JPH0466571A - Improver for brain and heart functional disorder - Google Patents

Abstract

NEW MATERIAL:A 4-amino-2,3-cycloalkenopyridine expressed by formula I [A is alkylene expressed by formula (n is 3-5) which can be bonded to adjacent two carbons of adjacent pyridine to form one cycloalkeno; when A forms cycloalkeno, Y is H, halogen, 1-4C alkyl, etc. and Z is H, OH, halogen, pyrrolidyl, etc.] and 4-aminoquinoline derivative or salt thereof. EXAMPLE:4-Amino-6-chloro-2,3-cyclopentenopyridine. USE:A medicine. Cerebral functional disorder improver and remedy for heart failure, capable of exhibiting acetylcholinesterase inhibiting action, 5- lipoxygenase inhibiting action, etc. PREPARATION:A pyridine derivative expressed by formula III (D is H or lower alkyl, etc.) is reacted with phosphorus halide and then reacted with a compound expressed by the formula Z-H (Z' is not H) to provide the aminopyridine expressed by formula I (Y is halogen, lower alkyl, etc.).

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel compound useful as a pharmaceutical and its pharmaceutical use. More specifically, the present invention relates to novel 4-amino-2,3-cycloalkenobiridine and 4-aminoquinoline derivatives and agents for improving brain dysfunction and cardiac dysfunction containing these as active ingredients. [Prior art and the problem to be solved by the present invention] A decrease in acetylcholine in the brain is observed in senile dementia, especially in Alzheimer's disease, and this can be reversed by administration of a cholinesterase inhibitor with low cholinergic function. Nine treatments have been attempted, and physostigmine (
"Neurology" vol. 8, p. 397, 1978)
and 9-amino-tetrahydroacridine derivatives (JP-A-61-148154.63-16681163-23
No. 9271) etc. are known. In addition, in clinical trials, 9-amino-1, which has cholinesterase inhibitory activity,
There is also a report that 2,3,4-te1-lahydroacridine (-name: tacrine) is effective for Alzheimer's disease when administered in combination with lecithin (New England Journal of Medicine, 315). Vol., p. 1241, 1986), but its effectiveness as an anti-dementia drug cannot be said to be 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, the emergence of a new senile dementia therapeutic agent having cholinesterase inhibitory activity is desired. Senile dementia is said to be caused by disorders of brain function caused by cerebrovascular disorders and disorders of energy metabolism in the brain. Conventionally, various drugs have been developed as anti-dementia drugs, but the mechanisms of development of senile dementia, memory impairment caused by cerebrovascular disorders, and the mechanism of the occurrence of memory impairment are still unclear. The current situation is that this has not been done. In general, the brain tissue of mammals, especially humans, has a higher demand for oxygen than other organ tissues, so it is said that the brain is extremely sensitive to oxygen deficiency conditions caused by cerebral ischemia, etc. be exposed. Therefore, compounds that have the effect of protecting the brain from anoxia (blood and oxygen deficiency) that occurs in the brain due to cerebral ischemia, etc., and oxygen-deficient conditions in the brain are useful as agents for improving brain dysfunction. Using model mammalian mammals with cerebral anoxia induced by exposure to oxygen-deficient conditions at low or normal pressures, i.e., by exposure to oxygen-deficient conditions, survival time of animals placed under oxygen-deficient conditions Therefore, attempts are being made to develop compounds that are recognized to be effective in improving cerebral circulation and metabolism or intracerebral energy metabolism (for example, ``Meyakuritsume'', Sen, pp. 323-328).
I985) ; Same magazine, pp. 86, 445-456 (] 986
); see JP-A-54-117468 and its corresponding US Pat. No. 4,369,139). In addition, in an animal model of subarachnoid hemorrhage using dogs,
Of the basilar artery! Although 5-lipoxygenase is observed to be clearly activated in small blood vessels, 5-lipoxygenase activity is not detected in the basilar artery of normal dogs, and It is known that when administered to drugs that exhibit oxidizing effects, the activity of 5-lipoxygenase and the relaxation of blood vessel lines are increased (Watanabe et al., Neurochem, J.
50,]]44-1150 (+988) and the same magazine 51.
