JP2660086B2 - Agent for improving brain and cardiac dysfunction - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel compound useful as a pharmaceutical and a pharmaceutical use thereof. More specifically, the present invention relates to novel 4-amino-2,3-cycloalkenopyridine and 4-aminoquinoline derivatives, and cerebral dysfunction and cardiac dysfunction improvers containing them as active ingredients.

[Conventional technology and problems to be solved by the present invention]

In senile dementia, especially in Alzheimer's disease, a decrease in acetylcholine in the brain is observed, and treatment for trying to restore this decrease in cholinergic nervous function by administration of a cholinesterase inhibitor has been attempted, and has cholinesterase inhibitory activity Physostigmine as a therapeutic agent for senile dementia (Neurology, vol. 8, p. 397, 1978
) And 9-amino-tetrahydroacridine derivatives (JP-A-61-148154, 63-166811, 63-239271) and the like. In clinical trials, 9-amino-1,2,3,4-tetrahydroacridine (commonly known as tacrine) having cholinesterase inhibitory activity has also been reported to be effective against Alzheimer's disease when administered in combination with lecithin ("The.
New England Journal of Medicine, Vol. 315, p. 1241, 1986), but its effect as an anti-dementia drug is far from perfect, and its side effects are also a problem. Therefore, known compounds for treating senile dementia having cholinesterase inhibitory activity are not always satisfactory. Therefore, a new drug for treating senile dementia having cholinesterase inhibitory activity has been desired.

It is said that senile dementia is caused by impaired cerebral function caused by cerebrovascular disorder and impaired energy metabolism in the brain. Conventionally, various drugs have been developed as anti-dementia drugs, but the mechanism of the occurrence of senile dementia, the memory disorder caused by cerebrovascular disorders, and the mechanism of the occurrence of the memory disorder are not always clear. It is not at present.

In general, tissues of mammals, especially human brain, have a higher oxygen demand than other organ tissues, and therefore, the brain is extremely sensitive to the unexpected state of oxygen caused by cerebral ischemia and the like. Be told. Therefore, a compound showing an effect of protecting the brain from anoxia (blood oxygen deficiency) occurring in the brain due to cerebral ischemia or the like and a brain oxygen deficiency state is useful as a cerebral dysfunction improving agent. The survival time of animals exposed to oxygen-deficient conditions by placing them under oxygen-deficient conditions at low or normal pressure, i.e., using a model mammal with cerebral anoxia caused by the loading of oxygen-deficient conditions, Attempts have also been made to develop compounds which can be prolonged and, from this, are found to be effective in improving cerebral circulation metabolism or energy metabolism in the brain (see, for example, Nihon Pharmaceutical Journal 85 , pp. 323-238 (19)
85); 86 , 445-456 (1986); JP-A-54-117468.
And US Patent No. 4,369,139).

In a subarachnoid hemorrhage model animal using dogs, 5-lipoxygenase was remarkably activated in the spasm blood vessels of the basilar artery, whereas 5-lipoxygenase was significantly activated in the normal canine basilar artery. It is known that -lipoxygenase activity is not detected, and that when a 5-lipoxygenase inhibitor and an agent exhibiting an antioxidant effect are administered, a decrease in 5-lipoxygenase activity and relaxation of vasospasm are observed ( Watanabe et al., `` J. Neurochem. '' 50 , 1144-11
50 (1988) and Ibid. 51 , 1126-1131 (1988), and Shimizu et al., "Proteins, Nucleic Acids, Enzymes" 35 (4), 546-560 (199)
0)).

In addition, metabolites in vivo due to 5-lipoxygenase are known to cause ischemic heart disease, arteriosclerosis, and ischemic encephalopathy not only in bronchial asthma, allergic diseases and inflammatory diseases but also in the circulatory system. Have been.

On the other hand, the following general formula Wherein R is hydrogen, chlorine, a methyl group or an acetyl group, and a 4-amino-2-hydroxy-6,7-dihydropyrindine derivative represented by the formula:
It is known that it can be synthesized by cyclization of (acylimino) -cyclopentanecarbonitrile by intramolecular condensation, and the following formula [Wherein ring A represents a benzene ring or a cyclohexene ring], 4-aminocarbostyril or 4-amino-2-hydroxy-tetrahydroquinoline represented by the formula ("J. Am. Chem. Soc., 71 , 2205-2209 (1949)), but there is no description of the biological activity of each compound of the formulas (a) and (b) in the above-mentioned literature.

In recent years, medical problems for the elderly have been greatly highlighted due to the increase in the aging population, and particularly, there has been a desire for a useful therapeutic agent for cerebral dysfunction. In order to meet these demands, the present invention provides a new and useful senile dementia. It is an object of the present invention to provide a therapeutic agent, and yet another object of the present invention is to provide a therapeutic agent for heart failure in a heart disease region.

[Means for solving the problem]

The present invention has been made in view of the above object, and as a result, the following general formulas (Ia), (Ib), (Ic), (Ic)
d) succeeded in creating novel 4-amino-2,3-cycloalkenopyridine and 4-aminoquinoline derivatives represented by (Ie) or (If), and these compounds were converted to the desired acetyl. The present invention has been found to have a cholinesterase inhibitory activity, a 5-lipoxygenase inhibitory activity, an anti-anoxya activity in the brain, and an activity of enhancing atrial muscle contractility, and completed the present invention.

That is, in the first present invention, the following formula (Ia) Wherein, Y ^a is a hydrogen atom, a halogen atom or a lower alkyl group of C ₁ ~C _6, Z ^a is a halogen atom, r is 1
4-amino-6-halo-2,
A 3-cyclopenteno or cyclohexenopyridine derivative or a pharmaceutically acceptable salt thereof is provided.

