JPH10287673A - Diazabicyclo compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diazabicyclo compound having improving effect on circulatory organ disorder caused by ischemia, hypoxia or anoxia and useful as an effective component of an improving agent for circulatory organ disorder. SOLUTION: This compound is a diazabicyclo compound of formula I R is CH2 XR<1> or CO(CH2 )n R<1> [R<1> is a heteroaryl; X is NH, O or S; (n) is an integer of 1 or 2]; R<2> is hydroxy, etc.: R<3> is a lower alkyl} or its pharmaceutically permissible salt, e.g. 2,5-diphenyl-7-hydroxy-6-methoxycarbonyl-8-(3-pyridyl) aminomethyl-1,9-diazabicyclo[4.3.0]nona-3, 8-diene. A compound of formula I can be obtained e.g. by subjecting a compound of formula II and a compound of formula II to Diels-Alder reaction, and treating the product by reductive reaction, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a diazabicyclo compound and a pharmaceutically acceptable salt thereof, and more particularly, to 1,9-diazabicyclo [4.3.0] nona-compound.
The present invention relates to 3,8-diene derivatives and pharmacologically acceptable salts thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a novel diazabicyclo compound and a pharmacologically acceptable salt thereof.
The present invention also provides a medicine containing these compounds as an active ingredient, particularly an agent for improving cardiovascular disorders. The diazabicyclo compound provided by the present invention is a completely novel compound which has never been known before, and therefore, such a compound has a ameliorating effect on cardiovascular disorders caused by ischemia, anoxia or hypoxia. That has never been considered. The diazabicyclo compound of the present invention
The following (A):

[0003]

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[0004] 1,9-diazabicyclo [4.
3.0] is a novel compound having a nonane ring as a common basic skeleton, and specifically has a general formula (I):

[0005]

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Wherein R is —CH ₂ —X—R ¹ or —CO— (CH ₂ ) _n —R ¹ (where R ¹ represents a heteroaryl group, and X represents NH, O or S And n is 1
Or an integer of 2. R ² represents a hydroxy group or a di-lower alkyl-substituted aminoalkylamino group, and R ³ represents a lower alkyl group.] And a pharmacologically acceptable salt thereof.

Further, as specific embodiments included in the general formula (I) of the present invention, the following compounds are further provided. General formula (Ia):

[0008]

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Wherein R ¹ , R ³ and X are as defined above. And a pharmacologically acceptable salt thereof. General formula (Ib):

[0010]

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Wherein R ¹ , R ³ and n are as defined above. And a pharmacologically acceptable salt thereof. General formula (Ic):

[0012]

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[Wherein, R ⁴ represents a di-lower alkyl-substituted aminoalkylamino group, and R ¹ , R ³ and X are as defined above. And a pharmacologically acceptable salt thereof. General formula (Id):

[0014]

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Wherein R ¹ , R ³ , R ⁴ and n are as defined above. And a pharmacologically acceptable salt thereof.

The above compounds of the present invention may have an asymmetric carbon atom. The resulting isomers can be separated from the mixture by a conventional means for isolation and purification. Needless to say, each isomer itself is also a compound included in the present invention.

The compound of the present invention can be isolated as an optional acid addition salt by treating the compound with an organic acid or an inorganic acid, if necessary. Examples of the organic acid used herein include lower fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid; (Halo) lower alkylsulfonic acids such as acid and trifluoromethanesulfonic acid; benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, and 2,4,6-triisopropylbenzenesulfonic acid; Substituted or unsubstituted arylsulfonic acids; organic phosphoric acids such as diphenylphosphoric acid; and the inorganic acids include, for example, hydrochloric acid,
Sulfuric acid, hydrobromic acid, hydroiodic acid, borofluoric acid,
Examples include perchloric acid and nitrous acid.

As a typical example of the embodiment of the present invention, for example, the following compound: 2,5-diphenyl-7-hydroxy-6-methoxycarbonyl-8- (3-pyridyl) aminomethyl-1,9-diazabicyclo [ 4.3.0] Nona-3,8-diene (Example Compound 8 described below); 2,5-diphenyl-7-hydroxy-6-methoxycarbonyl-
8- (3-pyridyl) thiomethyl-1,9-diazabicyclo [4.3.0] nona-3,8-diene; 2,5-diphenyl-7-hydroxy-6-methoxycarbonyl-
8- (3-pyridyl) oxymethyl-1,9-diazabicyclo [4.3.0] nona-3,8-diene; 2,5-
Diphenyl-7-hydroxy-6-methoxycarbonyl-8- (2-pyridyl) aminomethyl-1,9-diazabicyclo [4.3.0] nona-3,8-diene; 2,5
-Diphenyl-7-hydroxy-6-methoxycarbonyl-8- (2-pyridyl) propionyl-1,9-diazabicyclo [4.3.0] nona-3,8-diene hydrochloride (Example Compound 12 described later) 7- (dimethylaminoethyl) amino-2,5-diphenyl-6-methoxycarbonyl-8- (2-pyridyl) propionyl-1,9-
Diazabicyclo [4.3.0] nona-3,8-diene;
7- (dimethylaminoethyl) amino-2,5-diphenyl-6-methoxycarbonyl-8- (2-pyridyl)
Acetyl-1,9-diazabicyclo [4.3.0] nona-3,8-diene dihydrochloride (Example Compound 1 described later)
5); 7- (dimethylaminopropyl) amino-2,5
-Diphenyl-6-methoxycarbonyl-8- (2-pyridyl) acetyl-1,9-diazabicyclo [4.3.
0] nona-3,8-diene dihydrochloride; 7- (ethylmethylaminoethyl) amino-2,5-diphenyl-6-
Methoxycarbonyl-8- (2-pyridyl) acetyl-
1,9-diazabicyclo [4.3.0] nona-3,8-
Diene; 7- (ethylmethylaminoethyl) amino-
2,5-diphenyl-6-methoxycarbonyl-8-
(4-pyrimidyl) acetyl-1,9-diazabicyclo [4.3.0] nona-3,8-diene; 7- (ethylmethylaminoethyl) amino-2,5-diphenyl-6
Methoxycarbonyl-8- (2-thiazolyl) acetyl-1,9-diazabicyclo [4.3.0] nona-3,8
-Dienes;

