JPS59501318A - Heteroaryl-substituted aminomethylbenzene derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] heteroaryl-substituted aminomethyl benzene derivative Background of the invention Cardiac arrhythmia is a typical clinically significant disturbance of the heart's normal rhythm that is usually immediately treated. require specific treatment. A common cause of cardiac arrhythmia is coronary artery disease. A high incidence of arrhythmia has previously been observed during acute myocardial infarction. early ventricular collapse Sinus tachycardia and sinus tachycardia are among the most common types of arrhythmia associated with myocardial infarction. These o and other types of arrhythmias can be suppressed by the use of antiarrhythmic drugs, but , prevention of recurrence of tachyarrhythmia often takes a long time or even indefinitely. follow Therefore, these antiarrhythmic drugs must be effective and reliable. Not only that, but it is also necessary that the harmful side effects associated with them be as low as possible. It is essential.

The heart has a specialized mechanism for generating rhythmic impulses that cause rhythmic contractions of the heart muscle. the impulse system and the conduction system that carries these impulses to all parts of the heart. It is equipped with a system. The majority of heart problems are caused by this special type of sinus rhythm, which causes irregular sinus rhythm. Based on abnormalities in the excitatory and conduction systems. Cardiac arrhythmias as mentioned above and especially Tachyarrhythmias are caused by disturbances in electrical impulse formation, disturbances in impulse conduction, or Depends on the combination of both. Medications used to treat tachyarrhythmias can cause spontaneous diastole It generally reduces or lowers myocardial excitability by attenuating the depolarization of myocardial Influence conduction and the duration of the refractory period by altering the conduction velocity through the tissue. Ru.

Antiarrhythmic drugs, as indirectly mentioned above, can be used to treat a normal heart after electrical cardioversion. It is generally given long-term to maintain normal sinus rhythm after visceral function has returned.

Quinidine (6-methyl-α-(5'-vinyl-2-quinuclidinyl)-4-quine) zine methanol) and shisobiramite (α[2-(diisopropylamino)- [ethyl]α-phenol-2-pyridineacetamide) stimulates impulse formation. decreases, slows conduction velocity, and increases the duration of the refractory period of cardiac follicles, Two antiarrhythmic agents. They are therefore useful in the treatment of supraventricular and ventricular tachyarrhythmias. It is for use. However, in addition to their direct effects on heart rhythm, both drugs An indirect anti-colic agent that acts on the stimulation of the vagus nerve and the peripheral parasympathetic nerve. It shows a positive effect.

Both quinidine and schisopyramite are administered to patients to control arrhythmias. Sometimes, it shows harmful side effects.

Side effects associated with quinidine include cardiotoxicity, diarrhea, and nausea, among others. , vomiting, fever, hypertension, and decreased myocardial contractility. Similarly, shisopyramite Side effects associated with Decreased urinary and myocardial contractility.

Chuckrolin (4-(ro',5'-bis[N-pyrrolidinylmethylcy4'- Hydroxyanilino]-quinaprine) is an effective antiarrhythmic agent; It has significant anticholinergic effects as well as the ability to cause skin discoloration in some patients.

Have you ever been bothered by one or more of these unwanted and harmful side effects? No effective antiarrhythmic drug was obtained. Many side effects are caused by excessive anticholinergic activity and It arises from According to the present invention, preferably associated with these antiarrhythmic agents Disclosed are compounds that have no anticholinergic activity, little and effective antiarrhythmic activity. .

溌'1'L about 1 In the general formula disclosed herein by the present invention, R] is hydrogen, an aryl group or or a lower alkyl group. W is hydrogen, hydroxy group, amine group, alkyl sulfate It is a honami group or a 10-aralkyl group. (Y)A is the ortho place to W is an aminoalkyl group having the general formula -〇H2NR2R3, and whose formula is In R2 and R3, together with N, oxygen, nitrogen or sulfur is designated as the second heteroatom. It may also be a 5- to 7-membered heterocyclic group. A is 1 or 2, N and M are independently numbers from 0 to about 5. Ar is pyridine, pyridazine, pyrimidine a substituted or unsubstituted aryl group selected from the group consisting of be.

The pyridine is optionally fused with one or more heteroaryl groups; optionally fused with one or more aryl groups; pyrazine optionally fused with one or more allyl groups; match) and pharmaceutically acceptable salts thereof, which are cardiac antiarrhythmic agents. It is useful as

Detailed description of the invention The compound according to the invention comprises two aromatic compounds linked through one bond as described below. It is generally characterized structurally by the aromatic group.

first aromatic part is one or two alkyl- or arylamino in the adjacent (ortho) position The para substituent W containing a para-substituted phenyl group having a methyl substituent is It may be a file. Further, when A is 1, it may be hydroxyl. A is 1 or 2, W is 10-alkyl or 10-aralkyl. Examples of desirable W substituents include, but are not limited to: vinegar i.e. lower acyloxy such as acetoxy, propionyloxy, zotyryloxy and aryloxy groups such as benzyloxy. Formula −〇−alki Examples of W substituents having 10-aralkyl or 10-aralkyl are methoxy, ethoxy, Ropoxy, methoxy, pensiloxy, phenetyloxy, phenepropyloxy including, but not limited to, lower alkyloxy groups and aralkyloxy groups such as It is not something that will be done. With the present invention, the inventors advantageously enable parahydroquine It has been found that the compound is effective as an antiarrhythmic agent. Therefore, W is a hydroxy group It is most desirable that