In the second invention, the following formula (Ib) Wherein, Y ^b represents a hydrogen atom, a lower alkyl group having a halogen atom or a C ₁ ~C _6, Z ^b is an amino group, an alkylamino group,
Benzylamino group, a piperazyl group or N- substituted piperazyl group, N- substituent on the N- substituted piperazyl group, a lower alkyl group of C ₁ -C _6, a phenyl group or a hydroxyphenyl group, r A 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ic): Wherein Y ^c is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, and Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group. substituents on the substituted phenyl group include a halogen atom, a hydroxyl group, C ₁ ~
One or two or more of the same or different types selected from a C ₆ lower alkyl group, an amino group and a C ₂ -C ₆ acylamino group, particularly a (C ₁ -C ₄ ) alkylcarbonylamino group And r is an integer of 1 to 2] and a 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Id) Wherein Z ^d is a hydrogen atom or a halogen atom or a formula -SQ
Wherein Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group, and the substituent on the substituted phenyl group is a halogen atom, a hydroxyl group, a C ₁ ~ C ₆ lower alkyl group, amino group and C ₂
Acylamino group -C _6, especially (C ₁ -C ₄₎ can one selected from among alkylcarbonyl amino group or the same or different kinds of two or more, r is 1-2 integer 4,5-diamino-6-substituted or unsubstituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ie): Wherein Y ^e is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, p is 1 or 2, Q ′ is a phenyl group or a substituted phenyl group, and a substituent on this substituted phenyl group Is one or two or more of the same or different types selected from a hydroxyl group and a lower alkyl group of C _{1 to} C ₆ ], and a 4-amino-2-substituted-quinoline derivative represented by the following formula: Equation (If) Wherein, Y ^f is a hydrogen atom or a lower alkyl group of C ₁ ~C _6, T is (C ₁ ~C ₄₎ alkylamino group or piperidine -
4-amino-2 selected from the group consisting of 4-amino-2-substituted quinoline derivatives
A 3-cycloalkenopyridine derivative or a 4-aminoquinoline derivative, or a pharmaceutically acceptable salt thereof is provided.

The salts of the compounds of the general formulas (Ia) to (If) according to the present invention include the basic groups of the compounds, i.e. the nitrogen atom in the pyridine nucleus, the amino group at the 4-position, or a basic type of substitution. At the groups Y and X there are acid addition salts with pharmacologically acceptable acids which add to the compounds according to the invention. Examples of addition salts of the compounds of the present invention with the above-mentioned pharmacologically acceptable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and formic acid, propionic acid, succinic acid Examples include acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, benzoic acid, salicylic acid, organic acids such as methanesulfonic acid, and addition salts with amino acids such as aspartic acid and glutamic acid.

The compounds of the present invention represented by the general formulas (Ia) to (If) basically belong to acetylcholinesterase inhibitors for dementia, particularly Alzheimer's disease. A novel derivative characterized by having both an anoxia action and a 5-lipoxygenase inhibitory action. That is, the compound of the present invention exhibits, in addition to the action of activating cholinergic nerve function, a protective action of the brain against hypoxia such as ischemia which causes cerebral dysfunction, that is, an anti-anoxya action in the brain. It exerts a function of protecting brain function.

In addition, since the compound of the present invention has an inhibitory activity against 5-lipoxygenase, the compound of the present invention is expected to be used as a therapeutic drug for cerebral arteriosclerosis and ischemic cerebral dysfunction in brain disease areas.

That is, the present invention provides a novel specific compound useful as an agent for improving Alzheimer's type senile dementia, cerebrovascular dementia, sequela of cerebrovascular disorder, and various symptoms associated therewith.

The compound of the present invention exhibits acetylcholinesterase inhibitory activity, anti-anoxya activity and 5-lipoxygenase inhibitory activity, and is useful as a therapeutic agent for clinically treating Alzheimer's senile dementia, cerebrovascular dementia and the like and as an agent for ameliorating various symptoms based thereon.

Furthermore, the compounds of the present invention represented by the general formulas (Ia) to (If) show a cardiac contractile force increasing action, that is, a positive inotropic action, enhance the cardiac contractile force, and enhance the cardiac function. It is also useful as a cardiotonic agent for improvement and can be used as a therapeutic agent for heart failure in heart disease.

Therefore, further in the third invention, a derivative represented by the above general formula (Ia), (Ib), (Ic), (Id), (Ie) or (If), Alternatively, there is provided an agent for improving cerebral dysfunction, comprising a pharmacologically acceptable salt of these derivatives as an active ingredient.

Further, in the fourth invention, the above general formula (I
a), (Ib), (Ic), (Id), (Ie) or (I
A therapeutic agent for heart failure is provided which comprises a derivative represented by f) or a pharmacologically acceptable salt of these derivatives as an active ingredient.

Of general formula (I a), (I b ), in the cycloalkenyl Bruno pyridine derivative (I c) or (I d), when the group Y ^a or Y ^b is a halogen atom, as the halogen atom May be a fluorine, chlorine, bromine, iodine atom. C ₁ -C when group Y ^a, Y ^b or Y ^c is a lower alkyl group
₆ Examples of the lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, and isoamyl groups, and a (C ₁ -C ₄ ) alkyl group is preferable.

In the compound of the general formula (Ia) or (Id),
The halogen atom when Z ^a or Z ^d is a halogen fluorine, chlorine, bromine, iodine atom. The general formula (I
In the compound b), when Z ^b represents an alkylamino group represented by the group —N (R ¹ ) (R ² ), the lower alkyl group of R ¹ and R ² in this group is methyl, ethyl, n -Propyl, isopropyl, n-butyl, isobutyl and the like. Also, when Z ^b is a N- substituted piperazyl group, which is N- methylpiperazyl group, N- (o-hydroxy) phenyl pin Pella Gilles group, N- (p-FLUORO) phenylpiperidino Pella Gilles group, N- (o- Tolyl) piperazyl groups.