As is apparent from the results of the pharmacological tests described below, these compounds of the present invention have been confirmed to have excellent effects as ameliorating agents for cardiovascular disorders caused by ischemia, anoxia or hypoxia. Was. That is, the compound of the present invention is
It slows the progression of damage to circulatory tissues seen when a blood flow disorder such as cerebral infarction, myocardial infarction, or angina attack occurs in the liver, heart, and the like, and further promotes recovery from the damage. In particular, the present invention suppresses a decrease in myocardial contractile force seen at the time of blood flow recovery after myocardial infarction, and promotes functional recovery. Excellent drug therapy for such cardiovascular disorders due to ischemia, anoxia or hypoxia has not yet been established. The compounds of the present invention provide new therapeutic possibilities for these disorders, and are extremely useful especially in the field of cardiovascular diseases.
Therefore, the present invention also provides a medicament containing a diazabicyclo compound of the compound of the present invention and a pharmacologically acceptable salt thereof as an active ingredient.

The compound of the present invention will be described in more detail below. In the present specification, the term "lower" means that the group or compound to which this term is attached has 1 to 7 carbon atoms.
, Preferably 1 to 4.

The "lower alkyl group" may be linear or branched, and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
-Butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and the like, but preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , Sec-butyl and tert-butyl.

The "lower alkenyl group" may be linear or branched, and may be allyl, 2-methylallyl, ethenyl, 1-methylethenyl, 1-propenyl,
Examples thereof include a 2-propenyl group and a 2-butenyl group.

Examples of the "lower alkynyl group" include a propargyl group, a 2-methylpropargyl group and an ethynyl group.

"Lower alkoxy group" means a lower alkyl-substituted oxy group in which the lower alkyl group has the above-mentioned meaning, and is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert. -Butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy, isoheptyloxy and the like, but preferably methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

The term "lower acyl group" means the remaining atomic group obtained by removing the OH group from the carboxyl group of a lower aliphatic carboxylic acid, and is, for example, a lower alkanoyl group such as acetyl, propionyl and butyryl.

The "lower alkoxycarbonyl group" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-
Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The term "lower acyloxy group" means the remaining atomic group obtained by removing a hydrogen atom from the carboxyl group of a lower aliphatic carboxylic acid, and includes, for example, acetoxy, propanoyloxy and butanoyloxy.

The “lower alkylthio group”, “lower alkylsulfoxy group” and “lower alkylsulfonyl group” are
Each substituent of the substituted thio group, sulfoxy group and sulfonyl group is the above-mentioned lower alkyl group.

As the "halogen atom", for example, chlorine,
Examples include fluorine, bromine, and iodine.

An "aryl group" is monocyclic or polycyclic and may have one or more alkyl groups on the ring, for example, phenyl, tolyl, xylyl, α-naphthyl, β-naphthyl group and the like are included.

An “aryloxy group” is a phenoxy group,
Examples thereof include a tolyloxy group, a xylyloxy group, an α-naphthyloxy group, and a β-naphthyloxy group.

The "heterocyclyl group" is a 3- to 8-membered ring, preferably a 5- or 6-membered ring, containing at least one or more heteroatoms such as nitrogen, sulfur and oxygen as ring-constituting atoms. And means, for example, azetidinyl containing 1 to 4 nitrogen atoms, pyrrolidinyl, imidazolyl,
Imidazolinyl, piperidinyl, pyrazolidinyl, piperazinyl, tetrahydropyrimidinyl and the like; morpholinyl containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; thiazolidinyl containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms Can be.

"Heteroaryl group" means a 5- or 6-membered aromatic group containing at least one heteroatom such as a nitrogen atom, sulfur atom or oxygen atom as a ring-constituting atom. , Pyridinyl, piperazyl and the like containing 1 to 4 oxazolyl containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; thiazolyl and thiadiazolyl containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms Can be mentioned.

The compound of the present invention can be synthesized, for example, according to the method shown in each of the following steps. Step 1 :

[0035]

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[In the formula, R ³ represents a lower alkyl group. In this step, a 1,3-bis (diazo) -1,3-di-lower alkoxycarbonyl-2-propanone derivative (II) and a 1,3-butadiene derivative (III) are subjected to a Diels-Alder reaction, This is a step of producing a diazabicyclo compound represented by the formula (IV).

The reaction is carried out in an inert solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; hydrocarbons such as benzene, toluene, xylene and cyclohexane; halogenated hydrocarbons such as dichloromethane and chloroform; A compound of formula (II) in a suitable solvent selected from among dimethylformamide, acetonitrile, dimethylsulfoxide and the like;
On the other hand, about 0.2 to 5 times the molar amount of the formula (III)
Can be carried out by heating and stirring the compound represented by the formula (1). The reaction temperature and time vary depending on the raw materials and conditions and cannot be strictly limited. However, it is generally preferable to carry out the reaction at a relatively high temperature of about the boiling point of the solvent in the sealed tube. The target compound, a compound represented by the formula (IV), is obtained in a yield. The target compound obtained by the above reaction is a single endo-addition product, similarly to the compound generally obtained by the Diels-Alder reaction.

The compound represented by the formula (IV) is obtained by the above reaction, and if necessary, the reaction solution is subjected to a purification method usually used, for example, filtration, decantation, extraction, washing, solvent evaporation, column or thin layer. Chromatography, recrystallization,
The compound represented by the formula (V) of the present invention can be isolated and purified by subjecting it to distillation, sublimation and the like. In addition, this compound can be directly used in the next step without isolating the reaction solution.