The alkyl or arylamine methyl substituents of the present invention have the general formula -CH2NR2R 3, where R2 and R3 are the same or different and hydrogen, Lower alkyl, hydroxyalkyl (e.g. hydroxyl (If chain or branched chain) (lower alkyl group), cycloalkyl, aryl, alkokene, aralkoxy, a It may be a lucoxyaryl or heteroaryl group. R2 and R3 are both water If the amines are It is necessary to use a protective agent for linking amine substituents as described below. removed after. Moreover, this type of compound is unstable, so R2 and R3 are both It cannot be a co-alkoxy group. Alkyl having the formula -CH2NR2R3 or an arylamine methyl substituent, where R2 and R3 are methyl, ethyl, Lopyl, butyl, ethanol, 2-propanol, 3-7' lovanol, butano ole, methoxy, ethquine, fenoquine, pensoroxy, cyclophenyl, cyclophenyl lohexane, cycloheptyl, phenyl, pencil, thiophene, furan, pyro ole, pyran, thiophane, pyrrolidine, piperidine, morpholine, piperazine including, but not limited to, thiomorpholine and thioxane. .

According to one embodiment of the present invention, an alkylaminomer, such as dimethylamine methyl, The inventors have conveniently found that the til substituent is effective as an antiarrhythmic agent.

Therefore, it is preferable that the substituents are alkylamides/methyls. Also on the other side R2 and R3 together with N (nitrogen) form a saturated or unsaturated 5- to 7-membered heterocyclic group. optionally including oxygen, nitrogen or nihuang as the second foreign atom. But that's fine. Each heterocyclic group may have a substituent or may have no substituent.

Examples of heterocyclic groups formed by N are pyrrolidine, piperidine, morpholine including, but not limited to, pyridine, pyrrole, zaperazine, thiomorpholine, etc. Not done. According to one embodiment of the invention, R2 and R3 together with N form a heterocycle. alkylaminomethyl substituents (e.g. pyrrolidine, piperidine and molar Hollin) was invented to be more effective than dimethylamine methyl as an antiarrhythmic agent. They found it convenient. Therefore, these substituents are more preferred.

The most preferred heterocyclic substituent is pyrrolidine.

According to one embodiment of the invention, the bis-aminomethyl (A=2) substituted compound is - exhibiting greater antiarrhythmic activity than aminomethyl (A=1) substituted compounds; The inventor conveniently and surprisingly discovered that. Therefore, bis-aminomethyl substituted compounds is the most preferred.

According to a preferred embodiment of the invention, the parahydroxyl substituent (W) is absent. Compounds and hence the ability of phenol to conjugately extend through the aryl group (Ar) Compounds lacking a portion of this have made effective antiarrhythmic compounds. Inventors' ideas According to the study, skin discoloration associated with changr○lin The cause is the oxidation of the amine phenol moiety into a quinone-like structure, which causes a strong There is a possibility that chromophores may be formed and deposited on the skin. Therefore, one embodiment of non-invention According to , the W substituent is not capable of forming such a chromophore , preferably hydrogen. Preferably, when W is hydrogen, the aromatic group It is su-aminomethyl (A=2).

The second moiety that is important for the compounds of the present invention is the aryl group (Ar) , which may be unsubstituted or substituted with various chemical substituents. Alternatively, it may be optionally fused with one or more aromatic groups. Book According to the invention, the inertness of unsubstituted or acetyl-substituted para-aminophenol derivatives Similar to the evidence by The inventors found that although the agonistic activity was retained, the antiarrhythmic activity was lost. Ta.

, according to the invention, the aryl group is a 6-membered group having one or more nitrogen atoms as heteroatoms. Any teroaryl group may be used. The heteroaryl compounds according to the present invention include pyridine, pyridazone, pyrimidine or pyrazine, each of which has one or more ants. It is also optional that it is fused with a metal group. Examples of heteroaryl groups according to the invention is pyran/, pyridazo/, pyran/, pyrimidine, quinoline, acridine, i Contains soquinoline, phthalazine, cinnoline, pteridine, and quinophsarine, but this Not limited to these. Preferably, the heteroaryl group is pyridine, pyridazine , pyrazine, pyrimidine, phthalazine, quinoline, inquinoline, quinophsarin and cinnoline. More preferably, hetero ant The group is pyridine, pyridazine, pyrimidine, phthalazine, quinoline and in selected from the class consisting of quinolines;