1126-1.131 (I988), and Shimizu et al. "Proteins, Nucleic Acids, Enzymes J 35 (/I), 546-560 (
I990) #Sho). Furthermore, it is known that the in-vivo metabolic products of 5-lipoxygenase cause not only bronchial asthma, allergic diseases, and inflammatory diseases, but also ischemic heart disease, arteriosclerosis, and ischemic brain damage in the circulatory system. It is being On the other hand, 4-amino-2-hydroxy-6゜7- represented by the following general formula [wherein R is hydrogen, chlorine, methyl group or acetyl group]
dihydropyrindin
e) It is known that derivatives can be synthesized by cyclization by intramolecular condensation of 2-(acylimino)-cyclopentane carbonitrile and are represented by the following formula [where term 8 represents a benzene ring or a cyclohexene ring]. -Aminocarbostyryl or 4-amino-2-hydroxy-tetrahydroquinoline is known (rJ, Am, Chew, Soc,, J 71
．． 2205-2209 (see I949)), but there is no description of the biological activity of each compound of formula (a) and formula (b) in the above-mentioned literature. In recent years, due to the increase in the aging population, medical problems for the elderly have been greatly focused on, and there has been a strong desire for effective therapeutic agents for brain dysfunction. In addition to the objective of providing a therapeutic agent, another objective of the present invention is to provide a therapeutic agent for heart failure in the field of heart disease. [Means for Solving the Problem] In view of the above object, the present invention has been made after repeated studies, and as a result,
Novel 4-amino-2, represented by the following general formula (I),
We have succeeded in creating 3-cycloalkenopyridine and 4-aminoquinoline derivatives, and these compounds have the desired acetylcholinesterase inhibitory activity, 5-lipoxygenase inhibitory activity, anti-anoxia effect in the brain, and enhancement effect on atrial muscle contractility. The present invention was completed by discovering that the present invention has the following properties. That is, in the first aspect of the present invention, when forming the following general formula (I), Y represents a hydrogen atom, a halogen atom, a lower alkyl group of C1 to CG, or an amino group. and Z is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group,
A group of the formula -NR1R2 (R1 and R2 may be the same or different and represent a lower alkyl group or a benzyl group),
Pyrrolidyl group, piperidyl group, piperazyl group, N-substituted piperazyl group, pyridyl group or the following formula [wherein A is the formula -(
C) represents an alkylene group of 12h (where n is an integer of 3 to 5), which is bonded to two adjacent carbon atoms of the adjacent pyridine nucleus to form one cycloalkeno group; , or A is a group that combines with two adjacent carbon atoms of the adjacent pyridine nucleus to form one benzene ring, and (I) A is a cycloalkeno group (in the formula, B is oxygen atom or sulfur atom, m is O
R3, R4, and R' may be the same or different and represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a linear or branched (01 to
C, , ) represents a lower alkyl group, amino group, or acylamino group) or Z represents a pyridylthio group, and (n) when A forms a benzene ring, Y
represents a hydrogen atom or a lower alkyl group of C~CG, and 2 represents a formula -CONR' R7 (wherein R6 and R7 each represent a hydrogen atom or a lower alkyl group of 01~C6,
Alternatively, R'' and R7 jointly form a C1-C6 cycloalkyl group), or 2 represents a group of the formula (wherein E is an alkylene group of 02-C1 or a group of the formula (CH=
CH) represents a group of 7 (where p represents 1 or 2),
The present invention provides 4-amino-2,3-cycloalkenopyridine and 4-aminoquinoline derivatives and salts thereof, represented by the following formula: R3, R4 and RS have the above-mentioned meanings. The salts of the compound of general formula (I) according to the present invention include the basic group of the compound, that is, the nitrogen atom in the pyridine nucleus to the amino group at the 4-position, or the substituents Y and X that are basic. a pharmacologically acceptable compound added to a compound of formula (I) with

[There are acid addition salts with acids. -Sailor (I)
Examples of addition salts of the compound and the above-mentioned pharmacologically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Inorganic acids such as nitric acid, and formic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid,
Examples include addition salts with organic acids such as maleic acid, benzoic acid, salicylic acid, and methanesulfonic acid, as well as amino acids such as aspartic acid and glutamic acid. - The compound of the present invention, represented by Funato (I), basically belongs to acetylcholinesterase inhibitors targeted at dementia, especially Alzheimer's disease, but it also has an anti-anoxia effect on the brain. The compound of the present invention is a novel derivative characterized by having both cholinergic activity and 5-lipoxygenase inhibitory activity.In other words, the compound of the present invention has the effect of activating cholinergic nerve function, as well as reducing ischemia and other causes of brain dysfunction. It exhibits a protective effect on the brain against oxygen conditions, that is, an anti-anoxia effect in the brain, and exerts a protective effect on brain function in these respects.In addition, the compound of the present invention has inhibitory activity against 5-lipoxygenase, so the compound of the present invention is suitable for use in brain disease areas. It is also expected to be used as a therapeutic agent for cerebral arteriosclerosis and ischemic brain dysfunction.6 In other words, the present invention is useful as an agent for improving Alzheimer's type senile dementia, cerebrovascular dementia, sequelae of cerebrovascular disorders, and various symptoms associated therewith. The present invention provides a novel specific compound.The compound of the general formula (I) of the present invention exhibits acetylcholinesterase inhibitory activity, anti-anoxia activity, and 5-lipoxygenase inhibitory activity, and is effective in clinically treating Alzheimer's type senile dementia and cerebral senile dementia. It is useful for the treatment of vascular dementia, etc., and as an ameliorating drug for various symptoms thereof.Furthermore, the compound of the present invention represented by -Funenin (I) has an effect of increasing the contractile force of the heart, that is, a positive inotropic effect. (inotr
(opie action) and increase cardiac contractility;
It is also useful as a cardiotonic agent that improves cardiac function, and can also be used as a heart failure treatment for heart disease. When A in the general formula (I) representing the compound of the present invention is a cycloalkyl group, when the group Y represents a halogen, the halogen atom includes fluorine, chlorine, bromine, and iodine, and the group Y is a lower alkyl group. Examples of the 01-C5 lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, and isoamyl groups. Also, -Z in Shipman (I)
represents a halogen, and examples of the lower alkyl group of R1 and R2 in the group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl group, etc., and examples of the N-fPj-substituted piperazyl group include N-methylpiperazyl group, N-(0
-hydroxy)phenylpiperazyl group, N-(p-)0
0) Phenylpiperazyl group, N-(o-1~lyl)piperazyl group, etc. Further, the halogen atoms of R3, R4, and R5 of the group Z include fluorine, chlorine, bromine, and iodine atoms, and the lower alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy,
There are n-butoxy groups, etc., and linear or branched C□ to C
6 Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-amyl, and isoamyl groups, and examples of acylamino groups include acetylamino and benzoylamino groups. It will be done. Further, when A in formula (I) forms a benzene ring, the 01-C6 lower alkyl group in Y includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, isoamyl group, etc. can be mentioned. <CX~C of the group -CONR'R' as 2
G) Lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, isoamyl groups, etc.