It should be noted that the 1,3-bis (diazo) -1,3-di-formula (II)
Lower alkoxycarbonyl-2-propanone derivatives are
For example, the compound can be easily produced by diazotizing a commercially available di-lower alkyl acetonedicarboxylate according to the method described in Production Example 1 described below.

Step 2 :

[0041]

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Wherein R ³ is as defined above. This step is a step of subjecting the compound represented by the formula (IV) obtained in the above step 1 to a reduction reaction to synthesize a compound represented by the formula (V) in which the 7-oxo group is converted to a hydroxy group. is there.

The reduction reaction to the compound (V) is carried out in an inert solvent appropriately selected from those exemplified above by the formula (IV)
The compound represented by is, for example, using a reducing agent such as 0.25 to 2 times the molar amount of sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, under the usual reaction conditions to convert the carbonyl compound to alcohol For example, it can be performed under ice cooling. In the reaction,
For example, it can be carried out in the presence of a catalyst such as cerium chloride hydrate.

By the above reaction, a compound represented by the formula (V) in which the oxo group at the 7-position is converted to a hydroxy group is obtained. This compound, if necessary, by subjecting the reaction solution to a purification method usually performed, for example, filtration, decantation, extraction, washing, solvent evaporation, column or thin layer chromatography, recrystallization, distillation, sublimation, etc. It can be isolated and purified. The obtained compound of the formula (V) can be used in the next step without isolation of the reaction product solution without isolation. In addition, the compound represented by the formula (V) obtained in this step includes a compound in which the hydroxy group at the 7-position is α-coordinated and a compound having a β-position.
Some isomers are coordinated, and these isomers can be separated by ordinary separation and purification means. Therefore, in the following description of the present specification, unless otherwise specified, the compound of the present invention is meant to be any one of α- and β-isomers or a mixture thereof with respect to the substituent at the 7-position.

Step 3 :

[0046]

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[Wherein R ³ is as defined above. In this step, the alkoxycarbonyl group at the 8-position of the compound represented by the formula (V) obtained in the above step 2 is further reduced to synthesize a compound represented by the formula (VI) converted to a hydroxymethyl group. This is the step of performing

In the reduction reaction, the compound represented by the formula (V) is converted into an alcohol derivative in a suitable inert solvent suitably selected from the above-mentioned examples. The reaction can be carried out with a reducing agent under the conditions, for example, by treating with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, or triethyllithium borohydride.
Incidentally, by appropriately selecting the reaction conditions, the compound represented by the formula (IV) obtained in the step 1 can be directly used as a raw material without passing through the compound represented by the formula (V) in the step 2 above. It is also possible to carry out the reduction reaction of this step to derive the target compound represented by the formula (VI).

According to this step, the compound represented by the formula (VI) can be efficiently obtained, and if necessary, the reaction solution can be purified by a conventional purification method such as filtration, decantation, or the like.
The compound represented by the formula (VI) of the present invention can be isolated and purified by subjecting it to extraction, washing, solvent evaporation, column or thin layer chromatography, recrystallization, distillation, sublimation and the like. When this compound is used to derive another compound, the reaction solution can be directly used in the next step without isolation.

Step 4 :

[0051]

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[Wherein R ¹ , R ³ and X are as defined above. In this step, the hydroxymethyl group which is the 8-position substituent of the compound represented by the formula (VI) obtained in the above step 3 is variously converted to obtain a compound of the formula (I-
This is a step of synthesizing the compound represented by a). The reaction is
For example, in an inert solvent selected from those exemplified above,
The compound of formula (VI) is treated with a hydroxy group activating reagent such as mesyl chloride, preferably in the presence of a base, to give a synthetic intermediate in which the hydroxymethyl group at the 8-position is activated. The activated intermediate compound is then added to a compound of formula (VII) wherein R ¹ and X are as defined above. ] And stirring,
The compound of the present invention represented by the formula (Ia) can be obtained.

Examples of the base used in the above reaction include alkali metals such as lithium, sodium and potassium; alkaline earth metals such as calcium; alkali metal hydrides such as sodium hydride; alkaline earth metals such as calcium hydride. Metal hydrides; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; sodium methoxide; Alkali metal alkoxides such as sodium ethoxide and potassium tert-butoxide; alkali metal salts of alkanoic acids such as sodium acetate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate;
Tri (lower) alkylamines such as trimethylamine, triethylamine and N, N-diisopropyl-N-ethylamine; N, N-di (lower) alkylaminopyridines such as pyridine, picoline, lutidine and N, N-dimethylpyridine Pyridine compounds; quinolines; N-lower alkylmorpholines such as N-methylmorpholine; N, N-
An organic base or an inorganic base such as N, N-di (lower) alkylbenzylamine such as dimethylbenzylamine can be appropriately used.

By this step, a compound represented by the formula (Ia), which is one of the target compounds of the present invention, is obtained.
Such compounds may be purified by conventional purification means, such as filtration,
It can be isolated and purified by subjecting it to decantation, extraction, washing, solvent evaporation, column or thin layer chromatography, recrystallization, distillation, sublimation and the like.

It should be noted that the synthesis raw material of this step is represented by the formula (VI)
Since the 7-position of the compound represented by is substituted with a hydroxy group, the reaction is carried out after protecting the hydroxy group with an appropriate protecting group, and then the protecting group is eliminated to obtain the yield of this step. Can be improved. The protection of the hydroxy group at the 7-position is carried out in the compound represented by the formula (V) obtained in the above-mentioned step 2 by using a commonly used protecting group for a hydroxyl group such as a t-butyldimethylsilyl group or a trimethylsilyl group. It can be carried out by introducing a silyl protecting group or a lower acyl group such as an acetyl group.

The compound represented by the formula (VII), which is a raw material for the synthesis reaction of the compound represented by the formula (VI) in the step 4, includes R ¹ of the heteroaryl group,
Group: A compound in which an amino group, a hydroxy group or a mercapto group corresponding to -XH is substituted, and can be arbitrarily selected and used from various commercially available compounds according to the purpose of the present invention. . Examples of such a compound include imidazolyl, pyridyl, piperazyl, oxazolyl, thiadiazolyl, and the like, as long as an amino group, a hydroxy group, or a mercapto group is substituted at an arbitrary position.