In the compound of the general formula (Ic) or (Id), Q is (Wherein m is an integer of 0 to 4) phenyl- (C ₁
~ C ₄ ) an alkyl group or a substituted phenyl group, and when R ³ , R ⁴ , R ^{5 in} the group of the formula is a halogen atom, the halogen is a fluorine, chlorine, bromine, iodine atom There is, also when a straight-chain or branched C ₁ -C ₆ lower alkyl groups are methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, t- butyl, n- amyl, isoamyl And when it is an acylamino group, a (C ₁ -C ₄ ) alkylcarbonylamino group such as an acetylamino group, or a benzoylamino group.

4-amino-2-substituted of general formula (I e) or (I f) - if a quinoline derivative, C ₁ -C ₆ is Y ^e or Y ^f
Examples of the lower alkyl group include a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl and isoamyl group.

In the compound of formula (If), when the group at the 2-position —CO—T is represented as a group —CONR ⁶ R ⁷ , R ⁶ or R
Examples of the ⁷ (C ₁ -C ₆ ) lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl and isoamyl groups.

Specific examples of the compounds of the above formula (Ia) include the compounds of Examples 1a, 1b and 6 described below.

Specific examples of the compound of the above formula (Ib) include the compounds of Example 2, Example 3, Example 4, Example 5, Example 7, and Example 8 described below.

Specific examples of the compound of the formula (Ic) include the compounds of Examples 9, 10, 11, 12, 13, 14, and 15 described below.

Specific examples of the compound of the formula (Id) include those described in Example 1 below.
There are 7, 18, 19, 20 and 21 compounds.

Specific examples of the compound of the formula (Ie) include those described in Example 2 below.
There are 2, 23 and 24 compounds.

Specific examples of the compounds of the formula (If) include those described in Example 2 below.
There are 5 and 26 compounds.

Next, the synthetic methods (A) and (B) of the compound of the present invention will be described below, but the present invention is not limited to these methods.

(A) When the compound of the present invention is a 4-amino-2,3-cycloalkenopyridine of the formulas (Ia) to (Id), the above-mentioned "Journal of American Chemical.
Society, vol. 71, p. 2205 (1949), obtained by the following general formula (II): [Wherein n is an integer of 3 to 5, and D represents a hydrogen atom, a lower alkyl group or an amino group] as a starting compound, which is reacted with a phosphorus halide to give the following: General formula (I ¹ ) (Wherein, n has the same meaning as described above, Y ′ represents a halogen atom, a lower alkyl group or an amino group, and X ′ represents a chlorine atom or a bromine atom) or 6-halogeno or
A 5,6-dihalogenopyridone derivative is produced. As the phosphorus halide used in this halogenation step, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and the like are used. The reaction can be carried out in the presence or absence of a solvent, but preferably at a temperature of 50 to 200 ° C. in the absence of the solvent.
The desired product can be obtained by conducting the reaction for a period of from minutes to 24 hours. If the halogen atoms are the same, two types of phosphorus halides can be used.

Then, the following general formula (III) Z—H (III) is added to the 6-position halogeno group of the compound of the general formula (I ¹ ). Wherein Z is not hydrogen), by reacting the compound represented by the following general formula, if necessary, in the presence of a base. Wherein n, Y 'and Z have the same meanings as described above. Since there is a difference in reactivity between the 5-position and the 6-position of the compound of the general formula (I ¹ ), when the reactants of the formula (III) are reacted in substantially equimolar ratio, the 6-position reacts selectively. I do. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-N, N-dimethylaminopyridi, 1,8-diazabicyclo [5.4.0] -7-undecene, sodium hydroxide, potassium hydroxide, and carbonate. An inorganic base such as potassium can be used. The reaction is completed in the presence or absence of a solvent that does not participate in the reaction in a temperature range of 50 to 200 ° C. in 30 minutes to 24 hours.

(B) The compound of the present invention is a compound of the formula (Ie) or (If)
In the case of an aminoquinoline derivative (i) In the compound of formula (If), the group at the 2-position -CO-T
Is represented as a group -CONR ⁶ R ⁷ , which can be synthesized by the following method. That is, a carboxylic acid compound represented by the following general formula (IV) (wherein Y represents the above-mentioned meaning) is esterified to form a compound represented by the following general formula (V) (where Y is the above-mentioned Y ^f
Has the same meaning as R ⁸ represents a lower alkyl group of C _{1 to} C ₄ ), and then converts the hydroxyl group at the 4-position to an amino group to obtain a compound represented by the general formula (VI): Y,
R ⁸ represents the above-mentioned meaning).

Next, the 4-amino compound of the general formula (VI) is hydrolyzed to remove the alkyl group (R ⁸ ) which forms an ester to convert into a corresponding free carboxylic acid type compound. By reacting (amidating) an amino compound of the formula (VII) HNR ⁶ R ⁷ (VII) (wherein R ⁶ and R ⁷ have the same meanings as described above), the general formula (I ³ ) (Wherein, Y, R ⁶ and R ⁷ have the same meanings as described above).

For the esterification in the first step of the above synthesis method, a method as described in "Shin Jikken Kagaku Koza, Vol. 14, Synthesis and Reaction of Organic Compounds (II), page 1000" can be used.

The amination at the 4-position in the second step proceeds by reacting with chlorosulfonyl isocyanate and then treating with an acid. The reaction with chlorosulfonyl isocyanate is completed in a solvent that does not participate in the reaction at 0 to 150 ° C. for 30 minutes to 5 hours. Various acids can be used for the treatment with the acid, and conditions of 0 to 100 ° C. and 1 to 10 hours with hydrochloric acid in ethanol can be selected.

The reaction for producing the compound of the formula (I ³ ) by amidation in the third step proceeds in the presence or absence of a solvent that does not participate in the reaction. The reaction proceeds at 0 to 150 ° C. for 1 to 48 hours.