Illustrative examples of fused ring aryl groups according to the present invention include, but are not limited to: stomach. That is, phenyl fused with pyricine, a 6-membered heteroaryl group (e.g. , pyridine, pyridazine, pyrimidine, pyrazine) or 5-membered heteroaryl groups (e.g. pyrrole, imidazole, pyrazole, oxazole, thiazole , furan, thiophene, etc.); phenyl fused with pyridazine, 6-membered ring heteroa lyl group (e.g. pyridine, pyridazine, pyrimidine, pyrazine) or 5-membered Ring heteroaryl groups (e.g. pyrrole, imidazole, pyrazole, oxazo phenyl fused with pyrimidine , 6-membered heteroaryl groups (e.g. pyridine, pyridazone, pyrimidine, pyramidine) ) or a 5-membered heteroaryl group (e.g. pyrrole, imidazole, pyrazole) sol, oxazole, thiazole, furan, thiophene); pyrazine and condensed combined phenyl, 6-membered heteroaryl groups (e.g. pyridine, pyridazine, pyridazine, rimidine, pyrazone) or a 5-membered heteroaryl group (e.g. pyrrole, imidine). dazole, pyrazole, oxazole, thiazole, furan, thiophene) .

According to the present invention, a fused or unfused aryl group has no substituents. or may be substituted with various chemical substituents. stomach. Examples of substituents include, but are not limited to: i.e. halo Gen, lower alkyl, lower alkoxy, haloalkyl (e.g. ), amino, aminoalkyl (e.g. aminomethyl lower alkenyl, lower alkyl Nyl or phenyl Preferred substituents include herokane (e.g. chlorine), lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), and haloalkyl (eg trifluoromethyl).

The sixth important part is the covalent bond between the aromatic groups -(CH2)N(X) ( CH2) M-. According to the present invention, even if this binding part is slightly modified, its pharmaceutical properties No significant loss of activity occurs. In the bond according to the present invention, X is a lower straight chain alkali Kylene, or sulfur, where Ro is hydrogen, lower alkyl, or aryl (e.g. phenyl), substituted phenyl, benzyl, substituted pencil, or -, in which case R is hydrogen or lower alkyl, most preferably hydrogen. is also desirable. In a bond further preferred according to the invention, X is hydrogen or or lower alkyl, with hydrogen being most preferred. The most favorable outcome of non-invention At the joint, the alkylene group in the bond @ of these compounds independently has 0 to 5 carbon atoms. It can have elementary atoms, preferably 0 to 2 atoms. More preferably, the M+N of the joint is 0.1 or 2, and most preferably M+N is O or 1, for example, M is 0 or 1 and N is 0. [So, the conclusion of the following equation An example of a joint is (CH2)N　X　(CH2)M- Including, but not limited to, the following groups: That is, X, -CH2X-1-X CH2-1-CH2-CH2-X-1-CH2XCH2-11 and -C-N-CH2-.

Preferred compounds according to the invention include, but are not limited to, those represented in the table below. Not determined. However, W in the table is a hydroxy group. (Y) A is independently and preferably is pyrrolidinylmethyl, piperidinylmethyl or morpholinomethyl. A is 2. H] is carbon, oxygen, nitrogen or sulfur. Z is hydrogen or other It is a substituent. 2N is a 6-membered heteroaryl group containing 1 to 2 nitrogen atoms. . Also, the heteroaryl group is connected to the bonding moiety shown by a solid line or (preferably b) are connected by dotted lines.

4 Heteroaryl? (CH2)N--X--(CH2)M-0 Compounds of the invention and their equivalents having substantially similar pharmacological properties can be prepared according to several common methods, such as those described below.

Method I Arylamide derivatives of substituted amine phenols are manufactured by Mannich. ) produced by aminomethylation of adodominophen by reaction, in which The acetyl group is removed and the aniline derivative is reacted with a suitable aromatic acid chloride. be given

method concave Aryloquine derivatives of substituted amine phenols are suitable para-aryloxyphenols. produced by aminomethylation of

Keto derivatives of substituted phenols can be prepared by adding a suitable substituted phenol to a suitable paraphenol. Produced by aminomethylation.

Method b Arylamide derivatives of substituted phenols can be used for demethylation of paramethocinobenzylamine. reaction with a suitable aromatic chloride and aminomethylation. Therefore, it is manufactured.

1 Method■ 2 Mono-substituted aminoalkyl compounds according to the invention are produced together with di-substituted compounds, Medium pressure liquid chromatography (MPL) on a silica gel column from disubstituted compounds C).

The compounds of the present invention are useful for the treatment of cardiac arrhythmias, particularly for inhibiting supraventricular and ventricular arrhythmia. It has advantageous pharmacological properties that make it useful. These compounds can suppress arrhythmia tachycardia In addition to maintaining a more normal sinus rhythm, long-term treatment can reduce premature cardiac onset in patients. expected to be most effective prophylactically in preventing chamber complex formation. . Additionally, according to the present invention, the stiff compound can be administered to dogs by oral or parenteral injection. However, surprisingly, guinea pigs The inventors found that the ileal test showed advantageously low anticholinergic activity. . Kowara's compounds also exhibit antiarrhythmic properties superior to other known antiarrhythmic agents. obey However, the desired antiarrhythmic efficacy of these compounds is due to the desirability associated with anticholinergic activity. (・This is the largest in relation to side effects. Furthermore, these compounds have anti-malarial properties. It is anticipated that it can also be used as a reagent.

