JPH0782166A - Antishock agent - Google Patents

Abstract

PURPOSE:To obtain an antishock agent having low toxicity and excellent safety and useful for the prevention and treatment of cardiogenic shock, hemorrhagic shock, septic shock, etc., by using a specific dihydroorotyl, histidylprolinamide derivative (salt) as an active component. CONSTITUTION:This antishock agent is produced by using a 4, 5-dihydroorotyl- histidyl-prolinamide derivative (salt) of the formula (R is H or lower alkyl), e.g. (1-methyl-L-4, 5-dihydroorotyl)-L-histidyl-L-prolinamide as an active component. The dose of the active component is preferably 30 mug to 30 mg/kg body- weight per clay for oral administration.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to anti-shock agents.

[0002]

2. Description of the Related Art Shock is caused by circulating blood volume, heart pump function,
Acute peripheral vascular insufficiency caused by any one or more of the peripheral vascular resistance causing ataxia, and its clinical features are acute hypotension and tachycardia. Conventionally, phenylephrine hydrochloride, dopamine hydrochloride and the like have been used to improve acute circulatory failure such as cardiogenic shock and hemorrhagic shock or acute hypotension. In addition, it has recently been reported that thyroid-stimulating hormone secretagogue (TRH) also has an anti-shock action [Pathophysiology, Vol. 6, page 111 (198).
7 years); The 23rd Annual Meeting of the Japanese Medical Association [I], page 420
(1991); Anesthesia, Vol. 36, p. 918 (1987).
IRYO, Vol. 45, p. 225 (1991);
Arch. int. Pharmcodyn. , Second
99, 65 (1989) etc.].

On the other hand, 1-methyl-4,5-dihydroorotyl-histidyl-proline amide or its acid addition salt has a pentobarbital anesthesia antagonism, a locomotor activity-increasing effect, an anti-reserpine effect and a dopamine effect-enhancing effect.
It is known to have a central nervous system activating action and to be useful as a medicine (JP-A-61-33197 and JP-A-62-234029).

[0004]

The present invention is intended to prevent acute circulatory failure, acute hypotension, tachycardia, etc. of various shocks such as cardiogenic shock, hemorrhagic shock, septic shock, neurogenic shock, anaphylactic shock, etc. An anti-shock agent useful for treatment is provided.

[0005]

The present invention provides a compound of formula [I]

[0006]

[Chemical 2]

(Wherein R represents a hydrogen atom or a lower alkyl group) or a 4,5-dihydroorotyl-histidyl-proline amide derivative (hereinafter referred to as a dihydroorotic acid derivative) or pharmacologically thereof. The present invention relates to an anti-shock agent containing an acceptable salt as an active ingredient.

The dihydroorotic acid derivative [I] or a pharmaceutically acceptable salt thereof which is the active ingredient of the present invention is
Cardiogenic shock, hemorrhagic shock, septic shock,
Excellent anti-shock effect against various shocks such as neurogenic shock and anaphylactic shock. For example, as seen in Experimental Examples described later, when the survival time in hemorrhagic shock was examined using rats, (1-methyl-L-4,5-dihydroorotyl) -L- which is the active ingredient of the present invention. Histidyl-L-prolinamide is TRH
The survival time was extended by about 8 times compared to -T. Therefore, the anti-shock agent of the present invention can be suitably used, for example, for the prevention / treatment of the various shocks described above or the prevention / treatment of acute circulatory failure, acute hypotension or tachycardia in these shocks.

The dihydroorotic acid derivative [I], which is the active ingredient of the present invention, contains 3 asymmetric carbon atoms and has 8 optical isomers. Alternatively, all mixtures thereof are included in the range. However, when used for pharmaceutical purposes, the L-4,5-dihydroorotyl-L-histidyl-L-prolinamide derivative is preferable among these isomers.

Among the above-mentioned dihydroorotic acid derivatives [I], examples of compounds having an excellent therapeutic effect include compounds in which R is a lower alkyl group in the general formula [I], and particularly (1-methyl-L- 4,5-dihydroorotyl) -L-histidyl-L-prolinamide.

The dihydroorotic acid derivative [I] which is the active ingredient of the present invention can be used as a free base or as a pharmacologically acceptable salt. Preferred examples of such pharmacologically acceptable salts include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate and nitrate, and acetate, tartrate, maleate and succinic acid. Organic acid addition salts such as salts, citrates, methanesulfonates, malates, oxalates and benzenesulfonates can be mentioned. These salts can be produced, for example, by treating the dihydroorotic acid derivative [I] with an acid.