Step 5 :

[0058]

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Wherein R ³ is as defined above. This step is a step of converting the ester group of the 8-position substituent of the compound represented by the formula (V) obtained in the above step 2 to synthesize the compound represented by the formula (VIII).
The reaction is carried out by first treating the compound represented by the formula (V) with an acid or an alkali to hydrolyze the ester moiety at the 8-position, and then adding to the compound a suitable dehydrating condensing agent such as dicyclohexylcarbodiimide. After addition of methoxymethylamine under the conditions of dehydration and condensation or conversion to an acid chloride with thionyl chloride, methoxymethylamine is added in the presence of a suitable base to give the desired compound of formula (VIII) Can be obtained.

The target compound represented by the formula (VIII) is obtained by this step, and if necessary, the reaction solution is subjected to a purification method usually used, for example, filtration, decantation, extraction, washing, solvent evaporation, column removal. Or by subjecting it to thin layer chromatography, recrystallization, distillation, sublimation, etc.
The compound represented by II) can be isolated and purified, but the reaction solution can be directly used in the next step without isolation. In addition, since a hydroxy group is substituted at the 7-position of the compound represented by the formula (V), which is a synthesis raw material in this step, the reaction is carried out by protecting the hydroxy group with an appropriate protecting group, Thereafter, by removing the protecting group, the yield of this step can be improved. The protection of the hydroxy group at the 7-position can be carried out by introducing a hydroxyl-protecting group which is usually used as described above, into the compound represented by the formula (V).

Step 6 :

[0062]

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Wherein R ¹ , R ³ and n are as defined above. In this step, the methoxymethylaminocarbonyl group, which is the 8-position substituent, of the compound represented by the formula (VIII) obtained in the above step 5 is subjected to various conversions to obtain a compound represented by the formula ( This is a step of synthesizing the compound represented by Ib). The reaction is carried out by combining the compound represented by the formula (VIII) and the heteroaryl compound substituted with a methyl group or an ethyl group in the presence of an appropriate base appropriately selected from the above, and stirring the mixture to obtain a compound represented by the formula: (VII
The condensation is carried out by condensation of the methoxymethylamino group at the 8-position substituent of the compound (I) with a methyl or ethyl-substituted heteroaryl compound, or by reacting the compound represented by the formula (VIII) with vinylmagnesium bromide to convert the methoxymethylamino group to vinyl. After a vinylcarbonyl compound substituted with a group is obtained, a halogenated heteroaryl compound is added to the compound, followed by stirring.

According to the above step, a compound represented by the formula (Ib), which is one of the objects of the present invention, is obtained, and the compound is purified by a conventional purification method such as filtration, decantation, extraction, and washing. It can be isolated and purified by subjecting it to solvent evaporation, column or thin layer chromatography, recrystallization, distillation, sublimation and the like. In addition, even in the case of the compound represented by the formula (VIII), which is a synthesis raw material in this step,
Since a hydroxy group is substituted at the 7-position, the hydroxy group is protected with an appropriate protecting group, for example, a t-butyldimethylsilyl group, and the reaction is carried out. The yield of the process can be improved.

Step 7 :

[0066]

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Wherein R ³ and R ⁴ are as defined above. This step is a step of converting the hydroxyl group at the 7-position of the compound represented by the formula (V) obtained in the step 2 to synthesize a compound represented by the formula (IX). The reaction is carried out, for example, by activating a compound represented by the formula (V) in an inert solvent selected from those exemplified above, preferably in the presence of a suitable base exemplified above, by activation of a hydroxy group such as mesyl chloride. Treatment with a reagent gives a synthetic intermediate in which the hydroxymethyl group at position 7 has been activated. Next, a di-lower alkyl-substituted aminoalkylamine compound is added to the intermediate compound, followed by stirring.

By the above reaction, the compound represented by the formula (IX) is obtained. If necessary, the reaction solution is subjected to a purification method usually used, for example, filtration, decantation, extraction, washing, solvent evaporation, column or The compound represented by formula (IX) can be isolated and purified by thin-layer chromatography, recrystallization, distillation, sublimation, etc., but the reaction solution can be used in the next step without isolation. Can also.

Step 8 :

[0070]

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Wherein R ³ and R ⁴ are as defined above. In this step, the compound represented by the formula (X) is reduced to a hydroxymethyl group by reducing the alkoxycarbonyl group which is the 8-position substituent of the compound represented by the formula (IX) obtained in the above step 7. This step can be performed according to the reduction method described in Step 3 described above.

Step 9 :

[0073]

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[Wherein R ¹ , R ³ , R ⁴ and X are as defined above. This step comprises subjecting the compound of formula (X) obtained in the above step 8 to various conversions to the hydroxymethyl substituent at the 8-position to obtain a compound of the formula (Ic) which is one of the target compounds of the present invention. )
This is the step of synthesizing the compound represented by This step can be performed according to the method described in Step 4 described above. The compound represented by the formula (Ic) of the present invention obtained by this step can be purified by a commonly used purification means such as filtration, decantation, extraction, washing, solvent evaporation, column or thin layer chromatography, recrystallization, It can be isolated and purified by subjecting it to distillation, sublimation, or the like.

Step 10 :

[0076]

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[Wherein R ³ and R ⁴ are as defined above. This step is a step of synthesizing the compound represented by the formula (XI) by converting the 8-position substituent of the compound represented by the formula (IX) obtained in the step 7, and the step is as described above. It can be carried out according to the method described in Step 5.

