JP3049816B2 - Inotropic drugs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cardiotonic agent comprising a dihydropyridine derivative having a specific structure described below or an acid addition salt thereof as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Generally, inotropic drugs refer to drugs that increase the contractile force of the myocardium and improve the heart function. This includes drugs that act directly on the myocardium to increase their contractile force, and other drugs that act on the peripheral vasculature (resistance and capacity vessels) or indirectly affect heart function via the central nervous system. There are drugs that enhance it.

Hitherto, cardiac glycosides (digitalis preparations) and the like have been used as cardiotonic drugs, but it is not known that dihydropyridine derivatives have a mild and sustained cardiotonic action.

[0004] Conventionally known cardiotonic agents are usually immediate-acting and less persistent. However, if the cardiotonic effect is moderate and persistent, there are advantages such as ease of use for patients with chronic heart disease (for example, heart failure), and such cardiotonic drugs have been long-awaited.

[0005] It is an object of the present invention to provide a cardiotonic which has a mild and sustained cardiotonic effect.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, a dihydropyridine derivative having the following specific structure has a cardiotonic effect, particularly a relaxed and sustained cardiotonic effect. And completed the present invention.

The cardiotonic drug of the present invention has an active ingredient represented by a general formula

Embedded image Wherein R ₁ , R ₂ and R ₃ are the same or different and each represents alkyl, cycloalkyl or alkoxyalkyl,
R ₄ and R ₅ are the same or different and each represents a hydrogen atom, halogen, nitro, alkyl halide, alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ₄ And R ₅ are not hydrogen atoms at the same time), X is a group represented by vinylene or azomethine, A is alkylene,
B is _{-N (R 6) (R 7} ) or

Embedded image (R ₆ , R ₇ and R ₈ are the same or different and each represents a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar represents aryl or pyridyl,
n represents an integer of 0 to 2), and a dihydropyridine derivative [hereinafter referred to as dihydropyridine derivative (I)] and an acid addition salt thereof (usually a pharmacologically acceptable salt). Acid addition salt).

The dihydropyridine derivative (I) and the acid addition salt thereof used in the present invention have a particularly slow action, a long duration, and extremely low toxicity, and are therefore extremely effective and safe. Is a major feature.

In the general formula (I), the alkyl represented by R ₁ , R ₂ and R ₃ may be linear or branched, and is preferably a lower alkyl (C _1-6 ), for example, methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
_1-4 are preferred. These alkyls may further have a lower cycloalkyl (C _3-6 ) at the terminal (for example, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, etc.).

The cycloalkyl represented by R ₁ , R ₂ and R ₃ is preferably lower cycloalkyl (C _3-6 ), for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. R ₁ , R
_{As the} alkoxyalkyl represented by ₂ and R ₃ ,
Those having a total of 3 to 7 carbon atoms are preferable, for example, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl,
2-methoxy-1-methylethyl, 2-ethoxy-1-
Methyl ethyl and the like can be mentioned.

The substituents represented by R ₄ and R ₅ may be the same or different, and may be substituted at any position on the ring. And / or those in the 3-position are preferred. As the halogen for R ₄ and R ₅ , fluorine,
Each atom of chlorine, bromine and iodine is mentioned, and particularly, a fluorine atom or a chlorine atom is preferable. As the alkyl and cycloalkyl, those exemplified as R _{1 to} R ₃ are preferable. As alkoxy and alkylthio, those having lower alkyl (C _1-3 ) are preferable, and methoxy, ethoxy, propoxy, isopropoxy and methylthio, ethylthio, propylthio, and isopropylthio can be mentioned as examples. Examples of the alkoxycarbonyl include those having 2 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl. The same applies to the halogen of the halide, and the alkyl halide is obtained by partially halogenating the alkyl ((CF ₃ ) ₂ CHCH
_2- , CF ₃ CH ₂ -etc.], and those in which all of the hydrogen atoms are halogenated (such as trifluoromethyl). Further, the halogenated alkoxy may be one in which some hydrogen atoms are halogenated or one in which all hydrogen atoms are halogenated. The alkyl halide and the alkoxy halide each have 1 to 6, preferably 1 to 4, carbon atoms. Alkyl in alkylsulfonyl and alkylsulfinyl includes the aforementioned R _{1 to} R
Those exemplified in ₃ include those having 1 to 6 carbon atoms (preferably having 1 to 4 carbon atoms).

