JPH04316565A - New benzothiazole derivative - Google Patents

Abstract

PURPOSE:To provide a new compound useful as a cardiotonic agent for the treatment of cardiac failure, especially acute cardiac failure. CONSTITUTION:The compound of formula I (R<1> is H or lower alkyl; R<2> to R<4> are H, lower alkyl, etc.; R<5> and R<6> are lower alkyl, etc.; X is anion; m and n are 1-3), e.g. 1,1-dimethyl-4-(6-hydroxy-benzothiazol-2-yl)piperazinium iodide. The compound can be produced by reacting a compound of formula II (Y is eliminable group) with a compound of formula III and reacting the resultant compound of formula IV with a compound of formula V.

Description

Detailed Description of the Invention [0001] [Industrial Application Field] The present invention relates to a new benzothiazole derivative having excellent cardiotonic action.
The present invention relates to a benzothiazole derivative having a quaternary alicyclic diamine group at the position thereof and a cardiotonic agent containing the same as an active ingredient. [0002] Cardiotropic agents currently used for the treatment of heart failure include digitalis, catecholamine preparations, and β1
There are receptor stimulants such as denopamine, and recently,
Phosphodiesterase inhibitors such as amrinone have been developed. However, with these cardiotonic drugs, the current situation is that it is not always possible to separate the drug efficacy from its side effects. As a result of repeated search and research for new compounds that have excellent cardiotonic effects, are safe, and have few side effects, the present inventors have discovered that the new benzothiazole derivatives described below exhibit excellent cardiotonic effects. Completed the invention. Compounds having a benzothiazole skeleton have not been reported in the field of cardiotonic drugs, and are described in JP-A-64-79162 as derivatives having 5-lipoxygenase inhibitory activity, but quaternary salt derivatives of the compounds of the present invention are not included. Furthermore, the compounds of the present invention do not have 5-lipoxygenase inhibitory activity. [Summary of the Invention] [Problems to be Solved by the Invention] Accordingly, an object of the present invention is to provide a new benzothiazole derivative having excellent cardiotonic action and a cardiotonic agent having excellent action. [0004] That is, the novel benzothiazole derivative according to the present invention is represented by the following general formula (I). [0005] (In the formula, R1 represents a hydrogen atom or a lower alkyl group. R2, R3 and R4 may be the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogen Represents an atom, a hydroxyl group, and a lower alkoxy group.R5 and R6 may be the same or different, and each represents a lower alkyl group, a lower alkenyl group, or an optionally substituted aralkyl group.X-
represents a pharmacologically acceptable anion species. m and n
may be the same or different, and each represents an integer of 1 to 3. ) Furthermore, the cardiotonic agent according to the present invention contains a compound represented by the above general formula (I) as an active ingredient. [Detailed Description of the Invention] Compound The compound according to the present invention is represented by the above-mentioned general formula (I). As is clear from the general formula (I), the compound according to the present invention is a benzothiazole derivative having a quaternary alicyclic diamine group at the 2-position. [0007] In this specification, the alkyl moiety of the lower alkyl group and the lower alkoxy group is preferably a straight chain or branched C1-6 alkyl group, more preferably a C1-6 alkyl group.