Step 11 :

[0079]

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[Wherein R ¹ , R ³ , R ⁴ and n are as defined above. In this step, the 8-position substituent of the compound represented by the formula (XI) obtained in the above step 10 is converted to give a compound represented by the formula (Id), which is one of the target compounds of the present invention. This is the step of synthesis. This step can be performed according to the method described in Step 6 described above. The compound represented by the formula (Id) of the present invention obtained by this step can be purified by a commonly used purification means such as filtration, decantation, extraction, washing, solvent evaporation, column or thin layer chromatography, recrystallization, It can be isolated and purified by subjecting it to distillation, sublimation, or the like.

The compound (I) of the present invention produced by each of the above steps can be isolated as an optional acid addition salt by treating it with an organic acid or an inorganic acid, if necessary. Examples of the organic acid used herein include lower fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid; (Halo) lower alkylsulfonic acids such as acid and trifluoromethanesulfonic acid; benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, and 2,4,6-triisopropylbenzenesulfonic acid; Substituted or unsubstituted arylsulfonic acids; organic phosphoric acids such as diphenylphosphoric acid; and the inorganic acids include, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, borofluoric acid, and perchloric acid. Acids and nitrous acid can be exemplified.

When the compound (I) of the present invention is administered to humans as a medicament, it varies depending on the age and symptoms, but its effective amount, for example, usually 10 to 100 mg per day is orally administered in 1 to 3 divided doses. Is preferred. The therapeutic agent for circulatory system disease of the present invention can be made into various dosage forms, for example, orally administered preparations such as tablets, capsules, powders, troches and solutions. The above-mentioned preparation can be carried out by a method known per se. That is, the compound (I) of the present invention is used as an excipient such as starch, mannitol and lactose; a binder such as sodium carboxymethyl cellulose and hydroxypropyl cellulose; crystalline cellulose and calcium carboxymethyl cellulose. Tablets, capsules, powders, granules or troches by appropriately combining and disintegrating agents such as talc, magnesium stearate and the like; lubricants such as light anhydrous silicic acid; Can be manufactured. When such an orally administered drug is administered to humans, it varies depending on the age, symptoms and the like, but its effective amount, for example, usually 1 to 1 per day.
It is preferable to orally administer 0 to 100 mg in 1 to 3 divided doses.

The therapeutic agent for circulatory system diseases of the present invention can also be used as an injection. This formulation may be, for example, previously dispersed or solubilized in an aqueous carrier such as a physiological saline with a surfactant or a dispersant, or may be dispersed or solubilized whenever necessary. It may be a crystal preparation for injection or a lyophilized preparation. In addition to the above-mentioned components, a pH adjuster or a stabilizer may be added to the aqueous carrier as an optional component. The dose and route of administration of such an injection are not particularly limited, and a safe and necessary dose can be administered intravenously, intraarterially, subcutaneously or intraperitoneally according to the disease state and the characteristics of the patient. These administrations may be performed all at once, or may be performed gradually by infusion or the like.

[0084]

EXAMPLES The production of the compound of the present invention will be described in more detail with reference to Production Examples and Examples, but it goes without saying that the present invention is not limited by the following description.

In the following description, each abbreviation has the following meaning. Me: methyl Et: ethyl Pr: propyl Bu: butyl Hex: hexyl Ac: acetyl Ph: phenyl Py: pyridyl Production Example 1

[0086]

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28.6 g of diethyl acetonedicarboxylate
(141 mmol) and 101.9 g (290 mmol) of p-dodecylbenzenesulfonazide in 90 ml of acetonitrile were mixed with 40.4 m of triethylamine under ice-cooling.
1 (290 mmol) and stir at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane-ethyl acetate) to give 35.9 g (quantitative) of compound (1) as a pale yellow oil. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.31
(T, 3H, J = 6.9 Hz), 1.31 (t, 3H, J = 6.9 Hz)
J = 6.9 Hz), 4.28 (q, 2H, J = 6.9H)
z), 4.28 (q, 2H, J = 6.9 Hz) Production Example 2

[0089]

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The compound (2) was quantitatively obtained as a yellow oily substance according to the method of Production Example 1 described above. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (s, 3
H), 3.83 (s, 3H) Example 1

[0091]

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The compound (2) obtained in Preparation Example 2
5 g (2.2 mmol) and 1,4-diphenyl-
A solution of 2.23 g (10.8 mmol) of 1,3-butadiene in 4 ml of tetrahydrofuran was placed in a sealed tube at 80 ° C. for 6 hours.
Heat and stir for days. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n
-Hexane-ethyl acetate) to give compound (3) 357m
g (yield: 39.9%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 3.67
(S, 3H), 3.88 (s, 3H), 4.86 (d,
1H, J = 5.6 Hz), 5.72 (d, 1H, J =
2.0 Hz), 6.01-6.05 (m, 1H), 6.0.
14-6.20 (m, 1H), 7.20-7.29
(M, 5H), 7.44-7.51 (m, 5H) Example 2

[0094]

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Compound (3) obtained in Example 1 above
A solution of 357 g (0.88 mmol) in 4.5 ml of tetrahydrofuran was added to 19 mg of lithium borohydride.
(0.88 mmol) in tetrahydrofuran (2 ml) was added dropwise at 0 ° C. under a nitrogen stream, and then added dropwise at the same temperature.
Stir for hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform-acetone) to obtain 0.148 g of compound (4) (yield:
41%) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.16
(D, 1H, J = 8.2 Hz), 3.73 (s, 3
H), 3.82 (s, 3H), 4.59-4.60.
(M, 1H), 5.11 (d, 1H, J = 8.2H
z), 5.67 (s, 1H), 5.89 (s, 2H),
7.26-7.57 (m, 10H) Example 3

[0097]