As R ₄ and R ₅ , cyano and alkyl halides (particularly, trifluoromethyl) are preferred.

The alkyl and cycloalkyl represented by R ₆ , R ₇ and R ₈ include those exemplified for R _{1 to} R ₃ above. Aralkyl includes benzyl,
phenyl C _1-3 alkyl such as α-phenylethyl, β-phenylethyl, and γ-phenylpropyl; and aryl as phenyl, naphthyl and the like. These aromatic rings may have the same or different substitution at any position. It may have a group. Examples of the substituents on these aromatic rings include, for example, those exemplified above as R ₄ and R ₅ . The pyridyl 2-pyridyl, 3-pyridyl, 4-pyridyl and the like, which said R _4, R ₅
May have the substituent exemplified as.

The alkylene represented by A is preferably a linear or branched C _2-4 alkylene, and specific examples include ethylene, trimethylene, tetramethylene, and 1,2-dimethylethylene.

The aryl and pyridyl represented by Ar include those exemplified for R ₆ , R ₇ and R _{8 above} , and may have the same substituent. 4-substituent of dihydropyridine

Embedded image The ring represented by is a benzene ring when X is vinylene (-CH = CH-), and a pyridine when X is azomethine (-CH = N-), and these represent dihydropyridine at an arbitrary position thereof. May be bonded to the 4-position.

The substituents R ₄ and R ₅ are the same as those of dihydropyridine.
The carbon atom bonded to the position may be substituted at any of the ortho, meta and para positions, preferably at the ortho position or /
And at the meta position.

Specific examples of the dihydropyridine derivative (I) and the acid addition salt thereof include 2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,2
6-dimethyl-4- (3-nitrophenyl) -1,4-
Dihydropyridine-3,5-dicarboxylate, 2-
[P- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4- (4-cyano-
2-pyridyl) -1,4-dihydropyridine-3,5-
Examples include dicarboxylates and their acid addition salts.

The dihydropyridine derivative (I) can be produced by subjecting any part constituting the dihydropyridine derivative (I) and the remaining part to a means known per se, in particular, a dehydration ring closure reaction.

Specifically, JP-A-63-107975,
JP-A-63-112560, JP-A-63-22535
6, JP-A-58-201765, JP-A-63-99
042 Patent, JP-A-63-152351, JP-A-61-
It is manufactured by using a manufacturing method described in each publication of JP 260064.

The dihydropyridine derivative (I) thus produced can be collected in any purity by appropriately using known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, recrystallization and the like.

Since the dihydropyridine derivative (I) has a basic group, it can be converted into an acid addition salt by known means. Such salts are not particularly limited as long as they are pharmacologically acceptable. For example, salts with inorganic acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.) and salts with organic acids (Acetate, succinate, maleate, fumarate, malate, tartrate) and the like.

[0022]

[Effects] The dihydropyridine derivative (I) and the acid addition salt thereof, which are the active ingredients of the present invention, have extremely low toxicity, and moderately exhibit action in mammals (eg, mice, rats, rabbits, dogs, cats, humans, etc.). And a cardiotonic effect (cardiac function improving effect) having a long duration.

Accordingly, the dihydropyridine derivative (I) or an acid addition salt thereof is used as an inotropic drug for heart failure,
It is particularly useful for treatment and prevention of chronic heart failure and the like. The inotropic drugs of the present invention reduce the burden on the heart by lowering blood pressure and improve cardiac function by increasing cardiac blood flow through cardiovascular dilation.

When the dihydropyridine derivative (I) and the acid addition salt thereof are used as the above-mentioned pharmaceuticals, pharmaceutically acceptable additives such as pharmacologically acceptable additives (eg, carriers, excipients, diluents, etc.) may be used together with pharmaceutically necessary components. They can be mixed and made into a pharmaceutical composition in the form of powder, granules, tablets, capsules, injections, etc., and administered orally or parenterally. In the above-mentioned preparation, the dihydropyridine derivative (I) and the acid addition salt thereof are mixed in an effective amount. The dose varies depending on the route of administration, symptoms, body weight or age of the patient. For example, in the case of oral administration to an adult patient, 0.05 to 20 mg / dose is required.
It is desirable to administer kg body weight / day, particularly 0.1 to 4 mg / kg body weight / day, once or several times a day.