CG) Alkylene groups include methylene, ethylene, propylene, butylene, pentylene groups, and the like. Preferred embodiments of the compounds of general formula (I) of the present invention include six groups of compounds represented by formulas (Ia) to (If) shown below. (I) The following formula [wherein Y is a hydrogen atom, a halogen atom, especially a chlorine atom, or a 01-C6 lower alkyl group, preferably a 01-C4
is an alkyl group, 2 is a halogen atom J, preferably a chlorine atom, and r is an integer of 1 to 2.
-Amino-6-halo 2,3-cyclopenteno or cyclohexenopyridine derivatives. (2) The following formula [wherein Y is a hydrogen atom, a halogen atom, especially a chlorine atom,
A C1 to CG lower alkyl group, preferably a C3 to C4 alkyl group, and Z is an amino group, an alkylamino group,
It is a benzylamino group, a piperazyl group or a to-substituted piperazyl group, and the substituent at N-1 on this N-[substituted piperazyl group is a lower alkyl group of 01 to Cs, a phenyl group or a hydroxyphenyl group, and r is 1 4-amino-6-substituted-2,3-cyclopenteno or cyclohexenopyridine derivatives] (3) The following formula can be two or more of different types, and r is 1 to 2.
4-amino-6-substituted-2,
3-Cyclopenteno or cyclohexenopyridine derivative. (4) The following formula [wherein, Y is a hydrogen atom or a C0 to C6 lower alkyl group, preferably a 01 to C4 alkyl group, and Q is a phenyl-(CX-C4) alkyl group, a phenyl group, a substituted phenyl group. or pyridyl group, and the substituents on the substituted phenyl group are halogen atoms, hydroxyl groups, 01-C6 lower alkyl groups, amino groups and 02-CG acylamino groups, especially Ccx-C4) alkylcarbonylamino groups. one or the same or [wherein 2 is a hydrogen atom or a halogen atom or the formula 5-Q (however, Q is the above formula (I
has the same meaning as Q in c), and r is 1
4,5-diamino-6-, which is an integer of ~2]
Substituted or unsubstituted 2,3-cyclopenteno or cyclohexenopyridine derivatives. (5) The following formula [wherein Y is a hydrogen atom or a 01-C6 lower alkyl group, preferably a C1-C4 alkyl group, P is] or 2, and Q' is a phenyl group or a substituted phenyl group and the substituents on this substituted phenyl group are hydroxyl group and 01
~CG lower alkyl group, preferably one selected from 01 to C4 alkyl groups, or two or more of the same or different types] 4-amino-2-it represented by
Replaced-quinoline derivatives. (6) In the following formula C, Y is a hydrogen atom or a lower alkyl group of C□ to C6, preferably an alkyl group of 01 to C4, and T is (C
4-amino-2-substituted-quinoline derivative represented by X-C4) alkylamino group or piperidin-1-yl group. Specific examples of the compound of formula (Ia) above include compounds of Example 1a, Example 1b, and Example 6 described below. Specific examples of the compound of the above formula (I b) include Example 2, Example 3, etc. described below. There are compounds of Example 4, Example 5, Example 7 and Example 8. Specific examples of compounds of formula (I c) include compounds of Examples 9.10.11.12.13.14 and I5 below. Specific examples of compounds of formula (Id) include Example 1 below.
There are 7.18.19.20 and 21 compounds. Specific examples of compounds of formula (Ie) include the compounds of Examples 22.23 and 24 below. Specific examples of compounds of formula (If) include the compounds of Examples 25 and 26 below. Next, the synthesis methods (A) and (B) of the compound represented by the general formula (I) of the present invention will be explained below, but the method is not limited to these methods. (A) When the compound of the present invention is 4-amino-2,3-cycloalkenopyridine The method described in the aforementioned "Journal of the American Chemical Society" Vol. 71, p. 2205 (I949) The following general formula (wherein,
n is an integer of 3 to 5, and D is a hydrogen atom. When a pyridone derivative represented by (representing a lower alkyl group or an amino group) is used as a starting compound and is reacted with a phosphorus halide, phosphorus bromide, phosphorus pentachloride, phosphorus pentabromide, etc. of the first general formula (I1) are obtained. is used. The reaction can be carried out in the presence or absence of a solvent, but preferably in the absence of a solvent.