The compounds according to the invention can be prepared in a non-toxic, pharmaceutically acceptable manner, e.g. by conventional methods. drugs by neutralizing their free amine groups by inorganic or organic salts. Physically they can coexist with each other. Examples of pharmaceutically acceptable salts of these compounds These include, but are not limited to, the following: i.e. hydrochloric acid, tsukudic acid , phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, 7-euric acid, malic acid, salicyl such as acids. Furthermore, pharmaceutically acceptable salts of the compounds according to the invention may be It can be used in admixture with solid or liquid pharmaceutical carriers or diluents. child These compositions can be administered orally or parenterally by conventional methods. . For oral dosing, the fine powder or granules of the compound may be used as a diluent, binder, or lubricant. may contain dispersants, surfactants, etc., and coated tablets or Alternatively, it may be made into uncoated tablets or a suspension. For di-1 medicinal medication, use this These compounds can be made into aqueous injectable or injectable solutions, and these solutions contain anti-acid compounds. [agents, buffering agents, bacteriostatic agents, solubilizing agents, etc., or blood and salts (e.g. ) can contain solutes that give

The dosages of the novel compounds of the present invention are as prescribed for conventional antidyspulmonary agents. As such, there are a number of factors. Dosage of 1 to 20 μg per gram of body weight is recommended for adults. When injected into dogs (10-65 to 9) at a cumulative rate of 0.6 to 2 minutes per minute. It was found that it was effective.

The following examples serve as a detailed illustration of the invention (but do not limit the scope of the invention). It is not +i to be considered as something to do.

Example 16,5-bis(N-20 lysinylmethyl)-4-hydroxyaniline This example describes a method for synthesizing a compound having the following formula.

]Ro',5'-bis(N-pyrrolidinylmethyl)-4-hydroxyacetani Lido 100.0.9 (0,315 mol) in 200 ml of 6M HCl The solution was heated to reflux for an hour. Add solid KOH to the solution to make it basic to pH 11 did. The resulting solid was collected by filtration and washed with water and cold ether. ether When crystallized, a pale yellow needle-like body was obtained.The hydrochloride salt had a melting point of 100-105°co. Formed white crystals Melting point 219-221°C0 Infrared and NMR spectra corresponds to the specified structure, and the elemental analysis is based on the experimental formula (C16H25N30 ) matched.

Example 11 4-(4'-hydroxyanilino)-quinazoline This example describes the synthesis of a compound having the formula:

〉 This compound has been described by Liangguan, L; Zhixiang, Q; Zhi min.

W,; Yanlln, Z,; Guangsheng, D; Guojum , H, ; and Zueyi, Y. 3ci6nT, 1aSxn1ca, 2 2 + 1220 (1979). 9-251°c.

Example TI+1-(4'-hydroxyanilino)-phthalazine This example describes the synthesis of a compound having the formula:

1-chlorophthalazine 2.00, F (12.1 mmol) and para-aminophe Nord 2.64,! 9 (24.2 mmol) mixed in AO ml of absolute ethanol The combined solution was heated to reflux for 2 hours. After collecting the precipitate, add NaHCO3 saturated solution and and water. The product was crystallized from methanol, melting point 245-247°C. 0 The melting point of the hydrochloride was 30,000 or higher. Infrared and NMR spectra are It corresponds to the specified structure, and the elemental analysis is based on the experimental formula (C, H, H, N30, HCI). ]-4'-Hydroxyanilino]-phthalazine This example describes a compound having the formula Describe how to synthesize things.

Compound d, 65.9 (19.5 mmol) prepared according to Example 6.51 nl of maldehyde 67% solution and 4.5 ml of pyrrolidine 154 mmol ) was stirred for 6 hours at a temperature of 710℃. Rotate the solvent After removal in a converter, the product is dissolved in CHCl3 and the solution is washed with water; Dry (MgSO4) and then saturate with dry hydrogen chloride. After removing the solvent, Crystallization was carried out with isopropanol/ether to give bright yellow crystals: mp 18. The 185°C0 infrared and 1(1)R spectra are consistent with the assigned structure and also indicate that the element The analysis agreed with the empirical formula (C24H2ON50'' HCl.H2C).

Example v 1-N-[:3',5'-bis(N-pyrrolidinylmethyl)-4'- Hydroxyanilino]-4-chlorophthalazine This example describes the synthesis of a compound having the formula:

1.4-dichlorophthalazine 51.4g and para-aminophenol 28.2,? A mixed solution of 750 ml of absolute ethanol was heated under reflux for 10 hours. collect the precipitate Then, it was washed successively with Na, HCO3 saturated solution and water. This product 56.8 ．． 9. Ethanol of 42 ml of 37% formaldehyde solution and 62 ml of pyrrolidine The mixture of solutions in 3 ml of water was stirred for 3 hours while warming. Solvent in rotary evaporator The product was dissolved in CHCl3, the solution was washed with water and dried (Mg5O4). It was then saturated with dry hydrogen chloride. Remove the solvent and transfer to MPLC on Norikadel. Therefore, purification (EzOA・n'MeOH/NH4OH9:1:0.01) Crystallization was carried out with inpropatol/ether to obtain pale yellow crystals. melting point 169-170'C0 infrared and NMR spectra are consistent with the assigned structure and Elemental analysis was consistent with the empirical formula (C24H28CIN50).