In the case of intravenous administration, 0.1 to 300
It is desirable to administer μg / kg body weight / day, particularly 5 to 100 μg / kg body weight / day, once or several times a day.

[0026]

Experimental Examples / Examples / Reference Examples Hereinafter, the present invention will be described in more detail with reference to Experimental Examples, Examples and Reference Examples, but these Experimental Examples / Examples do not limit the present invention. In the ¹ H-NMR measurement, those not particularly described are C
DCl ₃ was used.

[0027] Use Example 1 (Toxicity) 10-11 weeks old weighing 14~16g of male mice (3-5 mice group) to obtain the LD _50. The results were at least> 1100 mg / kg body weight and most compounds were> 1400 mg / kg body weight.

Therefore, the dihydropyridine derivative and the acid addition salt thereof used in the present invention have significantly higher acute toxicity values and higher safety than known compounds.

Experimental Example 2 Circulating dynamics and cardiac function when a dihydropyridine derivative or an acid addition salt thereof was intravenously administered to male and female dogs weighing 7 to 12 kg (3 to 4 dogs per group, Cary). The effect on was investigated. That is, the mean central venous pressure (MCVP) and the maximum and minimum differential values (M
ax dp / dt, Min dp / dt) and cardiac output (CO) were examined.

Test drug: Compound 2 described below was dissolved in ethanol and Tween 80, and then diluted with physiological saline (Tween
The final concentration of 80 is less than 0.03%). The drug dose is 30 μg
/ Kg, and bolus was administered to the right vein in a volume of 1 ml / kg. As a control group, a 0.03% Tween 80 physiological saline solution was administered at a volume of 1 ml / kg.

Method: sodium pentobarbital 25
The dog anesthetized by intravenous administration of mg / kg was fixed in a dorsal position.

The mean central venous pressure (MCVP) was measured from a polyethylene catheter inserted into the right femoral vein via a pressure transducer (Stetham P-50; Gould).

The maximum and minimum differential values of the left ventricular pressure (Max d
p / dt, Min dp / dt) were measured through a microtip-transducer (Nihon Kohden) inserted into the left ventricle from the left carotid artery.

The cardiac output (CO) was measured from a Swan-Ganz catheter inserted through the left jugular vein into the pulmonary artery via a thermodilution type cardiac output measuring device (MLC-4100: Nihon Kohden).

The results are shown in Tables 1 to 4 as average values.
From the results shown in the table below, it can be seen that the active ingredient compound of the present invention has a modest onset of cardiotonic action and a remarkably long duration of action. In addition, an increase in cardiac output (CO) and a maximum differential value (Max dp / dt) of the left ventricular pressure showed an inotropic effect. Since the active ingredient compound of the present invention simultaneously exhibits the effect of reducing post-load due to the antihypertensive effect and the effect of increasing coronary blood flow, it is considered that the actual burden on the heart is small, and the decrease in mean central venous pressure (MCVP) Because it is recognized, it is useful as an inotropic drug.

[0036]

[Table 1]

[0037]

[Table 2]

[0038]

[Table 3]

[0039]

[Table 4]

Reference Example 1 2- [p- (4-benzhydrylpiperazino) phenyl] ethyl methyl 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-
Synthesis of dicarboxylate (Compound 1) and its hydrochloride (Compound 2):

In a 100 ml eggplant flask, 3-nitrobenzaldehyde (1.144 g, 7.57 mmol), acetoacetate [p- (4-benzhydrylpiperazino) phenyl] were added.
Ethyl (3.464 g, 7.59 mmol) and methyl 3-
Add aminocrotonate (873 mg, 7.58 mmol)
Isopropanol (12 ml) was added, a Dimroth condenser was attached, and the mixture was heated under reflux for 16 hours. The reaction solvent is distilled off under reduced pressure, and the residue is separated by column chromatography [silica gel, chloroform: methanol (45: 1)] and column chromatography [silica gel, ethyl acetate: n-hexane (2: 3)]. The crude product
Purification by high performance liquid chromatography afforded 2.503 g of the title compound 1 (48% yield).