The desired product can be obtained by carrying out the reaction at a temperature of ~200°C for 30 minutes to 24 hours. Also, two types of phosphorus halides can be used if the halogen atoms are the same. Next, at the 6-position halogeno group of the compound of general formula (I1), a compound represented by the following general formula (m) Z-H(m) (in the formula, 2 represents the above-mentioned meaning. However, 2 is not hydrogen) is added. If necessary, by reacting the compound in the presence of a base, a compound of the following general formula (where n has the same meaning as above, Y' is a halogen atom, a lower alkyl group, or an amino group, and X' represents a chlorine atom or a bromine atom)
, 6-cyhalogenopyridone derivatives are produced. As the phosphorus halide used in this halogenation reaction step, the compound of the present invention represented by phosphorus oxychloride, oxy [in the formula (2), Y' and Z have the above-mentioned meanings] can be synthesized. - Since there is a difference in reactivity between the 5th and 6th positions of the compound of Funato (I"), when the reactants of formula (III) are reacted in a substantially equimolar ratio, the 6th position is selectively Reacts.Bases include triethylamine, diisopropylethylamine,
Pyridine, 4-N,N-dimethylaminopyridine, 1.
Organic bases such as 8-diazabicyclo(5,4,0)-7-undecene, and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. can be used. The reaction is carried out in the presence or absence of a solvent that does not participate in the reaction.
The process is completed in 30 minutes to 24 hours at a temperature range of ~200°C. (B) When the compound of the present invention is a 4-aminoquinoline derivative (i) A compound in which Z is a group -CONR' R7 can be synthesized by the following method. That is, the following general formula (■) (in the formula,
A carboxylic acid compound represented by the following general formula (■) (wherein, Y has the above meaning, and R'' represents a lower alkyl group of 01 to C4) is esterified. The ester compound shown in the table is produced, and then the hydroxyl group at the 4-position is converted to an amino group, and the general formula (■) (in the formula,
A compound represented by Y and RI' have the above-mentioned meanings is produced. (IV) (V) (VI) Next, the 4-amino compound of general formula (VI) is hydrolyzed to remove the ester-forming alkyl group (R'') to form the corresponding free carboxylic acid type compound. The general formula (I3 )(
The compound of the present invention represented by the formula (wherein Y, R', and R7 have the above-mentioned meanings) can be synthesized. The first step of the above synthesis method is esterification ("New Experimental Chemistry Course" Volume 14, Synthesis and Reactions of Organic Compounds (n) 1000
You can use methods such as those described on page). Amination at the 4-position in the second step proceeds by reacting with chlorosulfonyl isocyanate and then treating with acid. The reaction with chlorosulfonyl isocyanate is completed in 30 minutes to 5 hours at 0 to 150°C in a solvent that does not participate in the reaction. Various acids can be used for the acid treatment, and conditions such as hydrochloric acid in ethanol at 0 to 100° C. for 1 to 10 hours can be selected. The reaction for producing the compound of formula (I3) by amidation in the third step proceeds in the presence or absence of a solvent that does not participate in the reaction. The reaction temperature is 0 to 150°C and the reaction proceeds for 1 to 48 hours. The compound of the general formula (I) represents a group -+CH=C)Ih, and R3, R4, R5 have the above-mentioned meanings,
The compound represented by the general formula (■) has the general formula (IX) (wherein R″, R4, R5, and p represent the above meanings)
An aldehyde compound represented by 10 with an acid anhydride
After reacting at a temperature of 0 to 200°C for 1 to 24 hours, and then treating with an acid at 50 to 150°C for 11 to 12 hours, the following general formula (I4) (wherein Y, R3, R4, RS and P are A compound of the present invention having the above meaning can be produced. The compound of general formula (I) synthesized by the following method can be purified by conventional purification methods, such as crystallization, precipitation, solvent extraction, column chromatography, etc. The compound represented by the above-mentioned shipman (I) of the present invention may be administered alone, but if necessary or desired, other conventional pharmacologically acceptable carriers, excipients, and diluents may be used. The desired dosage form can be prepared by mixing with the drug and administered orally. In this case, for adults, 5 to 500 μl of the compound represented by formula (I) is usually administered per 111 μl. Administered by injection