4'-Hydroxyanilino]-4-chlorophthalazine This example demonstrates the following compound: The synthesis method will be described.

l This compound was prepared in the same manner as the compound of Example Different points separated by totography: melting point 157-158°c0 infrared and The NMR spectrum is consistent with the assigned structure, and elemental analysis is based on the empirical formula (CIQHl(lN 40C1), this example describes the synthesis of the following compounds:

Compound 2.7.9 (6.2 mmol) prepared according to Example ■ and fresh NaOMe (1,58, j9 Na and MeOH) produced by 3.7! i(6 9 mmol) was heated at 12,000 for 18 hours, then cooled and quenched with water. It got cold.

Purification by MPLCK on silica shell (EtOAc/MeOH/NHaOH .

11°0.01), and then crystallized from CHCl3/Et and OAC, giving a yellow color. A crystal was obtained: melting point 178-179°c0 infrared and NMR spectra with the specified structure. The elemental analysis was consistent with the empirical formula (C25H3,N02.N20).

Example ■ 1-N-[6',5'-bis(pyrrolidinylmethyl)-4'-hydro Roxyanilino]-isoquinoline This example describes the synthesis of the following compound:

1-chloroisoquinoline 3g and rose aminophenol 2g absolute ethanol 40 The mixed solution in m1 was heated under reflux for 4 hours. Collect the precipitate and sequentially add NaHCO3 saturated solution After washing with and water, the product was crystallized from methanol. This product6. 8 g, 56 ml of pyrrolidine and 6.3 ml of formaldehyde 67% solution The mixed solution in 50 #ll of alcohol was stirred for 6 hours while being heated. Solvent in rotary evaporator The product was dissolved in CHCl3, the solution was washed with water and dried <　MgSO 4.) After that, it was saturated with dry hydrogen chloride. After removing the solvent, incubate the crystals. Working with lopanol/ether gave bright yellow crystals, melting point 95°C. infrared and The NMR spectrum is consistent with the assigned structure, and elemental analysis is consistent with the empirical formula (C25H3o N40-HCI-N20).

Example ■ 1-[ro',5'-bis[(N,N-dimethyl)aminomethyl]- 4'-Hydroxyanilinophthaladi This example describes the synthesis of the following compound: .

This compound was prepared similarly to the compound according to Example ■, but only in place of pyrrolidine. The difference is that dimethylamine was used instead: melting point 195°C (HCI salt). Infrared and NMR spectra are consistent with the assigned structure, and elemental analysis is based on the empirical formula (C20H 25N50'roHCI).

Example X 3-N-[6',5'-bis(N-pyrrolidinylmethyl)-4'- Hydroxyanilino-6-chloropyridazino This example describes the synthesis of the following compounds.

This compound was prepared in the same manner as the compound according to Example 2, but only with 1-chloro The difference is that 3゜6-dichloropyridazino was used instead of phthalazine: melting point 1 The 50-151°co infrared and NMR spectra are consistent with the assigned structure and are also consistent with the original The elementary analysis is based on the empirical formula (C2゜H26N50). state.

This compound was prepared similarly to the compound according to Example The difference is that 2-chloropyrimidine was used instead of radin: melting point 171-1 72°C0 infrared and NMP spectra are consistent with the given structure and elemental analysis corresponds to the empirical formula (C20H27N50) -4'-hydroxyanilino:]-6, 7,8-) Rimet This example describes the synthesis of a compound having the formula:

What 3 This compound was prepared M in the same way as the compound according to Example 4-chloro-6,7,8-)rimethquin quinazoline was used instead of radin. Melting point 189-191°C0 infrared and IJMR spectra have different points. It was consistent with the structure, and elemental analysis was consistent with the empirical formula (C27H35N504). .

Example Xm4-[ro',5'-bis(N-pyrrolidinylmethyl)-4'-hydro xyanilino:]-7-trifluoromethylquinoline This example describes the synthesis of a compound having the formula:

This compound was prepared analogously to the compound according to example The point is that 4-chloro-7-trifluoromethylquinoli/ was used instead of radin. Different: melting point 56-58°co infrared and N'lAR spectra to the specified structure agreement, and elemental analysis is the empirical formula % formula % 9 The following example describes the synthesis of a compound having the formula:

Compound 5.0 prepared according to Example 1, ? (18 mmol) and 2- A mixture of 3.23!1 (18 mmol) of methyl-4-chloroquinoline was added to 1600 and 145°C for 1 hour, making sure the temperature did not exceed 145°C.

The product was analyzed by MPLC (CHCl3/MeOH/NH,OH, 9:1:0.0 1) After purification, recrystallize from inzolopanol to obtain yellow crystals. Ta. Melting point 150-155°C (HCI salt). Infrared and NMR spectra are specified The structure is consistent with the structure of I did it.