IRν _max ^KBr cm ^-1 : 1680, 1520 ¹ H-NMR δ: 8.06 (1H, t, J = 2 Hz), 7.97 (1H, ddd,
J = 8; 2; 1Hz), 7.1-7.6 (12H), 7.03 (2H, d, J = 8.6Hz),
6.80 (2H, d, J = 8.6Hz), 6.02 (1H, s), 5.07 (1H, s),
4.26 (1H, s), 4.22 (2H, t, J = 7Hz), 3.64 (3H, s),
3.15 (4H, dd, J = 5; 4.7Hz), 2.81 (2H, t, J = 7Hz), 2.5
5 (4H, dd, J = 5; 4.7Hz), 2.33, 2.28 (3H,
s)

This compound 1 (2.124 g, 3.16 mm
ol) was placed in a 200 ml eggplant flask, and a septum rubber was attached. Methylene chloride (100 ml) was added to the flask to dissolve the contents, and the mixture was stirred at room temperature for 30 minutes while introducing hydrogen chloride gas. The precipitated crystals were collected by filtration to give about 2.22 g of the title compound 2.

IRν _max ^KBr cm ^-1 : 2450, 1680, 1525,
1350. ¹ H-NMR δ: 13.72 (1H, brs), 8.05-7.9 (6H), 7.8
_{2, 7.26 (4H, A 2} B 2 · q, J = 8.6Hz), 7.6-7.3 (8H), 6.28
(1H, s), 5.2-5.05 (2H), 5.01 (2H, s), 4.27 (2H, t,
J = 6.5Hz), 4.3-4.1 (2H), 3.66 (3H, s), 3.65-3.45
(4H), 2.95 (2H, t, J = 6.5Hz), 2.36, 2.33 (3
H, s).

Example 1: Tablet (1) Compound 2 10 g (2) Fine granules for direct hit No. 209 (manufactured by Fuji Chemical Co., Ltd.) 110 g Magnesium aluminate metasilicate 20% Corn starch 30% Lactose 50% (3) Crystalline cellulose 60g (4) CMC calcium 18g (5) Magnesium stearate 2g

(1), (3) and (4) are all 10
Pass through a 0 mesh sieve. These (1), (3), (4) and (2) are each dried to reduce the water content to a certain level, and then mixed with the above weight ratio using a mixer. (5) was added to the mixed powder of uniform quality and mixed for a short time (30 seconds), and the mixed powder was tabletted to give a tablet of 200 mg per tablet.

The tablet may be coated with a commonly used gastrosoluble film coating agent (eg, polyvinyl acetal diethylaminoacetate) or an edible coloring agent, if necessary.

Example 2: Capsules (1) Compound 2 50 g (2) Lactose 930 g (3) Magnesium stearate 20 g The above ingredients were weighed and mixed uniformly, and the mixed powder was filled into hard gelatin capsules in 200 mg each. did.

Example 3 Injection (1) Compound 2 5 mg (2) Glucose 100 mg (3) Physiological saline 10 ml After filtering the above mixture through a membrane filter, sterilization filtration was performed again, and the filtrate was sterilized. The solution was dispensed into vials, filled with nitrogen gas, and sealed to give an intravenous injection.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ Identification code FI C07D 401/14 C07D 401/14 (72) Inventor Masahiro Watanabe 2-1-1180 Shodai Otani, Hirakata-shi, Osaka 1 Midori Cross Central Co., Ltd. In the laboratory (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/4422 CA (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula Wherein R ₁ , R ₂ and R ₃ are the same or different and each represents alkyl, cycloalkyl or alkoxyalkyl,
R ₄ and R ₅ are the same or different and each represents a hydrogen atom, halogen, nitro, alkyl halide, alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio (provided that R ₄ And R ₅ are not hydrogen atoms at the same time), X is a group represented by vinylene or azomethine, A is alkylene,
B is -N (R ₆ ) (R ₇ ) or (R ₆ , R ₇ and R ₈ are the same or different and each represents a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar represents aryl or pyridyl,
and n represents an integer of 0 to 2).] A cardiotonic agent comprising a dihydropyridine derivative or an acid addition salt thereof as an active ingredient. 2. R ₁ , R ₂ and R ₃ are the same or different alkyl, R ₄ is a hydrogen atom, R ₅ is nitro, halogenated alkyl or cyano, R ₆ and R ₇ are the same or different alkyl, aralkyl Or aryl, R ₈
Is an aryl, Ar is an aryl, and n is 1.