j Sudame solution (well, pharmaceutically active compound Y + volume
2. The preferred water-soluble salt obtained is 17<0.5% to 10%
It can be obtained by dissolving it in a water faucet at a concentration of . For this injection,
Administer 0.1 to 10@g of the active ingredient per adult. Furthermore, the compounds of the present invention have low toxicity, for example, 14D when each compound of Examples 11, 12, and 15 described below is administered orally to mice. B〉500■/kg. Next, the method for producing 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. 4-amino-6-chloro-2,3-cyclopentenopyridine (compound 1a) 4-amino-5,6-dichloro-2,3-
Cyclopentinoviridine (compound) b) 4-Amino-6-hydroxy-2,3-cyclopentinoviridine [rJ, A, C, S, Jヱ mentioned above]-1220
5 (I949)] (I, 8 g), phosphorus pentachloride (6,2
4 g) in phosphorus oxychloride (I05++Q) and heated in a sealed tube at 120° C. for 20 hours. Reduced pressure 1: Concentrate the reaction solution, add toluene, and concentrate again. The residue was dissolved in methanol (I50 mg), water (I00 mg) was added, and the mixture was stirred overnight at room temperature, and then methanol was distilled off. After adding ethyl acetate, add sodium bicarbonate to bring the pH to 8. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated,
The residue was purified using a silica gel column (developed with chloroform) to obtain 94 μ of less polar compound 1a and 141 μ of higher polar compound 1b. Compound 1) and Compound 1b are both pale yellow crystalline powders. Compound 1a: “H-NMR (CD301)) δ:
2.1] (2H, +n), 2.69 (2H, t'), 2
．． 82 (2H, t), 6.37 (IH, s) Compound 1b
: 1H-NMR (CD, OD) δ: 2.15 (2
8,n), 2.77(21-1,t),, 2.83
(2)1. t,) A tiger example? 4-Ami8-6-(4-methylbiperazinol)-2,3-cyclopentenopyridine The compound of Example 1a (820 mg) was dissolved in pyridine (3
Dissolve in solution (I0mQ), add acid anhydride (I0mQ), and leave at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was purified using a silica gel column (developing solvent: chloroform-chloroform:methanol = 30:1) to give 4-acetamino-6-chloro-2,:3-cyclopentenopyridine (8
90■) was obtained. Next, this section (44IIg) was heated with 1-methylbiperazine (0.5 mU) at 160 °C for 2 days in a sealed tube. After cooling, water was added, extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dehydrated, and concentrated. .Silica gel chroma 1
-(Chloroform:methanol-10:1-5:]) to obtain 20 μl of the title compound as a light brown crystalline powder. 1) 1-NM! ((CDC1,)δ:2.07(2H,
l++), 2.34 (3tl, sL 2.52 (441
, m), 2.65 (2H, t), 2.84 (2H, t,
), 3.44 (4H, m), 3.88 (2H, br, s
), 5.72 (LH, s) m4-amino-6-benzylamino-2,3-cyclopentinoviridine The compound of Example 1a and benzylamine (2 companies) were heated at 180 to 195°C for 24 hours in a sealed tube. Heat for an hour. Hexane and ether were added, insoluble matter was collected by filtration, and the mixture was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain 75 μl 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-(piperazin-1yl)-2,3-cyclopentenopyridine brown crystalline powder. "H" NMR (CDCl2) δ: 2.14 (2H,
m), 2.70(2)1. t), 2.88 (2H, t)
, 3.02 (4H, m), 3.20 (4H, m), 4.
37(2H,br,s) Example 5: 4-Amino-5-chloro-6-(4-methylpiperazin-1-yl)-2,3-cyclopentenopyridine white crystalline powder 1H-NMR (CDCl2 ) δ: 2.13 (2) 1.
m), 2.36(3)1. s), 2.59 (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 Add phosphorus pentachloride (I, 2g) and phosphorus oxychloride (I+R) to -2,3-cyclopentenopyridine (see rJ, A, c, sJ above) (820■) and heat the mixture to 2,3-cyclopentenopyridine (see rJ, A, c, sJ above) (820■) in a sealed tube at 120°C. Heat for 6 hours. After cooling, ice water (40 mu) was added, and the mixture was stirred at room temperature for 3 hours, and potassium carbonate was added to make it alkaline. Extract with ethyl acetate and remove insoluble matter by filtration), wash the ethyl acetate layer with water,
After dehydration (magnesium sulfate) and concentration, 745 ml of the title compound was obtained as pale yellow-green crystals. 1H-NMR (CDC1,) δ: 2.13 (2H, m
), 2.18 (3H, s), 2.70 (2H, t), 2
．． 88 (2H, t), 3.61 (2H, br, s) Examples 7 and 8 The following two compounds were synthesized in the same manner as in Example 2 using the compound of Example 6 as a starting compound. Example 7: 4-Amino-5-methyl-6-(4-methylpiperazin-1-yl)-2,3-cyclopentenopyridine pale yellow crystalline powder. "H-NMR (CDCl2) δ: 2.07 (3H,
S), 2.11 (2Lm), 2.35 (3H,s), 2
．． 56 (4H, m), 2.67 (2H, t), 2.89
(2H, t), 3. ]0(4H,n), 3.87(2H
, br, s) Example 8: 4-amino-6-(4-(2-hydroxyphenyl)piperazin-1-yl)-5-methyl-2,3
- Cyclopentenopyridine pale yellow crystals. H-NMR (D, -DMSO+CD30D) δ: 1.
99 (2H, m), 2.01 (3t (, s), 2.65
(2H, t), 2.72 (2H, t), 3.07 (81
(, br, s), 6.75-6.98 (4H, m):!