(Ii) In the compound of formula (Ie), the group at the 2-position-(CH = C
H) Based on pQ (Wherein E represents an alkenylene group CH ＝ CH _p , R ³ ,
R ⁴ and R ⁵ represent the above-mentioned meanings), and the compound of the formula (Ie) is represented by the general formula (VIII) The compound represented by the general formula (IX) (Wherein, R ³ , R ⁴ , R ⁵ , and p represent the above-mentioned meanings).
After reacting for 1 to 24 hours at a temperature of 50 to 150 ° C,
After processing for ~ 12 hours, the following general formula (I ⁴ ) (Wherein, Y, R ³ , R ⁴ , R ⁵ and p represent the above-mentioned meanings)
Can be produced.

The compounds of the general formulas (Ia) to (If) synthesized as described above can be purified by a conventional purification method, that is, crystallization, precipitation, solvent extraction,
It can be purified by column chromatography or the like.

The compounds represented by the above general formulas (Ia) to (If) of the present invention may be administered alone, but if necessary or desired, other usual pharmacologically acceptable carriers and additives can be used. It can be orally administered by mixing with a form and a diluent to obtain a desired dosage form. In such a case, an adult usually receives 5 to 500 mg of a compound represented by any one of formulas (Ia) to (If) per day. Solutions for administration by injection are obtained by dissolving a pharmaceutically acceptable water-soluble salt of the active compound in water, preferably at a concentration of 0.5 to 10% by weight. For this injection,
For adults, 0.1 to 10 mg as an active ingredient per day is administered.

Furthermore, the compound of the present invention has low toxicity. For example, each compound of Examples 11, 12, and 15 described below is orally administered to mice by oral administration.
LD ₅₀ is> 500 mg / kg.

Next, the production method of the compound of the present invention will be illustrated by examples, and the usefulness of the compound will be illustrated by test examples, but the present invention is not limited thereto.

Example 1a 4-Amino-6-chloro-2,3-cyclopentenopyridine (Compound 1a) Example 1b 4-amino-5,6-dichloro-2,3-cyclopentenopyridine (compound 1b) 4-amino-6-hydroxy-2,3-cyclopentenopyridine [refer to the above-mentioned "JACS" 71 , 2205 (1949)]
(1.8 g), post-phosphorus chloride (6.24 g) and phosphorus oxychloride (105 ml)
And heat in a sealed tube at 120 ° C for 20 hours. The reaction solution is concentrated under reduced pressure, toluene is further added, and the mixture is concentrated again. The residue is dissolved in methanol (150 ml), water (100 ml) is added, and the mixture is stirred at room temperature overnight, and then methanol is distilled off. After adding ethyl acetate, sodium hydrogen carbonate is added to adjust the pH to 8. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated, and the residue was purified by a silica gel column (developed with chloroform) to obtain 94 mg of the less polar compound 1a and 14 mg of the higher compound 1b.
1 mg was obtained.

Compound 1a and compound 1b are both pale yellow crystalline powders.

Compound 1a: ¹ H-NMR (CD ₃ OD) δ: 2.11 (2H, m), 2.69 (2
H, t), 2.82 (2H, t), 6.37 (1H, s) Compound 1b: ¹ H-NMR (CD ₃ OD) δ: 2.15 (2H, m), 2.77 (2H, m)
H, t), 2.83 (2H, t) Example 2 4-Amino-6- (4-methylpiperazine-
1-yl) -2,3-cyclopentenopyridine The compound of Example 1a (820 mg) is dissolved in pyridine (30 ml), acetic anhydride (10 ml) is added, and the mixture is left at room temperature for 3 days.
The reaction solution is concentrated under reduced pressure, and the residue is subjected to a silica gel column (developing solvent, chloroform to chloroform: methanol = 3.
0: 1) and purified by 4-acetamino-6-chloro-2,3-
Cyclopentenopyridine (890 mg) was obtained. Then, this product (44 mg) was added to 1-methylpiperazine (0.5 ml) in a sealed tube, and
Heat at 60 ° C. for 2 days. After cooling, water is added, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dehydrated and concentrated. The residue was purified by silica gel chromatography (chloroform: methanol =
10: 1 to 5: 1) to give 20 mg of the title compound as a pale brown crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.07 (2H, m), 2.34 (3H, s), 2.5
2 (4H, m), 2.65 (2H, t), 2.84 (2H, t), 3.44 (4H,
m), 3.88 (2H, br.s), 5.72 (1H, s) Example 3 4-amino-6-benzylamino-2,3-cyclopentenopyridine The compound of Example 1a and benzylamine (2 ml) are heated in a sealed tube at 180-195 ° C for 24 hours. Hexane and ether were added, the insolubles were collected by filtration, and purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain 75 mg of the title compound as a yellow oily substance.

Examples 4 and 5 The following two compounds were synthesized in the same manner as in Example 2 using the compound of Example 1b as a starting compound.

Example 4: 4-amino-5-chloro-6- (piperazine-
1-yl) -2,3-cyclopentenopyridine Brown crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (2H, m), 2.70 (2H, t), 2.8
8 (2H, t), 3.02 (4H, m), 3.20 (4H, m), 4.37 (2H, b
rs) Example 5: 4-Amino-5-chloro-6- (4-methylpiperazin-1-yl) -2,3-cyclopentenopyridine White crystalline powder ¹ H-NMR (CDCl ₃ ) δ: 2.13 (2H, m), 2.36 (3H, s), 2.5
9 (4H, m), 2.70 (2H, t), 2.87 (2H, t), 3.29 (4H,
m), 4.34 (2H, br.s) Example 6 4-amino-6-chloro-5-methyl-2,3
-Cyclopentenopyridine 4-amino-6-hydroxy-5-methyl-2,3-cyclopentenopyridine (see "JACS" above) (82
0 mg), add phosphorus pentachloride (1.2 g) and phosphorus oxychloride (1 ml), and heat in a sealed tube at 120 ° C. for 6 hours. After cooling, ice water (40m
l) was added and stirred at room temperature for 3 hours, and potassium carbonate was added to make the mixture alkaline. The mixture was extracted with ethyl acetate (insoluble matters were removed by filtration), and the ethyl acetate layer was washed with water, dehydrated (magnesium sulfate), and concentrated to give the title compound as pale yellow-green crystals.
5 mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.13 (2H, m), 2.18 (3H, s), 2.7
0 (2H, t), 2.88 (2H, t), 3.61 (2H, br.s) Examples 7 and 8 The following two compounds were prepared in the same manner as in Example 2 using the compound of Example 6 as a starting compound. Was synthesized.

