JPH06211803A - Imidazoline derivative and medicine for maintaining blood pressure - Google Patents

Abstract

PURPOSE:To obtain a new effective and safe imidazoline derivative, effectively used as a medicine for maintaining the blood pressure having a new mechanism of action such as elimination of NO. CONSTITUTION:This imidazoline derivative of the formula (R<1> is carboxyl, its pharmaceutically permissible salt, carboxymethoxy or its pharmaceutically permissible salt), e.g. 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazolin-1-oxyl-3- oxide. The compound of the formula, e.g. R<1> is carboxyl or its pharmaceutically permissible salt is obtained by reacting a 2,3-bis-(hydroxyamino)-2,3-dialkylbutane with p-formylbenzoic acid. The compound of the formula in which R<1> is carboxymethoxy or its salt is prepared by reacting the 2,3- bis-(hydroxyamino)-2,3-dialkylbutane with p-formylphenoxyacetic acid. The compound of the formula in which R<1> is H is effectively used as a medicine for maintaining the blood pressure.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel imidazoline derivative and a blood pressure-maintaining drug containing the imidazoline derivative as an active ingredient.

[0002]

2. Description of the Related Art Endothelium-Derived Re, a substance in which vascular endothelial cells relax vascular smooth muscle
It has been known for a long time to secrete a laxing factor (EDRF for short) (Nature, 28).
8 , 373-376, 1980), but nitric oxide (NO) made from L-arginine was subsequently proved to be the essential form of EDRF (Nature, 327 , 5).
24-526, 1987, and Proc. Natl.
Acad. Sci. USA, 84 , 9265-926.
9, 1987).

Endothelial cell NO synthase (1) is resident (Pharm. Rev., 43 , 109-14).
2, 1991 and Lancet, ii , 997-10.
00,1989) and (2) those induced by endotoxin or cytokines such as tumor necrosis factor (Pharm. Rev., 43 , 109-142, 19).
There are two types, 91). While the former (1) is considered to contribute to the physiological regulation of vascular resistance,
It is considered that the rapid increase of NO synthesis due to the latter (2) causes a decrease in vascular resistance and a concomitant decrease in blood pressure, and causes a so-called shock state. Many patients in this condition do not respond to pressor drugs such as norepinephrine and dopamine and are fatal.

Various treatments for such shocks caused by endotoxin or cytocanin have been investigated, and one of them is L-, which is an NO synthase inhibitor.
Treatment of endotoxin shock with arginine analogs has been attempted in animal models or in patients with septic shock (Lancet, 338 , 155).
5-1557, 1991, and Lancet, 33.
8 , 1557-1558, 1991). Since the enhancement of EDRF (ie NO) production is the final and universal phenomenon in lowering blood pressure during endotoxin shock, a strategy for reducing NO is a superior method for treating endotoxin shock. However, considering that the treatment method for neutralizing the effects of endotoxin and individual cytokines is complicated and not easy, the advantage of a single agent for neutralizing the effects of NO is clear.

However, the blood pressure-maintaining effect of NO synthase inhibitors during shock is strongly dependent on the dose, and there is no effect at a small dose, and on the contrary, when it is excessive, it causes an extremely dangerous rise and fall of blood pressure. Therefore, it is reported that the dose should be set carefully (La
ncet, 338 , 1555-1557, 1991 and Lancet, 338 , 1557-1558, 19
91) etc., but there are still problems with safety. Also, NO
Since the synthase inhibitor is an L-arginine derivative, N
There is also the possibility of inhibiting L-arginine-dependent protein synthesizing systems other than O synthase and metabolic systems such as urea cycle,
In that respect as well, there may be side effects. There are many unknown problems, especially when a large dose is continued for a long period of time.

[0006]

SUMMARY OF THE INVENTION In order to solve the above problems without using an NO synthase inhibitor, the present inventors maintain a stable blood pressure by removing excess NO produced. I examined how to do it.

On the other hand, in order to remove NO from cigarette smoke, 2-phenyl-4,4,5,5-tetramethylimidazoline-1 in which R ² is a hydrogen atom in the general formula (2).
-Oxyl-3-oxide (hereinafter abbreviated as PTIO) production method of cigarette smoke filter (UK Patent 1
235880) and atmospheric nitrogen oxide (NO and NO ₂ ) measuring devices as oxidizers of NO
Method (environment and measurement technology, 12 , 32-39, 1
985) has already been reported, including PTIO,
It is not known that the compound represented by the general formula (2) has a blood pressure maintaining effect.

The present inventors examined the effect of PTIO and its derivatives as blood pressure maintaining agents. As a result, in addition to finding various new PTIO derivatives represented by the general formula (1) in which the phenyl group of PTIO is substituted with a specific substituent,
PTIO represented by the general formula (2) and the novel PTI described above.
The inventors have found that a composition containing an O derivative is effective as a blood pressure maintaining drug, and have completed the present invention.