1. ．． ．． u 4-Amino-6-(4-fluorophenylthio)5-methyl-2,3-cyclopentinoviridine Compound of Example 6 (I82 mg), 4-fluorothiophenol (L5ml), diisopropylethylamine (
0,] mR) in a sealed tube at 140° C. overnight. After cooling, add ethyl acetate and wash with dilute aqueous sodium hydroxide solution and then with water. After dehydration with magnesium sulfate, it was concentrated and the residue was deposited on a silica gel column (chloroform:methanol-5
0:]) to form colorless crystals, the Sakuraki compound was purified with 23
I got 0■. ' H-NMR (CDCI3) δ: 2.1O (2H, m
), 2.20(3t(,s), 2.70(2H,t)
, 2.89 (2+1.t), 4.01 (2H, br, s
), 6, 90 (2H, m), 7, 28 (2H,
m) Examples 10 to 15 Using the compound of Example 6 as a starting compound, six kinds of compounds of F were synthesized in the same manner as in Example 9. Example 10: 4-amino-6-benzylthio-5-methyl-2°3-cyclopentenopyridine' Fl-NMR (CDCI3) δ: 2.06 (3H,
s), 2.13 (2H, m), 2.70 (2H, t),
2.95 (2H, t), 3.89 (2H, br, s),
4.45 (2H, s), 7.20 (IH, t), 7.2
7 (2H, t), 7.40 (2H, d) Example 11:4
-amino-6-(4-hydroxyphenylthio)-5-
Methyl-2,3-cyclopentinoviridine colorless crystals. ”H-NMR(CI)C13+CD□OD)δ: 2
．． 11 (211, m), 2.20 (3H, s), 2.7
1(2H,t)-2,88(2)1. t), 6.73(
2H,d), 7.14 (2H,d) Example 12: 4-amino-64(3,5-di-t-butyl-4-hydroxyphenyl)thio]-5-methyl-2°3-cyclo Pentenopyridinyl)thio)-2,3-cyclopentinoviridine pale yellow crystalline powder. ” Old NMR (CDCQ, ') δ: 1.39 (I8
1 (), 2.10 (2H, m), 2.25 (3H, s)
, 2.73 (2H, t), 2.90 (2H, t), 4.
41(2)1. br, s), 7J6 (:14.s) Example 13: 4-Amino-6-(4-acetylaminophenylthio)-5-methyl-2,3-cyclopentenopyridine White crystalline powder. 'I(-NMR(CDCI,+CD300)δ:
2.12(3)1. s), 2.13 (21-1, m),
2.2] (3H, s), 2.74 (2H, t), 2.
88 (2H, t), 7.13 (2) 1. d), 7.43
(211, d) Example +4: /I-amino-5-methyl-6-[(pyridine-4 brown crystals.
), 2.23 (3H, s), 2.77 (2) 1. t),
2.98 (2H, t), 4.14 (2t+, br, s)
, 6.97 (2H, d), 8.32 (2N, d) Example +5: 4-amino-6-(4-aminophenylthio)5-methyl-2,3-cyclopentenopyridine pale yellow crystals sex powder. 1H-to'MR (CDCI 3+CD, 0I)) δ
: 2.10 (2H, m), 2.19 (3H, s
), 2.69 (2H, t) - 2,85 (2H, t), 5
．． 61 (2)1. d), 7.12 (2H, d) Osei-
Example-Kon 4-amino-5-2methyl-2,3-cyclopentenopyridine The compound of Example 6 (50 mg) was added to ethanol (Im+Q
) and subjected to catalytic reduction with 10% Pd-C (I5 mg) at room temperature and atmospheric pressure for 5 hours to remove the chloro group at the 6-position. After adding methanol, the catalyst is filtered off. Concentrate the filtrate to obtain 45 mg of the title compound as a hydrochloride salt as a white powder.
Obtained. ” H-NMR (D20) δ: 2.13 (3H, s)
, 2.25 (2H, m), 2.79 (2H, t), 3.
05 (2H, t), 7.75 (IH, s) Example 17 Rhochloro 4,5-diamino-2,3-cyclopentenopyridine 4.5-diamino-6-hydroxy-2,3-cyclopenteno Pyridine (410 mg) and phosphorus pentachloride (610 mg)
) and phosphorus oxychloride (I++U) and stirred in a sealed tube at 160°C for 15 hours. Add ice water (50+++Q) and stir for 1 hour, and adjust the pH to 10 with 5N sodium hydroxide. Extract with ethyl acetate. , washed with water, dehydrated with magnesium sulfate, and concentrated to obtain 340+I1 g of the title compound as crystals. Brown crystalline powder. "H-NMR (CDC1x) 8: 2.12 (2H
, +a), 2.70 (2H, t), z-g9 (2H, t
), 3.40 (28, br, s), 4.00 (2) 1.
br, s) Example 18 4,5-diamino-2,3-cyclopentenopyridine Synthesized by catalytic reduction in the same manner as in Example 16 using the compound of Example I7. Pale yellow powder. 1H-NMR (D20) δ: 2.26 (2H, ++)
, 2.82 (2H, t), 3.03 (2H, t), 7.
Example 9 Using the compound of Example 17 as the starting compound,
The following three compounds were synthesized in the same manner as above. Example 19: 4,5-diamino-6-(4-fluorophenylthio)-2,3-cyclopentenopyridine light brown crystals. 1H-NMR (CDCI, )δ: 2.14(2)1
．． m), 2.75(2)1. t), 2.93 (2H, t
), 3.72 (21 (, br, s), 3.89 (2H,
br, s), 6.93 (2H, t), 7.18 (2H,
(I) Example 20: 4,5-diamino-6-(4-hydroxyphenylthio)-2,3-cyclopentenopyridine 1H-NMR (DG-DMSO) δ: 1.95 (2H
, m), 2.64 (4H, m), 6.68 (2) 1. d
), 7.07(2)1. d) Example 21: 4.5-
Diamino-6-(3,5-di-t-butyl-4-hydroxyphenylthio)-2,3-cyclopentenopyridine pale yellow powder. 1H-MR (CDCI3) δ: 1.35 (I8H),
2.10 (2H, m), 2.73 (2N, t), 2.8
9(2)1. t), 4.01 (28, br, s), 4.