Example 7: 4-Amino-5-methyl-6- (4-methylpiperazin-1-yl) -2,3-cyclopentenopyridine Pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.07 (3H, s), 2.11 (2H, m), 2.3
5 (3H, s), 2.56 (4H, m), 2,67 (2H, t), 2.89 (2H,
t), 3.10 (4H, m), 3.87 (2H, br.s) Example 8: 4-amino-6- {4- (2-hydroxyphenyl) piperazin-1-yl} -5-methyl-2, 3-cyclopentenopyridine Pale yellow crystals. ¹ H-NMR (D ₆ -DMSO + CD ₃ OD) δ: 1.99 (2H, m), 2.01 (3
H, s), 2.65 (2H, t), 2.72 (2H, t), 3.07 (8H, br.
s), 6.75-6.98 (4H, m) Example 9 4-Amino-6- (4-fluorophenylthio) -5-methyl-2,3-cyclopentenopyridine Compound of Example 6 (182 mg), 4-fluorothiophenol (0.5 ml), diisopropylethylamine (0.1 ml)
Is heated in a sealed tube at 140 ° C. overnight. After cooling, ethyl acetate is added, and the mixture is washed with a dilute aqueous sodium hydroxide solution and then with water.
After dehydration with magnesium sulfate, concentration, the residue was purified by silica gel column (chloroform: methanol = 50: 1),
230 mg of the title compound were obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.10 (2H, m), 2.20 (3H, s), 2.7
0 (2H, t), 2.89 (2H, t), 4.01 (2H, br.s), 6.90 (2
H, m), 7.28 (2H, m) Examples 10 to 15 Using the compound of Example 6 as starting compound, Example 9
The following six compounds were synthesized in the same manner as described above.

Example 10: 4-amino-6-benzylthio-5-methyl-
2,3-cyclopentenopyridine ¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H, s), 2.13 (2H, m), 2.7
0 (2H, t), 2.95 (2H, t), 3.89 (2H, br.s), 4.45 (2
H, s), 7.20 (1H, t), 7.27 (2H, t), 7.40 (2H, d) Example 11: 4-amino-6- (4-hydroxyphenylthio) -5-methyl-2,3 -Cyclopentenopyridine colorless crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.11 (2H, m), 2.20 (3H,
s), 2.71 (2H, t), 2.88 (2H, t), 6.73 (2H, d), 7.1
4 (2H, d) Example 12: 4-amino-6-[(3,5-di-t-butyl-
4-hydroxyphenyl) thio] -5-methyl-2,3-
Cyclopentenopyridine Pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (18H), 2.10 (2H, m), 2.25
(3H, s), 2.73 (2H, t), 2.90 (2H, t), 4.41 (2H, br.
s), 7.26 (2H, s) Example 13: 4-amino-6- (4-acetylaminophenylthio) -5-methyl-2,3-cyclopentenopyridine White crystalline powder. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.12 (3H, s), 2.13 (2H,
m), 2.21 (3H, s), 2.74 (2H, t), 2.88 (2H, t), 7.1
3 (2H, d), 7.43 (2H, d) Example 14: 4-amino-5-methyl-6-[(pyridine-
4-yl) thio] -2,3-cyclopentenopyridine Brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (2H, m), 2.23 (3H, s), 2.7
7 (2H, t), 2.98 (2H, t), 4.14 (2H, br.s), 6.97 (2
H, d), 8.32 (2H, d) Example 15: 4-amino-6- (4-aminophenylthio)
-5-methyl-2,3-cyclopentenopyridine pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 2.10 (2H, m), 2.19 (3H,
s), 2.69 (2H, t), 2.85 (2H, t), 6.61 (2H, d), 7.1
2 (2H, d) Example 16 4-Amino-5-methyl-2,3-cyclopentenopyridine Dissolve the compound of Example 6 (50 mg) in ethanol (1 ml) and add 10% Pd-C (15 mg) at room temperature. Under a normal pressure, catalytic reduction was performed for 5 hours to remove the chloro group at the 6-position. After addition of methanol, the catalyst is filtered off. The filtrate was concentrated to obtain 45 mg of the title compound as a hydrochloride as a white powder. ¹ H-NMR (D ₂ O) δ: 2.13 (3H, s), 2.25 (2H, m), 2.79
(2H, t), 3.05 (2H, t), 7.75 (1H, s) Example 17 6-Chloro-4,5-diamino-2,3-cyclopentenopyridine Phosphorus pentachloride (610 mg) and phosphorus oxychloride (1 ml) are added to 4,5-diamino-6-hydroxy-2,3-cyclopentenopyridine (410 mg), and the mixture is stirred at 160 ° C. for 15 hours in a sealed tube. Add ice water (50 ml), stir for 1 hour, and add 5N sodium hydroxide
Adjust the pH to 10. Extracted with ethyl acetate, washed with water, dehydrated with magnesium sulfate and concentrated to give the title compound as crystals, 340 mg
Obtained.

Brown crystalline powder. ¹ H-NMR (CDCl ₃ ) δ: 2.12 (2H, m), 2.70 (2H, t), 2.8
9 (2H, t), 3.40 (2H, br.s), 4.00 (2H, br.s) Example 18 4,5-Diamino-2,3-cyclopentenopyridine Using the compound of Example 17 Synthesized by catalytic reduction in the same manner as in Example 16.

Pale yellow powder. ¹ H-NMR (D ₂ O) δ: 2.26 (2H, m), 2.82 (2H, t), 3.03
(2H, t), 7.63 (1H, s) Examples 19 to 21 Using the compound of Example 17 as a starting compound, Example 9
The following three compounds were synthesized in the same manner as described above.

