl group, an alkoxycarbonyl group, may be substituted by a hydroxyalkyl group or carboxyalkyl group, also CH ₂ is O may be substituted with O, NH or S), and Y represents a monocyclic or bicyclic heterocyclic group having at least one 5 to 10-membered nitrogen atom. Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein Ar is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyridine ring, an oxazole ring or a thiazole ring, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein Y is pyridyl, dihydroisoindolyl or tetrahydroisoquinolyl, or a pharmaceutically acceptable salt thereof. 4. Q is-(CH ₂ ) ₃ -,-(CH ₂ ) ₄ -,-
_{(CH 2) 5 -, -} CH 2 CH 2 CH = CH -, - CH = C
HCH ₂ CH ₂ —, —CH ₂ C≡CCH ₂ —, —C≡CC
_{H 2 CH 2 -, - NHCH} 2 C≡C -, - CH 2 C≡CCH
_{2 NH -, - NHCH 2 C≡CCH} 2 OCH 2 -, - OCH
_2. C ₁ CCH ₂ NHCH ₂ — wherein the hydrogen atom in the alkylene group, alkenylene group or alkynylene group may be substituted with a carboxyl group, an alkoxycarbonyl group, a hydroxyalkyl group or a carboxyalkyl group. Or a pharmaceutically acceptable salt thereof. 5. An anticoagulant comprising the compound represented by the general formula [I] according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A prophylactic / therapeutic agent for thrombus or emboli comprising the compound represented by the general formula [I] according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.