33(2H,br,s)Example 224-amino Y-2-
Styrylquinoline 4-amino-2-methylquinoline (9
48mg), benzaldehyde (I,83+n12)
, acetic anhydride (I, 7mQ) at 160°C 3.
Stir for 5 hours. After cooling, IN sodium hydroxide (]O
mQ) was added, 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 mixed with 5N salt # (I5I
Add Ilρ) and heat under reflux for 4 hours. After cooling, the precipitated hydrochloride was collected by filtration and mixed with concentrated ammonia water (20 mΩ) at room temperature.
Stir for 4 hours. The crystals were collected by filtration and recrystallized from 60% aqueous ethanol to obtain 680 mg of the title compound. Yellow crystal. 'H-NMR (CDCI3) δ: 4.73 (2H,
S), 6.89 (IH, s), 7.27 (IH, d),
7.3-7.46 (4H, m), 7.60 (2H, m)
, 7.62 (l) I, d), 7.66 (IH, dd),
7.73<IH, d), 8.02 (IH, d) Example 2
3.24 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 round % i fresh 25 4-amino-2-(N-methylcarbamoyl)quinoline brown powder. 'H-NMI((CDCI3)δ: 1.45(I8
)1), 4.73 (2H, s), 5.40 (IH, s)
, 6.89 (IH, s), 7.26 (I) 1. d), 7
．． 51 (IH, +11), 7.63 (I1 (, d), 7
．． 67-7.90 (4H, m), 8.08 (IH, d)
Example 24: 4-amino-3-methyl-2-styrylquinoline colorless crystals. ' H-NMR (CDCI3) δ: 2,39 (3H,
S), 4.65 (2H, s), 7.30 (Itl, dd
t), 7.33-7.43<3H,m), 7.5
2-7.70 (5H, m), 7.88 (IH, d), 8
．． 01 (IH, d) (A) Ethyl 4-hydroxy-2-quinolinecarboxylic acid 4-hydroxy-2-quinolinecarboxylic acid (50g) was sSed in dimethyl sulfoxide (250mR), and ethyl iodide (32mΩ) and hydrogen carbonate were added. Sodium (44.5g
) and stirred at room temperature for 18 hours. Add water (IQ),
The precipitated crystals were collected by filtration, washed with water, and then dried to obtain 53.5 g of the title compound. 'H-1 morning R (CDCI3) δ: 1.45 (:utl
, t), 4.49 (2H, Q), 7.00 (IH
, d), 7.39 (IH, dd), 7.46 (IH, d
), 7.67 (H+, ddd), 1'l, 38 (], H
, d), 9.20 (IH, br, 5) (B) Ethyl 4-
Amino-2-quinolinecarboxylate A compound (21.7g) was converted into ace1-2! -Lil (50
0+IIQ) and talolosulfonylisocyanate.
1-(I0,4mQ) is soaked in F, and then heated under reflux for 1 hour. After cooling, 10% hydrochloric acid ethanol solution (500ff
l#) and stirred at room temperature for 2 hours. After distilling off the solvent,
Water (200ml) is added to the residue and washed with ethyl acetate. The aqueous layer is made alkaline with IN sodium hydroxide and extracted with chloroform. The extract was washed with water, dried, and the solvent was distilled off to obtain 15.5 g of the title compound. 'H-NMR (CDCI, )δ: 1.47 (3H
, t), 4.53 (2H, q), 4 , 96 (2H,
s), 7.43 (]H, s), 7.54 (IH, dd
d), 7.71 (IH, ddd), 7.79 (]H,
d), 8.20 (LH, d) (C) Compound B (4,
32,) was dissolved in a 40% methylamine aqueous solution (40+nll), stirred at room temperature for 4 hours, and then dissolved in water (300ml+2).
) and extract the precipitate with ethyl acetate. The extract was washed with water, dried, and concentrated, and the resulting 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. "H-NMR (CDCI3) δ: 3.08 (3H,
s), 4.99 (2H, S), 7.31 (IH, ddd
), 7. :(6(Itl,s), 7.48(I)1.d
dd), 7.59 (I11, d), 7.97 (IH, d
), 8.30 (IH, br, 5) KN@ma ρ 4-amino-2-(piperidin-1-yl-carbonyl) Same as Example 25(C) using the compound of Example 25(B) The title compound was synthesized as colorless crystals using the method described above. 'H-NMR (CI)CL') δ: 1,57 (
21 (,br.s), 1, 70 (4Lbr.s), 3
．． 51 (2H, m), 3, 66 (llLdd), 3.7
5 (+11, dd), 3, 77 (2) 1, br. s),
3.99 (], H, d), 5,00 (2H, br.s)
, 6.83 (IH, s), 7, 46 (IH, dd) g-aq↓- Acetylcholinesterase inhibitory activity The acetylcholinesterase inhibitory activity of the compounds of the present invention was determined by the following method. 100 mM phosphate buffer (pH
A solution of the compound of the present invention is added to the reaction mixture consisting of 7 and 4), and acetylcholinesterase derived from electric eel is added to start the reaction (total amount: 100 J). After reacting for 30 minutes at room temperature, the absorbance (a) of 405n+11 was measured. At the same time, the absorbance of a blind reaction solution not containing the compound of the present invention (
b) was measured, and the acetylcholinesterase inhibition rate was calculated using the formula [(b-a)/b)X100. IC,o value (g/mQ), which is the concentration of the compound of the present invention that inhibits acetylcholinesterase activity by 50%
are listed in Table 1. Example 1: Effect of prolonging survival time on mice loaded with vacuum hypoxia Using a group of 6 ddy mice, the compound of the present invention (suspended in 1% Tween aqueous solution so that the administered volume was 0.1 mQ/Log) (cloudy) was administered into the M cavity, and after 30 minutes, each animal was placed in a transparent sealed container, and 190 nu+ was added using a vacuum pump.