Example XV4-[3',5'-bis(N-pyrrolidinylmethyl)-4'-hydro Roxyanilino]-7-chloroquinolino This example describes the synthesis of a compound having the formula:

This compound was prepared similarly to the compound according to Example XIV, but only with 2-methyl The difference is that 4,7-dichloroquinoline was used instead of ru-4-chloroquinoline. Become. Melting point 92°C0 Infrared and NMR spectra are consistent with the assigned structure and Elemental analysis agreed with the empirical formula (c25H2, N4ocl・4HC1・3H20) .

Example x■4-[3',5'-bis(N-pyrrolidinylmethyl)-4'-hydro Roxyanilino]-quinoline This example describes the synthesis of a compound having the formula .

This compound was prepared similarly to the compound according to the example, but only with 2-methyl- Melting point differs in that 4-chloroquinoline 7 is used instead of 4-chloroquinoline 67°C0 infrared and NMP, spectra are consistent with the assigned structure and elemental analysis was consistent with the experimental formula (c25H2oN40・4Hc1・2H20).

-4'-Hydroxyanilino]-quinolino The method for synthesizing the compound will be described.

This compound was prepared similarly to the compound according to Example ■, but with only 1-chlorophthalate. The difference is that 2-chloroquinoline was used instead of radin. Melting point 64-66Q Co infrared and NMR spectra are consistent with the assigned structure, and elemental analysis is consistent with the empirical formula (C25H3oN, 0-3HC1-3H20) K Matched.

Example X■ 2-[3'-(1,r-pyrrolidinylmethyl)-4'-hydroxy Anilino]-quinoline This example describes the synthesis of a compound having the formula:

This compound was prepared similarly to the compound in Example X■, except that it was a by-product. The difference is that it is separated as a product. Infrared and NMR spectra with the specified structure The agreement is consistent, and the elemental analysis shows the empirical formula (C20H21N30・0.5H20) methyl )-4'-Hydroxybe/dylamino:]-]4-chlorophthaladi The following example describes the synthesis of a compound having the formula:

p-Hydroxybenzylamine is obtained by heating p-methquinbenzylamine in concentrated hydrochloric acid. produced by refluxing. Add solid KOH to the solution to neutralize it and then Material was collected by filtration. This compound was prepared with p- Produced using hydroxybenozyl γmine and 1,4-dichlorophthalazine: Melting point 197-199°C0 infrared and NM Lis vectors are consistent with the given structure, In addition, elemental analysis is performed using the empirical formula 0 formula% Example XX4-N-4 (ro',5'-bis(pyrrolinonylmethyl)-4'-hydro Roxyanilino]-pyridine This example describes the synthesis of a compound having the formula .

This compound was prepared similarly to the compound of Example The difference is that 4-chloropyridine was used instead of ion: melting point 158-159° C0 infrared and NMR spectra are consistent with the assigned structure, and elemental analysis is consistent with the empirical formula (021H28N40).

methyl)-anilino]-chlorophthalazine This example describes the synthesis of a compound having the formula: Describe the law.

I Weinreb, Tetra hedron Letters (197,7 ) Using the procedure on p-4171, add 5.5 ml of bilorin yt to CHCH2Cl21. QQ solution in nitrogen atmosphere Limethylfluminilum filtration 9m1C78mmo 1). After gas evolution has stopped, dimethyl-5-aminoisof tallate (prepared by preparing 5-aminoisophthalic acid in HCI/MeOH) ) 8.2 g (39 mox) was added and the solution was heated under reflux for 38 hours. Ta. The cooled solution was gradually added to ice water. The aqueous mixture was filtered and then Extracted with H,C13. The extracts were combined and dried (Mg, SO4). The solvent was removed to give 8.97i of solid product.

5.0.9 (16 mmol) of this crude product and 2.43 (6.3, g, mol. ) of lithium aluminum hydride in 100 ml of ether under nitrogen atmosphere. At 4:00 a.m., fever returned to the entrance of the lock. The solution was cooled in a water bath and then quenched with water. aqueous The mixture was filtered and then extracted with ether. Dry the extracts together (Mg5O,) and then the solvent was removed to obtain a yellow oil. Kukerlow A/ Distillation using a Kugelrohr ('Kugelrohr) apparatus (open temperature 900 G, 0. A colorless oil was obtained.

This product 5.00 & (19,6 mmol) and 1,4-cyclophthalazine A mixture of 3.84 g (19.3 mmol) was filtered under nitrogen atmosphere for 160' C (oil bath temperature) heated to K7JD. Product purification is carried out using gel chromatography. (CHCl3/MeOH,/NH4OH: 9: 1: 0.05) Thus, yellow crystals were obtained (melting point 180-18).Oco infrared and NMR. The spectrum is consistent with the designated structure, and elemental analysis is based on the empirical formula (C24H28N5C 1).