Example 19: 4,5-Diamino-6- (4-fluorophenylthio) -2,3-cyclopentenopyridine Light brown crystal. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (2H, m), 2.75 (2H, t), 2.9
3 (2H, t), 3.72 (2H, br.s), 3.89 (2H, br.s), 6.93
(2H, t), 7.18 (2H, q) Example 20: 4,5-Diamino-6- (4-hydroxyphenylthio) -2,3-cyclopentenopyridine ¹ H-NMR (D ₆ -DMSO) δ: 1.95 (2H, m), 2.64 (4H, m),
6.68 (2H, d), 7.07 (2H, d) Example 21: 4,5-Diamino-6- (3,5-di-tert-butyl-4-hydroxyphenylthio) -2,3-cyclopenteno Pyridine Pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (18H), 2.10 (2H, m), 2.73
(2H, t), 2.89 (2H, t), 4.01 (2H, br.s), 4.33 (2H,
br.s) Example 22 4-Amino-2-styrylquinoline A mixture of 4-amino-2-methylquinoline (948 mg), benzaldehyde (1.83 ml) and acetic anhydride (1.7 ml) was added to 1
Stir at 60 ° C. for 3.5 hours. After cooling, 1N sodium hydroxide (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was treated with 5N hydrochloric acid (15 ml)
And heat to reflux for 4 hours. After cooling, the precipitated hydrochloride is collected by filtration and stirred with concentrated aqueous ammonia (20 ml) at room temperature for 14 hours. The crystals were collected by filtration and recrystallized from 60% aqueous ethanol to obtain 680 mg of the title compound.

Yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.73 (2H, s), 6.89 (1H, s), 7.2
7 (1H, d), 7.3 to 7.46 (4H, m), 7.60 (2H, m), 7.62
(1H, d), 7.66 (1H, dd), 7.73 (1H, d), 8.02 (1H,
d) Examples 23 and 24 The following two compounds were synthesized in the same manner as in Example 22.

Example 23: 4-amino-2- (3,5-di-t-butyl-4
-Hydroxy) styrylquinoline Brown powder. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (18H), 4.73 (2H, s), 5.40
(1H, s), 6.89 (1H, s), 7.26 (1H, d), 7.51 (1H,
m), 7.63 (1H, d), 7.67-7.90 (4H, m), 8.08 (1H,
d) Example 24: 4-amino-3-methyl-2-styrylquinoline colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 4.65 (2H, s), 7.3
0 (1H, ddt), 7.33 to 7.43 (3H, m), 7.52 to 7.70 (5H,
m), 7.88 (1H, d), 8.01 (1H, d) Example 25 4-Amino-2- (N-methylcarbamoyl) quinoline (A) Ethyl 4-hydroxy-2-quinoline carboxylic acid 4-Hydroxy-2-quinoline carboxylic acid (50 g) was suspended in dimethyl sulfoxide (250 ml), and ethyl iodide (32 ml) and sodium hydrogen carbonate (44.5 g) were added. Stir at room temperature for 18 hours. Water (1) was added, and the precipitated crystals were collected by filtration, washed with water, and dried to give 53.5 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t), 4.49 (2H, q), 7.0
0 (1H, d), 7.39 (1H, dd), 7.46 (1H, d), 7.67 (1H, d
dd), 8.38 (1H, d), 9.20 (1H, br.s) (B) Ethyl 4-amino-2-quinolinecarboxylate A compound (21.7 g) was dissolved in acetonitrile (500 ml), and chlorosulfonyl isocyanate was dissolved. (10.4 ml) was added dropwise, and the mixture was heated under reflux for 1 hour. After cooling, a 10% ethanol solution of hydrochloric acid (500 ml) was added, and the mixture was stirred at room temperature for 2 hours.
After evaporating the solvent, water (200 ml) is added to the residue, and the mixture is washed with ethyl acetate. The aqueous layer is made alkaline with 1N sodium hydroxide and extracted with chloroform. The extract was washed with water and dried, and the solvent was distilled off to obtain 15.5 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, t), 4.53 (2H, q), 4.9
6 (2H, s), 7.43 (1H, s), 7.54 (1H, ddd), 7.71 (1H,
ddd), 7.79 (1H, d), 8.20 (1H, d) (C) A compound (4.32 g) of B was dissolved in a 40% aqueous solution of methylamine (40 ml), and the mixture was stirred at room temperature for 4 hours.
l) is added and the precipitate is extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained pale yellow solid was washed with a mixture of ether and ethyl acetate to obtain 3.58 g of the title compound of Example 25. ¹ H-NMR (CDCl ₃ ) δ: 3.08 (3H, s), 4.99 (2H, s), 7.3
1 (1H, ddd), 7.36 (1H, s), 7.48 (1H, ddd), 7.59 (1
H, d), 7.97 (1H, d), 8.30 (1H, br.s) Example 26 4-amino-2- (piperidin-1-yl-
Carbonyl) quinoline The title compound was obtained as colorless crystals by synthesizing the compound of Example 25 (B) in the same manner as in Example 25 (C). ¹ H-NMR (CDCl ₃ ) δ: 1.57 (2H, br.s), 1.70 (4H, br.
s), 3.51 (2H, m), 3.66 (1H, dd), 3.75 (1H, dd),
3.77 (2H, br.s), 3.99 (1H, d), 5.00 (2H, br.s), 6.
83 (1H, s), 7.46 (1H, dd) Test Example 1 Acetylcholinesterase inhibitory activity The acetylcholinesterase inhibitory activity of the compound of the present invention was measured by the following method.