-4 alkyl group, and the lower alkenyl group preferably means a linear or branched C2-6 alkenyl group, more preferably a C2-4 alkenyl group. In addition, halogen atoms include, for example, fluorine, chlorine, bromine,
and means an iodine atom. Particularly preferred examples of R2 include a hydrogen atom and a methyl group. The substitution positions of R1 are not particularly limited, but are preferably the 5- and 6-positions of the benzothiazole skeleton. Specific examples of the aralkyl group represented by R5 and R6 include phenyl lower alkyl,
Examples include benzyl group and phenethyl group. The hydrogen atom of this aromatic hydrocarbon group may be substituted, and specific examples of the substituent include a halogen atom, a lower alkyl group, an alkoxy group, and a nitro group. Specific examples of the alicyclic diamine present at the 2-position of the benzothiazole skeleton include imidazolidine, piperazine, homopiperazine, and the like. The type of X- is not particularly limited as long as it is a pharmacologically acceptable anion species, but specific examples thereof include halogen ions, acetate anions, formate anions, and sulfate anions. Production of Compound The compound of general formula (I) of the present invention can be produced by various methods, but the preferred production method is as follows. ##STR00003## That is, the general formula (II) [wherein R1, R2, R3 and R4 represent the same meanings as above, and Y represents a leaving group, such as a halogen atom. ] The compound represented by the general formula (III) [wherein R5, m and n represent the same meanings as above. is reacted with an N-substituted alicyclic diamine represented by the general formula (IV) [wherein R1, R2, R3,
R4, R5, m and n have the same meanings as above. ], and then form a compound of formula (V) [wherein R6 and X have the same meanings as above, and X represents a halogen atom. ] By reacting with a compound represented by
can be obtained. The reaction between compound (II) and compound (III) usually proceeds rapidly by heating to 50-150° C. in an inert solvent such as DMF without a solvent or in the presence of a base. The reaction between compound (IV) and compound (V) is
(I) can be easily advanced by reacting in an inert solvent such as DMF at 0° C. to room temperature for 1 to 5 hours. The compound represented by the general formula (II) has the following general formula (VI): ##STR4## where R1, R2, R3 and R4 have the same meanings as above. ] From the compound represented by Stuckwis
ch method (J. Am. Chem. Soc., 7
1, 3417, (1949)) via a diazonium salt. Use of Compound/Carotonic Agent The compound represented by the general formula (I) according to the present invention has a cardiotonic effect (for details of the cardiotonic effect, please refer to the experimental examples described later). Therefore, the compounds according to the invention can be used as cardiotonic agents.
It can be used to treat heart failure, especially acute heart failure. The cardiotonic agent containing the compound according to the present invention as a main ingredient can be administered to humans and non-human animals by either oral or parenteral routes of administration. Therefore, the cardiotonic agent according to the present invention can be administered in a variety of dosage forms, such as injections such as intravenous and intramuscular injections, and oral preparations such as capsules, tablets, and powders, in an appropriate dosage form depending on the route of administration. and used. These various preparations contain commonly used excipients, fillers, binders, wetting agents, disintegrants,
It can be manufactured by conventional methods using surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, and the like. [0017] The dosage is appropriately determined depending on the individual case, taking into account the symptoms, age, gender, etc., but it is usually 0.1 to 200 mg per day for adults, preferably 0.5 to 50 mg when administered orally. , 0.1-100m for parenteral administration
g, preferably 0.5 to 50 mg, once a day
~Administer in 3 doses. [Example] [Experiment example] The present invention will be further explained in detail by the following examples, but these examples are mere examples and do not limit the present invention, and do not limit the scope of the present invention. It goes without saying that various modifications and modifications can be made without departing from the above. In addition, the NMR data in the examples is 400MHz N
Using MR, the δ value is shown based on TMS. Example 1 1,1-dimethyl-4-(6-hydroxybenzothiazol-2-yl)piperazinium iodide 1)
9 g of 2-amino-6-methoxybenzothiazole was dissolved in a mixture of 25 ml of formic acid, 10 ml of acetic acid and 30 ml of hydrochloric acid, and 5 ml of an aqueous solution containing 3.5 g of sodium nitrite was added dropwise at -5°C. After reacting for 30 minutes, a solution of 6.43 g of cuprous chloride dissolved in 40 ml of hydrochloric acid,
It was added little by little at 0°C. After reacting for 1 hour, the mixture was further stirred at room temperature for 30 minutes. The reaction solution was poured into 200 ml of ice water, and the resulting precipitate was collected. The obtained precipitate was dissolved in EtOH
The solution was dissolved in 200 ml, and the insoluble portion was filtered off. After concentrating the perilla liquid under reduced pressure, 200 ml of ethyl acetate was added, and after washing with water, Mg
It was dehydrated with SO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate = 30:1) to obtain 4.94 g of 2-chloro-6-methoxybenzothiazole. NMR (CDCl3) δ 7.81 (1H, d), 7
．． 22 (1H, d), 7.07 (1H, dd), 3.8
6(3H,s) 2) 2-chloro-6-methoxybenzothiazole (2 g) was dissolved in 10 ml of N-methylpiperazine and reacted at 130° C. for 6 hours. The reaction solution was diluted with CHCl3
The mixture was diluted with 150 ml, washed with water, dehydrated with MgSO4, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.05 g of 2-(4-methyl-1-piperazinyl)-6-methoxybenzothiazole.