Example xxn The following examples describe the pharmacological evaluation of compounds prepared according to the present invention. . In particular, these examples are based on the well-known Harrls dog model. We describe the evaluation of antiarrhythmic activity by coronary ligation. Arrhythmia of both sexes A mixed breed dog (10-15 KP) was treated by double ligating the left ventral descending coronary artery. It was induced. The next day there was a high rate (90-100%) of ectopic beats. in saline solution of the test compound intravenously at a cumulative rate of 0.6~/KP/min (base) into normal sinuses. infusions until rhythm or toxicity occurred. Normal sinus rhythm is 90-100 for 5 minutes. % normal complex. The results of these tests are shown in Table 1.

The following examples demonstrate in vitro anticholinergic activity in isolated guinea pig ileum. Describe your evaluation. Fasted male HarZley guinea pigs ( 300-400g) to the head. 1. Remove a cm ileum fragment. and with physiological saline (-primary mol/): NaCl 1,120; NaHCO2, 25 ; KCI, 4.7; Mg5O,.

0.57; PJ(2PO4,1,:2; CaCl2, 1.96; Bu placed in a bath containing a solution of sucrose, 11.1). Push one end of the ileum piece into a platinum wire electrode. The other end was tied to a fixed gala, su stick. Basal tension: 0.1-3g of skin Electrolytic stimulation (1oo = 150V, I040 seconds pulse duration, 0.2Hz) The peak developed tension corresponding to was measured using a tension transducer. Then test for tension generation Evaluation was made after the drug concentration reached 4 m9/1. Contraction tension in this specimen is due to the anticholinergic activity, so the percentage inhibition is the anticholinergic activity of the drug. means. In other words, the more the inhibition percentage is in dogs, the more the anticolitic/action activity is in dogs. be. The results of these tests are shown in Table 1.

4ro l Inert 23 ■ Inert 2 13 m inert 226 ■ Low activity 84 ■ 1.1 Activity XI Low activity 6 xn low activity 14 XIII Ro, 0 Ro6 XIV 9,5 XV Low activity 27 XVI Low activity 19 X ■ 650 X■　1172 xrx 4.5 78 Quinidine 10.1 62 Jinpyramite 6.8 81 Cyanoglorin 10.3 46 44 Sekisho 59-501318 (1st table 1 note: 1. FD is the effective amount necessary to maintain normal sinus rhythm.

2. No effect on sinus rhythm until the cumulative dose reached 9Vc at 30m9/.

Although the invention has been described in detail and with reference to particularly preferred embodiments, the invention has been described in detail and with reference to particularly preferred embodiments. It will be understood by those skilled in the art that various changes may be made without departing from scope and scope. Probably.

international search report 1m1. . 5llansl　Aoolleaaaa. ,. ? CT/US8310 11031, Inc. 31/435,44,47,495,5 to C17-A61 0,51,535; C07D213/38,56,74°U, S, C1, -5 44158, 6, 82, 116, 119, 120, 124, 127, 128, 2 24,237,238°329,334;424/246.248.54. 248.56. 2.50.251.258.263゜Continuation of page 1 oInt, C1,3 identification symbol Internal office reference number C07D 237/20 697 0-4C237/34 6970-4C 239/42 6970-4 C 239/94 6970-4 C 295/12 6917-4 C

Claims (1)