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(A) 91 g of imidazole (1.33) was added to a solution of 100 g (0.664 mol) of tert-butyldimethylchlorosilane in acetonitrile (1000 ml).
8 mol), and the mixture was stirred in a nitrogen stream under ice-cooling for 30 minutes. Next, the compound (4) 9 obtained in Example 2 was added to this solution.
0.3 g (0.222 mol) was added, and the mixture was heated under reflux for 6 days. After the completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure,
Extracted with chloroform and saturated aqueous ammonium. The extract was dried over magnesium sulfate, and the solvent was distilled off. Ethyl acetate was added to the obtained residue for crystallization, hexane was added to push out the crystals, and 99 g of compound (5) was obtained.
(Yield: 86%) was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: 0.01
(S, 3H), 0.06 (s, 3H), 0.46 (s,
9H), 3.73 (s, 3H), 3.84 (s, 3
H), 4.40-4.42 (m, 1H), 5.25
(S, 1H), 5.49-5.51 (m, 1H), 5.
58 (dd, 1H, J = 2.6 & 9.9 Hz), 5.9
7-6.04 (m, 1H), 7.09-7.39 (m,
10H)

(B) Compound (5) obtained in the above (a)
94 g (5.65 mmol) of dichloromethane (15 m
l) and ethyl ether (30 ml) were mixed in a nitrogen stream under ice-cooling and diisobutylammonium hydride (15.2 m).
1 (14.1 mmol) was added and stirred for 3 hours. After completion of the reaction, ethyl acetate and a 1N-hydrochloric acid aqueous solution were added for extraction, and the extract was washed with water and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 2.644 g (yield: 95%) of compound (6) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: -0.2
6 (s, 3H), 0.00 (s, 3H), 0.55
(S, 9H), 3.71 (s, 3H), 4.21-4.
38 (m, 3H), 5.02 (s, 1H), 5.32-
5.34 (m, 1H), 5.55 (dd, 1H, J =
2.0 & 9.9 Hz), 5.87-5.94 (m, 1
H), 7.10-7.52 (m, 10H) Example 4

[0102]

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Compound (6) 0.5 g (1.0 mmol)
0.16 mesyl chloride in a dichloromethane solution (6 ml)
ml (2.0 mmol) and triethylamine 0.2
9 ml (2.0 mmol) was added, and the mixture was added at -78 ° C under a nitrogen stream.
For 30 minutes. Then, a solution of 0.48 g (5 mmol) of 3-aminopyridine in 4 ml of dichloroethane was added dropwise to the solution at the same temperature, and the mixture was further stirred for 1 hour under ice-cooling. After completion of the reaction, chloroform and a saturated aqueous solution of ammonium chloride were added for extraction, and the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform-
Methanol) to give 0.267 g (yield: 46%) of compound (7) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: -0.1
2 (s, 3H), 0.00 (s, 3H), 0.57
(S, 9H), 3.74 (s, 3H), 3.94 (s,
2H), 4.37 (d, 1H, J = 4.3 Hz), 4.
97 (s, 1H), 5.36 (d, 1H, J = 2.3H
z), 5.57 (dd, 1H, J = 1.7 & 9.9H
z), 5.92 (ddd, 1H, J = 1, 7, 6.3 &
9.9 Hz), 6.88 (dd, 1H, J = 1.3 &
7.0 Hz), 6.90-7.52 (m, 1H), 7.
98-8.01 (m, 2H) Example 5

[0105]

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Compound (7) 0.385 g (0.68 mm
ol) in tetrahydrofuran (5 ml) solution
-Butyl ammonium fluoride 0.75 ml (0.7
5 mmol), and the mixture was stirred in a nitrogen stream under ice-cooling for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (chloroform-methanol) to obtain 0.27 of the compound (8) of the present invention.
4 g (yield: 89%) were obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 3.59
(S, 3H), 3.98 (d, 2H, J = 4.0H)
z), 4.16 (brs, 1H), 4.52 (dd, 1
H, J = 2.3 & 5.3 Hz), 4.68 (s, 1
H), 5.52 (d, 1H, J = 2.3 Hz), 5.7
7 (ddd, 1H, J = 2.3, 5.3 & 10.3H
z), 5.86 (dd, 1H, J = 1.6 & 10.3H)
z), 6.85 (ddd, 1H, J = 1, 3, 3.0 &
8.3 Hz), 7.04 (dd, 1H, J = 4.6 &
8.3 Hz), 7.28-7.61 (m, 10H),
7.94 (td, 2H, J = 1.3 & 4.6 Hz) Example 6

[0108]

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(A) 81.63 g of compound (5) (0.1
To a mixture of 57 mol) of tetrahydrofuran (800 ml) and methanol (800 ml) was added 267 ml (0.267 mol) of a 1N aqueous solution of sodium hydroxide, followed by stirring at room temperature overnight. After completion of the reaction, the mixture was neutralized with a 2N-hydrochloric acid aqueous solution, and the solvent was distilled off under reduced pressure. Ethyl acetate and a 2N-hydrochloric acid aqueous solution were added to the obtained residue for extraction. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue for crystallization. Hexane was added and the crystals were extruded to give 66.6 g of carboxylic acid (yield: 66%) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: -0.1
0 (s, 3H), 0.06 (s, 3H), 0.46
(S, 9H), 3.86 (s, 3H), 4.41 (d
d, 1H, J = 1.7 & 6.6 Hz), 5.25 (s,
3H), 5.49-5.51 (m, 1H), 5.59.
(Dd, 1H, J = 2.0 & 9.9 Hz), 6.03
(Ddd, 1H, J = 2.0, 6.6 & 9.9 Hz),
7.10-7.64 (m, 10H)

(B) Next, the carboxylic acid 2 obtained above
g (4 mmol) was converted into an acid chloride, and then a dichloromethane (20 ml) solution was added. To this, 0.58 g (6 mmol) of N, O-dimethylhydroxylamine hydrochloride and 1.4 ml (9.9 mmol) of triethylamine were added, and the mixture was added at room temperature. Was stirred overnight. After completion of the reaction, dichloromethane and a saturated aqueous solution of ammonium chloride were added for extraction, and the extract was washed with water and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate-hexane) to obtain 2.03 g (yield: 94%) of compound (9) as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ: -0.2
9 (s, 3H), -0.02 (s, 3H), 0.49
(S, 9H), 3.18 (s, 3H), 3.48 (s,
3H), 3.84 (s, 3H), 4.39 (d, 1H,
J = 4.6 Hz), 5.39 (s, 3H), 5.48
(D, 1H, J = 2.3 Hz), 5.58-5.62
(M, 1H), 5.95-5.98 (m, 1H), 7.
11-7.38 (m, 10H) Example 7