A solution of the compound of the present invention in a reaction solution consisting of 100 mM phosphate buffer (pH 7.4) containing 1 mM 5,5'-dithiobis. (2-nitrobenzoic acid), 0.01% gelatin and 0.5 mM acetylthiolycon. And add acetylcholinesterase derived from electric eel to start the reaction (total amount of 10).
0μ). After reacting at room temperature for 30 minutes, the absorbance (a) at 405 nm was measured. At the same time, the absorbance (b) of the blind reaction solution containing no compound of the present invention was measured, and the acetylcholinesterase inhibition rate was calculated by the formula [(ba) / b] × 100. Table 1 shows the IC ₅₀ value (g / ml), which is the concentration of the compound of the present invention that inhibits acetylcholinesterase activity by 50%.

Test Example 2 Prolongation of Survival Effect of Decompressed Hypoxia-Loaded Mice Using 6 ddy mice per group, the compound of the present invention (suspended in a 1% aqueous solution of Tween so as to give a dose of 0.1 ml / 10 g) was used. It was intraperitoneally administered, and 30 minutes later, each animal was placed in a transparent sealed container, and the pressure was reduced to 190 mmHg by a vacuum pump. The time from the start of depressurization to the death of the mouse due to respiratory arrest was measured and defined as the survival time. The ratio of the survival time of the group to which the compound of the present invention was administered to the survival time of the control group to which a 1% aqueous solution of Tween was administered was determined and is shown in Table 2. Test compound: 30 mg
/ kg dose.

Test Example 3 5-Lipoxygenase inhibitory activity Rat basophilic leukemia cells (BRL-1) were transformed into Eagle's basal medium {Gibco Laboratorie
s) Suspend the cells in a culture solution containing 10% FCS and culture at 37 ° C in a 5% CO ₂ incubator. After collecting the cells by centrifugation and washing 2-3 times with phosphate buffered saline solution pH 7.4, the cells were washed with ice-cold 50 mM potassium phosphate buffer pH 7 containing 1 mM EDTA and 10% ethylene glycol. Float to .4. The cells are repeatedly sonicated at 20 KHz for 15 seconds twice while cooling on an ice bath, centrifuged at 17,000 × g for 30 minutes, and the supernatant is collected as a 5-lipoxygenase enzyme solution.

0.38 mM arachidonic acid, 0.1 M potassium phosphate buffer (pH
7.4), the above enzyme solution is added to a reaction solution comprising 2 mM ATP, 2 mM CaCl ₂ and a methanol solution of the compound of the present invention (total amount: 185 μm), and reacted at 37 ° C. for 5 minutes. 0.2M citric acid 1
Add 0μ to stop the reaction, and add the MCDP color developing solution [Lipid peroxide quantitative reagent reagent LPO (Kyowa Medix) second reagent] 2
Add 50μ. After reaction at 37 ° C for 20 minutes, centrifuge (4000
rpm, 10 minutes), and the absorbance (a) at 675 nm of the supernatant was measured. At the same time, the absorbance (b) of a blind reaction solution using only methanol not containing the compound of the present invention was measured, and the 5-lipoxygenase inhibition rate was calculated by the formula [(ba) / b] × 100. Table 3 shows the IC ₅₀ value, which is the concentration of the compound of the present invention that inhibits 5-lipoxygenase activity by 50%.

Test Example 4 Atrial Muscle Contractile Strength Enhancing Action The heart of an SD rat was excised, the right atrial muscle was cut off, fat tissues and blood vessels attached to the atria were cut off, and the right atrial muscle sample was saturated with 95% O ₂ + 5% CO ₂ . Was suspended in a Magnus tube filled with the prepared Krebs-Henseleit solution. 0.25g
After confirming that the contraction force has become constant,
Compounds of the invention dissolved in DMSO and diluted with purified water to a constant concentration were administered cumulatively until the increase in contractile force was maximal. The test compound concentration shrinkage force increases 30% as -log PIE ₃₀ described in Table 4.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07D 401/04 C07D 401/04 401/12 401/12 (72) Inventor Kiyoshi Yoshida Yokohama-shi, Kanagawa 760, Meiji Confectionery Co., Ltd., Pharmaceutical Research Institute, Meiji Seika Co., Ltd. (72) Inventor Akiko Shinohara 760, Meiji Confectionery Co., Ltd., Pharmaceutical Research Institute, Kohoku-ku, Yokohama, Kanagawa Prefecture (72) 760 Meijiokacho, Pharmaceutical Research Institute, Inc. (72) Inventor, Keiko Taniguchi 760 Mokaokacho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Meiji Confectionery Co., Ltd. 760 Meiji Seika Seiyaku Co., Ltd. (72) Inventor Takashi Tsuruoka 760 Meijikacho, Kohoku-ku, Yokohama-shi, Kanagawa Candy Co., Ltd. medicine comprehensive within the Institute (72) inventor Shigeharu Inoue Kohoku-ku, Yokohama Morooka-cho, 760 Meiji Seika Co., Ltd. Chemicals Research Institute in

Claims (4)