[Claims] 1. general formula %formula% -C-O-1-〇-C-1-0-1-C-1 lower straight chain alkylene, or -8- In the above formula, R1 is hydrogen, aryl, or lower alkyl group. W is hydrogen , hydroxy, amino, 0-C-aryl, 0-C-alkyl, 0-alk11 Il 0 , alkylsulfonamide or O-aralkyl group. (Y') A becomes W an aminoalkyl group in the ortho position and having the formula -CH2NR2R3. In the above formula, R2 and R3 are the same or different and represent hydrogen, lower alkyl, hydroxyl, alkyl, cycloalkyl, alkoxyquinoalkyl, alkoxyaryl, aryl , heteroaryl, or R2 and R3 are both N (nitrogen) and 5- A 7-membered heterocyclic group optionally containing oxygen, nitrogen or sulfur as a second foreign element. can be formed. Further, A is 1 or 2, and N and M are independently aryl groups. selected from the group consisting of pyridine, pyridazine, pyrimidine or pyrazine. selected. In that case, the pyridine is optionally fused with one or more heteroaryl groups. , pyridazine is optionally fused with one or more aryl groups, and pyrazine is optionally fused with one or more aryl groups. fused with one or more aryl groups. ) 2 W is hydroxy, amino, 0-C-aryl, or 1 is 0-C-alkyl, 0-alkyl or O-aralkyl The compound according to claim 1, wherein A is 2 and A is 2. 3 W is a hydroxy group, A is 2, and Ar is pyridine, pyridadi from the class consisting of pyrimidines, phthalazines, quinolines, and isoquinolines Selected compounds according to claim 1. 4 (Y)A is pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, or -CH2NR2R3, where R2 and R3 are the same or different, and Lower alkyl, hydroxyalkyl, cycloalkyl, alkoxy, alkoxy alkyl, aralkoxy, alkoxyaryl, aryl, or heteroaryl 3. The compound according to claim 2 or 3, which is a ru group. 5(Y) is pyrrolidinylmethyl, piperidinylmethyA , morpholinomethyl, or -cH2NR2R3, where R2 and R3 are Claims that are the same or different and are lower alkyl or hydroxyalkyl groups A compound according to item 2 or 3 of the scope. 6, (Y) is pyrrolidinylmethyl, piperidinylmethyl, or molpolyzate 6. The compound according to claim 5, which is a chill group. 7. The compound according to claim 2 or 3, in which M1N is 0, 1 or 2. . 8. The compound according to claim 2 or 5, wherein M+N is 1. 9. M+N is 0 or 1, in which case N is 0 and M is 0 or 1. The compound according to claim 2 or 6, wherein 10. The compound according to claim 9, wherein R1 is hydrogen or a lower alkyl group. 11. The compound according to claim 10. 12. General formula % formula % of effective amount as an antiarrhythmic agent (wherein, X is -N-1-C-N-1-N-C-1-C-0, -0-C-1111 l -0-1-c'=, lower straight chain alkylene, or -S-, and in the above formula, R is hydrogen , aryl, or lower alkyl group. W is hydrogen, Hibiroki/, amine, 0-C-Ali 1 Partially, 0-C-alkyl, 0-alkyl, alkylsul1 Honamido or 0-aralkyl group. (Y) A is in the ortho position relative to W is an aminoalkyl group having the formula -CH2NR2R3, in which R2 and R 3 is the same or different, hydrogen, lower alkyl, hydroxyalkyl, cycloalkyl Kyl, alkoxyalkyl, alkoxyaryl, aryl, heteroaryl or R2 and R3 are both N (nitrogen) and a 5- to 7-membered heterocyclic group with oxygen, can be formed that optionally includes nitrogen or sulfur as a second foreign element. . Also, A is 1 or 2, and N and M are values from independent KO to about 5. A r is a substituted or unsubstituted aryl group, such as kylidine, giridazine, pyrimidine or or pyrazine. In that case, pyridine is optionally one or more pyridazine is optionally fused with one or more aryl groups. V radines are optionally fused with one or more aryl groups. ) has a compound and a pharmaceutically acceptable salt of the compound in a pharmaceutically acceptable carrier; or a composition for cardiac arrhythmia containing a mixture with a diluent. and A is 2, the composition according to claim 12. 14, W is a hyroquine group, A is 2, and Ar is pyridine, pyridine From the class consisting of gin, pyrimidi/, phthalazine, quinoline and inquinol/ 13. The composition of claim 12, wherein the composition is selected. 15, (Y)A is pyrrolidinylmethyl, piperidinylmethyl, morpholinomethythyl or -CH2NR2R3, where R2 and R3 are the same or different, and lower alkyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl , an alkoxyaryl, aryl, or heteroaryl group. The composition according to item 16 or 14. 0 16, CY) eka) ff pyrrolidinylmethylpiperidinylmethyl, morpholinome or -CH2NR2R3, where R2 and R3 are the same or different. , and is a lower alkyl or hydroxyalkyl group, or the composition according to item 14. 17, (Y)A is pyrrolidinylmethyl, piperidinylmethyl, or morpholinylmethyl 17. The composition according to claim 16, which is a methyl group. 18, M+N is 0, 1 or 2, as described in claim 16 or 14 Composition. 19. M+N is O or 1, in which case N is 0 and M is 0 or 1. A composition according to claim 16 or claim 14. 20. The composition according to claim 19, wherein R is hydrogen or a lower alkyl group. O0 111 21, Teaanaki 21. The composition according to claim 20. 22 Effective amount of general formula 11 II II II as an antiarrhythmic agent (In the formula, or -N-1-C-N-, -N-C-1-C-〇, -0-C-1111 l -0-1-C-5 lower straight chain alkylene, or -8-, where R1 is hydrogen , is an aryl or lower alkyl group. W is hydrogen, hydroxy, amino, 0 -C-ary-1 ru, 0-C-alkyl, alkylsulfonamide, ○-1 It is an alkyl or 0-aralkyl group. (The chip is in the ortho position relative to W. and -CH2NR2R3, in which R2 and R3 are the same or different, and Hydrogen, lower alkyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl Kyl, alkoxyaryl, IJ/l/, heteroaryl , or R2 and R3 together can form a 5- to 7-membered heterocyclic group with N (nitrogen). Ru. A is 1 or 2, and M and N are independently values from 0 to about 5.　 Ar is a substituted or unsubstituted aryl group, such as pyridine, 2ridazine or &amp; Selected from the category consisting of gin. In that case, the village can optionally contain one or more hetero tridazine is optionally fused with one or more aryl groups; The straddledazine is optionally fused with one or more aryl groups. ), and pharmaceutically acceptable salts of the compound in a pharmaceutically acceptable carrier or diluted form. A method of treating cardiac arrhythmia by administering the drug in combination with a diluent. 26. The claim that the composition is administered for the suppression of supraventricular or ventricular arrhythmia. The method according to paragraph 22. 24 The composition suppresses premature supraventricular complex or premature ventricular complex. 23. The method of claim 22, wherein the method is administered for control.