I got it. NMR (CDCl3) δ 7.47 (1H, d), 7
．． 14 (1H, d), 6.96 (1H, dd), 3.8
2 (3H, s), 3.61 (4H, t), 2.53 (4
H,t), 2.35(3H,s) 3) 2-(4-methyl-1-piperazinyl)-6-methoxybenzothiazole 2g with 25%H
It was dissolved in 15 ml of Br/acetic acid and heated at 125° C. for 4 hours in a sealed tube. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 ml of water, and the pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution. The resulting precipitate was filtered, washed with water and chloroform, and dried to give 2-(4-methyl-1-piperazinyl).
1.64 g of -6-hydroxybenzothiazole was obtained. NMR (CDCl3) δ 7.31 (1H, d), 7
．． 08 (1H, d), 6.79 (1H, dd), 3.5
8 (4H, t), 2.58 (4H, t), 2.35 (3
H,s) [0022] 4) 100 mg of 2-(4-methyl-1-piperazinyl)-6-hydroxybenzothiazole was dissolved in 5 ml of DMF, 86 mg of MeI was added under ice cooling, the mixture was reacted for 1 hour, and then the mixture was stirred at room temperature. The reaction was allowed to proceed for 1 hour. The reaction solution was concentrated under reduced pressure, and CHCl3:MeOH was added to the residue.
10 ml of a 9:1 mixture was added, the resulting precipitate was collected, washed with CHCl3, and dried to obtain the title target compound 137.
mg was obtained. NMR (D2O) δ 7.45 (1H, d), 7.2
8 (1H, d), 6.97 (1H, dd), 3.89 (
4H, t), 3.64 (4H, t), 3.30 (6H,
s) Example 2 1-allyl-1-methyl-4-(6-hydroxybenzothiazol-2-yl)piperazinium iodide 100 mg of 2-(4-methyl-1-piperazinyl)-6-hydroxybenzothiazole and By using 101 mg of allyl iodide and treating in the same manner as in Example 1-4), 154 mg of the title target compound was obtained.
I got it. NMR (D2O) δ 7.44 (1H, d), 7.2
7 (1H, d), 6.96 (1H, dd), 6.10 (
1H, m), 5.90-5.70 (2H, m), 4.1
1 (2H, d), 4.00-3.88 (2H, m), 3
．． 88-3.78 (2H, m), 3.70-3.55 (
4H,m), 3.20(3H,s) Example 3 1-Benzyl-1-methyl-4-(6-hydroxybenzothiazol-2-yl)piperazinium bromide 2-(4-methyl-1 -Piperazinyl)-6-hydroxybenzothiazole (100 mg) and benzyl bromide (103 mg) were treated in the same manner as in Example 1-4) to obtain 164 mg of the title compound. NMR (D2O) δ 7.7-7.77 (5H, m)
, 7.44 (1H, m), 7.27 (1H, m), 6.