(57) [Claims] (1) The following formula (Ia) Wherein, Y ^a is a hydrogen atom, a halogen atom or a lower alkyl group of C ₁ ~C _6, Z ^a is a halogen atom, r is 1
4-amino-6-halo-2,
3-cyclopenteno or cyclohexenopyridine derivatives or pharmacologically acceptable salts thereof. 2. The following formula (Ib) Wherein, Y ^b represents a hydrogen atom, a lower alkyl group having a halogen atom or a C ₁ ~C _6, Z ^b is an amino group, an alkylamino group,
Benzylamino group, a piperazyl group or N- substituted piperazyl group, N- substituent on the N- substituted piperazyl group, a lower alkyl group of C ₁ -C _6, a phenyl group or a hydroxyphenyl group, r A 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ic): Wherein Y ^c is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, and Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group. substituents on the substituted phenyl group include a halogen atom, a hydroxyl group, C ₁ ~
One or two or more of the same or different types selected from a C ₆ lower alkyl group, an amino group and a C ₂ -C ₆ acylamino group, particularly a (C ₁ -C ₄ ) alkylcarbonylamino group And r is an integer of 1 to 2] and a 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Id) Wherein Z ^d is a hydrogen atom or a halogen atom or a formula -SQ
Wherein Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group, and the substituent on the substituted phenyl group is a halogen atom, a hydroxyl group, a C ₁ ~ C ₆ lower alkyl group, amino group and C ₂
Acylamino group -C _6, especially (C ₁ -C ₄₎ can one selected from among alkylcarbonyl amino group or the same or different kinds of two or more, r is 1-2 integer 4,5-diamino-6-substituted or unsubstituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ie): Wherein Y ^e is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, p is 1 or 2, Q ′ is a phenyl group or a substituted phenyl group, and a substituent on this substituted phenyl group Is one or two or more of the same or different types selected from a hydroxyl group and a lower alkyl group of C _{1 to} C ₆ ], and a 4-amino-2-substituted-quinoline derivative represented by the following formula: Equation (If) Wherein, Y ^f is a hydrogen atom or a lower alkyl group of C ₁ ~C _6, T is (C ₁ ~C ₄₎ alkylamino group or piperidine -
4-amino-2-substituted-
4-amino- selected from the group consisting of quinoline derivatives
2,3-cycloalkenopyridine derivatives or 4-aminoquinoline derivatives, or pharmacologically acceptable salts thereof. 3. The following formula (Ia): Wherein, Y ^a is a hydrogen atom, a halogen atom or a lower alkyl group of C ₁ ~C _6, Z ^a is a halogen atom, r is 1
4-amino-6-halo-2,
3-cyclopenteno or cyclohexenopyridine derivative; the following formula (Ib) Wherein, Y ^b represents a hydrogen atom, a lower alkyl group having a halogen atom or a C ₁ ~C _6, Z ^b is an amino group, an alkylamino group,
Benzylamino group, a piperazyl group or N- substituted piperazyl group, N- substituent on the N- substituted piperazyl group, a lower alkyl group of C ₁ -C _6, a phenyl group or a hydroxyphenyl group, r A 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ic): Wherein Y ^c is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, and Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group. substituents on the substituted phenyl group include a halogen atom, a hydroxyl group, C ₁ ~
One or two or more of the same or different types selected from a C ₆ lower alkyl group, an amino group and a C ₂ -C ₆ acylamino group, particularly a (C ₁ -C ₄ ) alkylcarbonylamino group And r is an integer of 1 to 2]; a 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Id): Wherein Z ^d is a hydrogen atom or a halogen atom or a formula -SQ
Wherein Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group, and the substituent on the substituted phenyl group is a halogen atom, a hydroxyl group, a C ₁ ~ C ₆ lower alkyl group, amino group and C ₂
Acylamino group -C _6, especially (C ₁ -C ₄₎ can one selected from among alkylcarbonyl amino group or the same or different kinds of two or more, r is 1-2 integer 4,5-diamino-6-substituted or unsubstituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ie): Wherein Y ^e is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, p is 1 or 2, Q ′ is a phenyl group or a substituted phenyl group, and a substituent on this substituted phenyl group Is one or more selected from the group consisting of a hydroxyl group and a C ₁ -C ₆ lower alkyl group, or two or more of the same or different types.] 4-amino-2-substituted-quinoline derivatives; Equation (If) Wherein, Y ^f is a hydrogen atom or a lower alkyl group of C ₁ ~C _6, T is (C ₁ ~C ₄₎ alkylamino group or piperidine -
4-amino-2-substituted-
An agent for improving cerebral dysfunction, comprising a quinoline derivative or a pharmacologically acceptable salt of these derivatives as an active ingredient. 4. The following formula (Ia) Wherein, Y ^a is a hydrogen atom, a halogen atom or a lower alkyl group of C ₁ ~C _6, Z ^a is a halogen atom, r is 1
4-amino-6-halo-2,
3-cyclopenteno or cyclohexenopyridine derivatives; (Ib) Wherein, Y ^b represents a hydrogen atom, a lower alkyl group having a halogen atom or a C ₁ ~C _6, Z ^b is an amino group, an alkylamino group,
Benzylamino group, a piperazyl group or N- substituted piperazyl group, N- substituent on the N- substituted piperazyl group, a lower alkyl group of C ₁ -C _6, a phenyl group or a hydroxyphenyl group, r A 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ic): Wherein Y ^c is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, and Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group. substituents on the substituted phenyl group include a halogen atom, a hydroxyl group, C ₁ ~
One or two or more of the same or different types selected from a C ₆ lower alkyl group, an amino group and a C ₂ -C ₆ acylamino group, particularly a (C ₁ -C ₄ ) alkylcarbonylamino group And r is an integer of 1 to 2]; a 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Id): Wherein Z ^d is a hydrogen atom or a halogen atom or a formula -SQ
Wherein Q is a phenyl- (C ₁ -C ₄ ) alkyl group, a phenyl group, a substituted phenyl group or a pyridyl group, and the substituent on the substituted phenyl group is a halogen atom, a hydroxyl group, a C ₁ ~ C ₆ lower alkyl group, amino group and C ₂
Acylamino group -C _6, especially (C ₁ -C ₄₎ can one selected from among alkylcarbonyl amino group or the same or different kinds of two or more, r is 1-2 integer 4,5-diamino-6-substituted or unsubstituted-2,3-cyclopenteno or cyclohexenopyridine derivative represented by the following formula (Ie): Wherein Y ^e is a hydrogen atom or a C ₁ -C ₆ lower alkyl group, p is 1 or 2, Q ′ is a phenyl group or a substituted phenyl group, and a substituent on this substituted phenyl group Is one or more selected from the group consisting of a hydroxyl group and a C ₁ -C ₆ lower alkyl group, or two or more of the same or different types.] 4-amino-2-substituted-quinoline derivatives; Equation (If) Wherein, Y ^f is a hydrogen atom or a lower alkyl group of C ₁ ~C _6, T is (C ₁ ~C ₄₎ alkylamino group or piperidine -
4-amino-2-substituted-
A therapeutic agent for heart failure, comprising a quinoline derivative or a pharmacologically acceptable salt of these derivatives as an active ingredient.