The pressure was reduced to +Hg. The time from the start of decompression until the mouse died due to respiratory arrest was measured and defined as the survival time. 1%
The ratio of the survival time of the group administered with the compound of the present invention to the survival time of the control group administered with the Tween aqueous solution was determined and is listed in Table 2. The test compound was administered at a dose of 30 mg/kg. Table 2 Test Example 35 - Lipoxygenase Inhibition Effect Rat basophilic leukemia cells (BRL-1) were cultured in Eagle's basal medium (Gibco Laboratories).
ies) in a culture solution containing 10% FC5 and cultured at 37°C in a 5% CO2 incubator. Cells were collected by centrifugation in phosphate buffered saline pH 7.
After washing 2-3 times with .,4, the cells were washed with water-cooled 1.
50m containing mMEDTA and 10% ethylene glycol
Suspend in M potassium phosphate buffer po 7.4. While cooling on a water bath, the cells are sonicated twice at 20 KHz for 15 seconds, centrifuged at +7000 x g for 30 minutes, and the supernatant is collected as a 5-lipoxygenase enzyme solution. 0.38mM arachidonic acid, 0.1M potassium phosphate buffer (pH 7,4), 2mM ATP, 2mM CaC
The above enzyme solution was added to the reaction solution consisting of +Q2 and a methanol solution of the compound of the present invention (total amount 185 d), and the mixture was heated at 37°C.
Let it react for 5 minutes. Stop the reaction by adding 0.2M citric acid, and add MCDP coloring solution (second reagent of lipid peroxide quantitative reagent Determiner-LPO (Kyowa Medics)) 250
Add uIl. After incubating at 37°C for 20 minutes, centrifugation (
4000 rp+n, 10 minutes) and 675 nm of -L supernatant.
The absorbance (a) of the sample was measured. At the same time, the absorbance (b
), and calculate the 5-lipoxygenase inhibition rate using the formula [(
Calculated by ba)/b)X100. IC, which is the concentration of the compound of the invention that inhibits 50% of 5-lipoxygenase activity. The values are listed in Table 3. After confirming this, the compound of the present invention dissolved in DMSO and diluted with purified water to a constant concentration was administered cumulatively until the increase in contractile force reached the maximum. The concentration of the test compound at which the contractile force increases by 30% is listed in Table 4 as Rog PIE3o. Skin L %m@4□ Atrial muscle contraction force enhancement effect

Claims (1)

[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A is the formula ■CH_2■_n (however, n is an integer from 3 to 5) ) represents an alkylene group which is bonded to two adjacent carbon atoms of the adjacent pyridine nucleus to form one cycloalkeno group, or A represents the two adjacent pyridine nuclei of the adjacent pyridine nucleus. is a group that forms one benzene ring in combination with the carbon atoms of (i) A
When forms a cycloalkeno group, Y is a hydrogen atom,
Represents a halogen atom, a lower alkyl group of C_1 to C_6, or an amino group, and Z is a hydrogen atom, hydroxyl group, halogen atom, amino group, formula -NR^1R^2 (R^1, R^2
may be the same or different, and may represent a lower alkyl group or a benzyl group), a pyrrolidyl group, a piperidyl group, a piperazyl group, an N-substituted piperazyl group, a pyridyl group, or the following formula ▲ mathematical formula, chemical formula, table, etc. ▼ (In the formula, B represents an oxygen atom or a sulfur atom, and m is 0 to 2
R^3, R^4, and R^5 may be the same or different and represent hydrogen atoms, halogen atoms, trifluoromethyl groups, hydroxyl groups, lower alkoxy groups, linear or branched (C_
1 to C_6) representing a lower alkyl group, amino group, or acylamino group, or Z represents a pyridylthio group, and (ii) when A forms a benzene ring, Y represents a hydrogen atom or represents a lower alkyl group of C_1 to C_6, and Z has the formula -CONR^6R^7 (however, R^6 and R^7 each represent a hydrogen atom or a lower alkyl group of C_1 to C_6, or R^6 and R^ 7 jointly forms a C_3-C_6 cycloalkyl group) or Z is a formula ▲ There is a numerical formula, chemical formula, table, etc. ▼ (wherein, E is a C_2-C_6 alkylene group or a formula ■ C
H=CH■_p (where p represents 1 or 2), R^3, R^4 and R^5 have the above meanings)
4-amino-2,3-cycloalkenopyridine and 4-aminoquinoline derivatives represented by the following groups and their salts. 2. A brain dysfunction improving agent containing the compound of general formula (I) according to claim 1 as an active ingredient. 3. A heart failure therapeutic agent containing the compound of general formula (I) according to claim 1 as an active ingredient.