96 (1H, m), 4.68 (2H, s), 4.03 (
2H, d), 3.80 (2H, t), 3.69 (2H,
t), 3.59 (2H, d), 3.16 (3H, s) [
Example 4 1-allyl-1-methyl-4-(6-methoxybenzothiazol-2-yl)piperazinium iodide 100 mg of 2-(4-methyl-1-piperazinyl)-6-methoxybenzothiazole and 191 mg of allyl iodide 159 mg of the title target compound was obtained by treating in the same manner as in Example 1-4). NMR (CD3OD) δ 7.62 (1H, d), 7
．． 43 (1H, d), 7.11 (1H, dd), 6.3
5-6.20 (1H, m), 6.03-5.94 (2H
, m), 4.37 (1H, d), 4.25-4.15 (
4H, m), 4.11-4.01 (2H, m), 3.9
8 (3H, s), 3.87-3.75 (4H, m), 3
．． 40 (3H, s) Example 5 (Formulation Example) Tablets containing 1 mg of the active ingredient were prepared from the following composition. Compound 1 of Example 2
mg lactose
45mg crystalline cellulose
40mg cornstarch
12 mg Magnesium stearate 2 mg Next, test examples regarding the pharmacological effects of the compounds of the present invention will be shown. Test Example 1 Positive inotropic effect (method using isolated guinea pig left atrial electrical stimulation model) F. The method of Erjavek et al. (Arch. Int.
Pharmacodyn. , 155 , 251,
(1965)), the isolated left atrium of a guinea pig was
They were immersed in a nutrient solution containing 1/3 of the normal concentration of calcium ions at 2°C, electrical stimulation was applied, and the rate of increase in contractile force when a test compound was added was determined. The results are shown in Table 1. [0028]
Table 1
Test compound Dose (mcg/ml) Rate of increase in guinea pig left atrial contractile force (%) Compound of Example 1 0.1
100 Compound of Example 2
0.1
87 Compound of Example 4 3.0
65
Test Example 2 Cardiac action (method using guinea pigs) Pentobarbital sodium (35-50 mg/kg
The following experiment was conducted using male guinea pigs weighing 250-350 g that were anesthetized with Body temperature was maintained at 36-38°C. Insert a tracheal cannula and
Artificial respiration was performed using a breathing pump (respiration volume 1 ml/100 g, respiratory rate 55 times/min). A polyethylene catheter was inserted into the jugular vein for intravenous administration of the test compound. The left ventricular pressure was determined by inserting a 19-gauge hypodermic needle directly into the left ventricle.
It was connected to a thman pressure transducer and measured. The time differential value dp/dt max of the pressure in the left ventricle was obtained by introducing the pressure in the left ventricle to a differential amplifier. In addition, heart rate was recorded using a cardiotachometer. The results are in Table 2
As shown in [0030]
Table 2
Test compound Dose dp/dt
max Left ventricular pressure Heart rate increase rate
(mg/kg)
Increase rate (%) Increase rate (%)
(%) Compound of Example 1
0.01 136±2.3 138±
2.3 103±0.6 Example 2
Compound of 0.01 140±0.
9 171±1.2 106±1.7
Compound of Example 3 0.01
163±1.2 137±1.5
100±0 Test Example 3 Changes in Cardiotonic Effect (Method Using Guinea Pigs) Due to Drug Amount By the same method as Test Example 2, the relationship between the drug amount and its cardiotonic effect for the compound of Example 2 was measured. The results are shown in Table 3. [0032]
Table 3
Dose (mg/kg) dp/dt max Increase rate (%) Increase rate in left ventricle (%)
0.001 133±2.9
157±1.8 0
．． 01 140±0.9
171±1.2 0.1
207±1.2
180±1.2 1
247±2.4
191±1.5 [0033] Acute toxicity The compound of Example 2 showed the following acute toxicity in an acute toxicity test using mice.
Oral administration 300mg/kg, intraperitoneal administration 30mg/kg
And I didn't see any deaths.

Claims (2)

[Claims] [Claim 1] A compound represented by the following general formula (I). [Formula 1] (In the formula, R1 represents a hydrogen atom or a lower alkyl group. R2, R3, and R4 may be the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogen atom, and a hydroxyl group. and a lower alkoxy group.R5 and R6 may be the same or different and each represents a lower alkyl group, a lower alkenyl group, or an optionally substituted aralkyl group.X-
represents a pharmacologically acceptable anion species. m and n
may be the same or different, and each represents an integer of 1 to 3. ) [Claim 2] The compound according to Claim 1 as an active ingredient;
Cardiotropes.