[0113]

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Compound (9) 0.963 g (1.57 mm
ol) in tetrahydrofuran (10 ml) solution, vinylmagnesium bromide (0.98M-THF solution)
4.5 ml (4.38 mmol) was added under a nitrogen stream, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate and a saturated aqueous solution of ammonium chloride were added for extraction, and the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give compound (10).
0.796 g (yield: 88%) was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: -0.2
1 (s, 3H), 0.11 (s, 3H), 0.46
(S, 9H), 3.83 (s, 3H), 4.41 (d
d, 1H, J = 1.3 & 6.6 Hz), 5.34 (s,
1H), 5.52-6.66 (m, 3H), 6.06.
(Ddd, 1H, J = 2.3, 6.6 & 9.9 Hz),
6.29 (dd, 1H, J = 2.3 & 17.2 Hz),
7.08-7.26 (m, 6H), 7.33-7.39
(M, 5H) Example 8

[0116]

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0.15 ml of 2-bromopyridine (1.5
Tert-butyllithium (1.56M) in a nitrogen stream at -78 ° C.
-Pentane solution) (1.0 ml, 1.58 mmol) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes (this was taken as one liquid). On the other hand, 0.409 g of compound (10) (0.79 m
mol) was stirred at −78 ° C. (this was made into two liquids). Solution 1 was transported by cannula to Solution 2 and then stirred at the same temperature for 30 minutes. After completion of the reaction, ethyl acetate and a 1N aqueous solution of hydrochloric acid were added for extraction, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 0.383 g of compound (11) (yield: 81).
%) As colorless amorphous crystals.

¹ H-NMR (CDCl ₃ ) δ: -0.2
5 (s, 3H), 0.07 (s, 3H), 0.44
(S, 9H), 3.01-3.30 (m, 4H), 3.
82 (s, 3H), 4.38 (d, 1H, J = 5.0H
z), 5.26 (s, 1H), 5.48-5.50
(M, 1H), 5.61 (dd, 1H, J = 2.6 &
9.9 Hz), 6.02 (ddd, 1H, J = 2.3,
6.6, & 9.9 Hz), 7.04-7.37 (m, 1
2H), 7.52 (td, 1H, J = 7.6 & 2.0H)
z), 8.47 (d, 1H, J = 4.6 Hz) Example 9

[0119]

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Compound (11) 0.383 g (0.64 m
mol) in a solution of tetra-n-butylammonium fluoride (5 ml) in tetrahydrofuran (5 ml).
96 mmol), and the mixture was stirred in a nitrogen stream under ice-cooling for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (chloroform-acetone), and further treated with a hydrochloric acid-methanol solution to obtain 0.204 g of the compound (12) of the present invention. (Yield: 6
1%) as pale brown amorphous crystals.

¹ H-NMR (D ₂ O) δ: 3.27
(S, 4H), 3.86 (s, 3H), 4.66 (s,
1H), 5.28 (s, 1H), 5.62 (s, 1
H), 5.89 (s, 1H), 5.97 (s, 1H),
7.31-7.85 (m, 12H), 8.35-8.4
3 (m, 2H) Example 10

[0122]

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Compound (4) 1.0 g (2.46 mmol)
To a solution of 1) in dichloromethane (50 ml) was added 0.95 ml (12.3 mmol) of mesyl chloride and 1.7 ml (12.3 mmol) of triethylamine, and the mixture was stirred at −30 ° C. for 1 hour under a nitrogen stream. Thereafter, 4 ml of N, N-dimethylethylenediamine (36.
9 mmol) was added dropwise, and the mixture was further stirred at room temperature for 1 hour.
After completion of the reaction, chloroform and a saturated aqueous solution of ammonium chloride were added for extraction, and the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform-methanol) to give 0.761 g of compound (13) (yield:
65%) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 2.19
-2.49 (m, 2H), 2, 23 (s, 6H), 2.
67-2.86 (m, 2H), 3.66 (s, 3H),
3.81 (s, 3H), 4.06 (s, 1H), 4.5
8-4.62 (m, 1H), 5.31-5.33 (m,
1H), 5.77-5.82 (m, 1H), 5.92-
5.99 (m, 1H), 7.27-7.51 (m, 10
H) Example 11

[0125]

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Compound (13) 0.761 g (1.6 mm
ol) in a mixture of tetrahydrofuran (7.6 ml) and methanol (7.6 ml), 2.7 ml (2.7 mmol) of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. After the completion of the reaction, 2.7 m of 1N hydrochloric acid aqueous solution
The residue obtained by distilling off the solvent under reduced pressure was extracted with chloroform. The extract was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.755 g of a crude carboxylic acid. On the other hand, N, O-
0.234 g of dimethylhydroxylamine hydrochloride (2.
To a solution of 4 mmol) in dichloromethane (4 ml) was added 0.31 ml (2.2 mmol) of triethylamine, and the mixture was stirred at room temperature under a nitrogen stream for 1 hour. To the suspension, 0.755 g of the previously obtained crude carboxylic acid in dichloromethane (5
ml) solution and 1- (3-dimethylaminopropyl)
-3-Ethyl-carbodiimide hydrochloride (WSC)
49 g (2.56 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, chloroform and water were added for extraction, and the extract was dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (chloroform-methanol) to obtain 0.68 g (yield: 84%) of compound (14) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 2.17
-2.46 (m, 2H), 2, 22 (s, 6H), 2.
63-2.84 (m, 3H), 3.21 (s, 3H),
3.46 (s, 3H), 3.83 (s, 3H), 4.1
0 (s, 1H), 4.58 (dd, 1H, J = 2.0 &
5.6 Hz), 5.25 (d, 1H, J = 2.0H)
z), 5.80-5.84 (m, 1H), 5.95-
6.02 (m, 1H), 7.27-7.52 (m, 10
H) Example 12