The therapeutic agent containing the dihydroorotic acid derivative [I] or a pharmacologically acceptable salt thereof as an active ingredient can be administered orally or parenterally, and the compound [I ] Or a pharmaceutically acceptable salt thereof is preferably mixed with an excipient suitable for oral or parenteral administration. Examples of suitable excipients include starch, lactose, potassium phosphate, corn starch, acacia, stearic acid, and other known pharmaceutical excipients. As the dosage form, for example,
It may be a solid preparation such as tablets, powders, capsules and granules, or a liquid preparation such as a solution or suspension. Furthermore, when administered parenterally, it can be used as an injection or a suppository. The dose of the therapeutic agent according to the present invention varies depending on the route of administration; age, weight, condition of patient; kind of disease and the like, but generally the dose of compound [I] or a salt thereof is 3 μg to 30 mg /
kg / day, especially 30 μg to 30 m for oral administration
g / kg / day, or parenteral administration (eg, intravenous administration,
3 to 3000 μg / k for intramuscular administration or subcutaneous administration)
It is preferable that it is g / day.

The dihydroorotic acid derivative [I], which is the active ingredient of the present invention, is disclosed, for example, in JP-A-62-234029.
It can be manufactured by the method described in the publication.

In the present specification, "4,5-dihydroorotic acid" and "4,5-dihydroorotyl" mean "
1,2,3,4,5,6-hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid "and" 1,2,3,
4,5,6-hexahydro-2,6-dioxo-4-pyrimidinecarbonyl "respectively.
The lower alkyl group may have 1 to 6 carbon atoms, especially 1 to 4 carbon atoms.

[0015]

[Action]

Experimental Example (Sample used in Experimental Example) (1-Methyl-L-4,5-dihydroorotyl) -L-
Histidyl-L-prolinamide (comparative sample) Thyroid stimulating hormone secretagogue / tartrate (TR
(HT) (Experimental method) Crj: Wistar male rats (Charles River Japan) having a body weight of about 300 g were treated with urethane (1.
2 g / kg) Anesthetized by intraperitoneal administration, and then fixed in the dorsal position. After midline cervical incision, a cannula was inserted into the trachea and connected to a differential pressure transducer (TP-602P, Nihon Kohden) via an airflow resistance tube (TP-241T, Nihon Kohden), and a breathing amplifier (AR- (601G, Nihon Kohden) was used to measure the respiratory rate per minute. Next, a polyethylene cannula is placed in the left iliac vein, and about 40% of the estimated circulating blood volume (body weight × 0.08 × 0.6 ml) is exsanguinated for 7 minutes to cause hemorrhagic shock. Immediately after the blood was removed, the sample solution was injected through the tail vein (0.3 mg / kg), and the time from immediately after that to the respiratory arrest was recorded as the survival time. The control group was administered with 0.9% physiological saline instead of the sample solution. Rats were preliminarily treated with heparin (600 IU / kg, i.p.
v. ) Treatment and death was determined by respiratory arrest.

The results are shown in Table 1 below.

(Result)

[0018]

[Table 1]

As is apparent from Table 1, the compound-administered group of the present invention survived for 71 minutes longer than the control group, and the survival time was significantly prolonged (P <0.01). Recognize. On the other hand, in the TRH-T-administered group, only the survival time was extended by 9 minutes as compared with the control group, and it can be seen that the compound of the present invention prolongs the survival time by about 8 times as compared with TRH-T. .

[0020]

INDUSTRIAL APPLICABILITY The dihydroorotic acid derivative [I] or a pharmacologically acceptable salt thereof which is the active ingredient of the present invention has an excellent anti-shock action. Further, the dihydroorotic acid derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, has low toxicity and is highly safe as a medicine. For example, the acute toxicity (LD ₅₀ ) of (1-methyl-L-4,5-dihydroorotyl) -L-histidyl-L-prolinamide is 1589 (mg / kg). Therefore, the dihydroorotic acid derivative [I] or a pharmaceutically acceptable salt thereof which is the active ingredient of the present invention is used for the prevention / treatment of hemorrhagic shock, cardiogenic shock, septic shock, neurogenic shock, anaphylactic shock and the like. Alternatively, it can be effectively used for the prevention / treatment of acute circulatory failure, acute hypotension, tachycardia, etc. in these shocks.

Claims (5)

[Claims] 1. A compound represented by the formula [I]: (However, R represents a hydrogen atom or a lower alkyl group.) An anti-shock agent comprising a 4,5-dihydroorotyl-histidyl-proline amide derivative represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The anti-shock agent according to claim 1, wherein R is a lower alkyl group. 3. The active ingredient is (1-methyl-L-4,5).
-Dihydroorotyl) -L-histidyl-L-prolinamide or a pharmaceutically acceptable salt thereof.
The described anti-shock agent. 4. The anti-shock agent according to claim 1, which is a prophylactic / therapeutic agent for cardiogenic shock, hemorrhagic shock, septic shock, neurogenic shock and / or anaphylactic shock. 5. The anti-shock agent according to claim 1, which is a prophylactic / therapeutic agent for acute circulatory failure, acute hypotension and / or tachycardia.