[0128]

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1.65 ml of n-butyllithium (2.7
mmol) in tetrahydrofuran (2.4 ml) at −78 ° C. in a nitrogen stream at 0.27 ml of α-picoline.
(2.7 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes (this was taken as one liquid). On the other hand, compound (14)
68 g (1.35 mmol) of tetrahydrofuran (8
The solution was stirred at −78 ° C. in a stream of nitrogen (this was
Liquid). Solution 1 was transported by cannula to Solution 2 and then stirred at the same temperature for 30 minutes. After the reaction was completed, ethyl acetate and a 1N-hydrochloric acid aqueous solution (5 ml) were added for extraction, washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform-methanol), and further treated with a hydrochloric acid-methanol solution to obtain a compound (15) of the present invention.
0.468 g (yield: 57%) was obtained as pale brown amorphous crystals.

¹ H-NMR (D ₂₀ ) δ: 2.96
(S, 3H), 2,97 (s, 3H), 3.00-3.
23 (m, 4H), 3.97-4.16 (m, 2H),
4.00 (s, 3H), 4.63 (d, 1H, J = 5.
9Hz), 4.87 (s, 1H), 5.61 (s, 1H)
H), 5.98 (d, 1H, J = 10.9 Hz), 6.
08-6.14 (m, 1H), 7.31-7.62
(M, 11H), 7.39 (t, 1H, J = 7.2H
z), 8.42 (t, 1H, J = 7.9 Hz), 8.5
2 (d, 1H, J = 5.9 Hz)

Pharmacological test: Myocardium by rat reperfusion model
Protective action [Test method] (1) Preparation of rat isolated perfused heart SD male rats (body weight 300 to 500 g) were used. After administration of heparin (1000 U / kg, intravenous) and anesthesia with pentobarbital sodium (40 mg / kg, intraperitoneal administration), the heart was immediately removed and suspended in a Langendorff apparatus. The perfusate was Krebs-Henserite (Krebs-He
nseleit) solution (118 mM NaCl, 4.7 mM KCl, 2.55 mM CaC
l ₂ , 1.18 mM KH ₂ PO ₄ , 24.88 mM NaHCO ₃ , 11.1 mM Glucos
e) and maintain at 37 ° C using a mixed gas (95% O ₂ , 5% CO 2
₂ ) After aeration and oxygenation, filter through a 75mmH
Perfused at a constant pressure of g. The measurement of each parameter of the circulatory dynamics was performed as follows. That is, a polyethylene cannula equipped with a latex balloon was inserted into the left ventricle from the left atrium, and the left ventricular pressure (LVP) was measured via a blood pressure transducer. The balloon was inflated with saline, the end diastolic pressure was 5 to 10 mmHg, and the left ventricular diastolic pressure was used as an index of the systolic force. The heart rate was recorded by an instantaneous counting unit synchronized with the contraction waveform. The coronary flow was measured by an electromagnetic blood flow meter through an extracorporeal blood flow probe attached to a catheter inserted retrograde into the aorta.

(2) Preparation of ischemia / reperfusion model After the isolated heart was suspended, the sample was stabilized for 15 to 20 minutes.
The perfusate in which the test substance was dissolved was perfused for 15 minutes. Thereafter, ischemia was performed for 25 minutes. The preparation of ischemia was performed by stopping the perfusion of the specimen. At that time, the specimen was immersed in a liquid tank storing a perfusate kept at 37 ° C. Reperfusion was performed by perfusing a perfusate in which a test substance was dissolved for 30 minutes following ischemia. The measurement of the cardiac function is performed before the perfusion of the test substance, before the ischemia and during the reperfusion.
Performed after minutes. The test compound was D- ^{5 at a} concentration of 10 ^-5 M.
The MSO solution was used adjusted to a concentration of 0.04% in the perfusate.

(3) Evaluation of Test Substance The myocardial protective effect of the test substance on ischemic injury was evaluated by the degree of recovery of left ventricular pressure (LVP) after reperfusion. In this case, a perfusate containing no test compound was used as a control.

[Results] The evaluation was performed using the left ventricular pressure (LV) before ischemia.
Percentage of recovery by each test compound relative to P) (LVD
P). From the results of the above tests, it was found that all the compounds of the present invention successfully restored left ventricular pressure after ischemia-reperfusion.

[Toxicity test] CrjC weighing 20 to 23 g
Using 10 D (SD) male mice, 10% aqueous solution of each of the compounds (8), (12) and (15) of the present invention in 10% polyethylene glycol 400 was subcutaneously administered and observed for one week. As a result, it was observed that all the compounds of the present invention survived without any abnormality at a dose of 10 ml / kg.

Claims (6)

[Claims] 1. A compound of the general formula (I): [In the formula, R, -CH ₂ -X-R ¹ or -CO- (C
H ₂ ) _n -R ¹ (where R ¹ represents a heteroaryl group, X represents NH, O or S, and n represents an integer of 1 or 2), and R ² represents a hydroxy group or a di group. R ³ represents a lower alkyl group; and R ³ represents a lower alkyl group. And a pharmacologically acceptable salt thereof. 2. A compound of the general formula (Ia): Wherein R ¹ , R ³ and X are as defined above. And a pharmacologically acceptable salt thereof. 3. A compound of the general formula (Ib): Wherein R ¹ , R ³ and n are as defined above. And a pharmacologically acceptable salt thereof. 4. A compound of the general formula (Ic): Wherein R ⁴ represents a di-lower alkyl-substituted aminoalkylamino group, and R ¹ , R ³ and X are as defined above. And a pharmacologically acceptable salt thereof. 5. A compound of the general formula (Id): Wherein R ¹ , R ³ , R ⁴ and n are as defined above. And a pharmacologically acceptable salt thereof. 6. A circulatory disorder improving agent comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.