Therefore, an object of the present invention is to provide an effective and safe blood pressure-maintaining drug by a novel compound having an effect as a blood pressure-maintaining drug having a new mechanism of NO elimination.

[0010]

Means for Solving the Problems That is, the present invention provides an imidazoline derivative represented by the following general formula (1):

[Chemical 3] (In the formula, R ¹ is a carboxyl group or a pharmaceutically acceptable salt thereof, or a carboxymethoxy group or a pharmaceutically acceptable salt thereof.) And the following general formula (2).
Is a blood pressure-maintaining drug containing an imidazoline derivative represented by as an active ingredient.

[Chemical 4] (In the formula, R ² is a hydrogen atom, a carboxyl group or a pharmaceutically acceptable salt thereof, or a carboxymethoxy group or a pharmaceutically acceptable salt thereof.) As the pharmaceutically acceptable salt, Particularly, sodium and potassium salts are preferable.

The chemical synthesis of PTIO in which R ² is a hydrogen atom in the general formula (2) can be carried out by the reaction of 2,3-bis- (hydroxyamino) -2,3-dialkylbutane and benzaldehyde (J. .Am.Che
m. Soc. , 90 , 1078-1079, 196.
8).

In the general formula (1), R ¹ is a carboxyl group or a pharmaceutically acceptable salt thereof 2-
(4-Carboxyphenyl) -4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (hereinafter abbreviated as C-PTIO) is 2,3-bis- (hydroxyamino) -2,3. It can be carried out by the reaction of -dialkylbutane and p-formylbenzoic acid.

In the general formula (1), R ¹ is a carboxymethoxy group or a pharmaceutically acceptable salt thereof 2-
(4-Carboxymethoxyphenyl) -4,4,5,5
-Tetramethylimidazoline-1-oxyl-3-oxide (hereinafter abbreviated as CM-PTIO) is 2,3-bis-
(Hydroxyamino) -2,3-dialkylbutane and p
-It can be carried out by reaction with formylphenoxyacetic acid.

Further, the PTIO thus obtained,
And an imidazoline derivative having a substituent represented by the general formula (1) (these may be generically referred to as PTIO and its derivatives hereinafter) are ¹ H- of the product and its intermediate.
NMR, infrared absorption spectrum, mass spectrum, ES
It can be identified by an analysis method such as R.

The blood pressure-maintaining drug of the present invention can be used as a composition containing an effective and low toxic amount. The effective and low toxic amount of the blood pressure-maintaining drug of the present invention is 5 to 500 mg / kg.
Weight / day.

The blood pressure maintaining agent of the present invention can be used as an injection, an oral administration, a suppository or an aerosol spray.

In the case of an injection, any of subcutaneous injection, intramuscular injection, intravenous injection and intraarterial injection may be used. In addition, continuous infusion is possible inside the blood vessel. The injection can be manufactured according to a conventional method. In the injection, there is no particular limitation on the content of PTIO and its derivative, but the content of PTIO and its derivative is 0.001 to 5% (w /
w) is preferred. Alternatively, PTIO and its derivative powder and a solution for dissolution may be separately prepared, and at the same time, both may be integrated into an injection.

The dosage form of the orally-administered agent is, for example, any of tablets, granules, pills, liquids, syrups, troches, drops and the like. These can be manufactured according to a conventional method. Furthermore, it is possible to improve the intestinal absorption by appropriately converting to oil.

Suppositories can be manufactured according to a conventional method, and can be rectal suppositories and vaginal suppositories.

The aerosol propellant can be produced by a conventional method using a suitable propellant.

[0021]

[Function] PTIO and its derivatives are in a molar ratio with NO of 1:
It reacts with 1, adding one oxygen atom to NO, and converting it to nitrogen dioxide (NO ₂ ) which is inactive to vascular smooth muscle, and further, in aqueous solution, NO ₂ is converted to nitrite ion and nitrate ion. . When PTIO and its derivatives themselves become substances inactive to NO by the reaction with NO, PTI
O and its derivatives strongly inhibit NO-dependent relaxation of vascular smooth muscle, and animals administered with these compounds showed normal blood pressure and heart rate even when an NO-saturated aqueous solution was administered intravascularly. It was found to be stable. As mentioned above, PTIO and its derivatives do not inhibit NO synthesis but eliminate excess NO produced, and are extremely safe blood pressure maintenance agents.

[0022]

EFFECTS OF THE INVENTION The present invention provides a drug for maintaining blood pressure during shock. That is, it is a highly safe drug for the purpose of maintaining blood pressure for treatment during shock due to blood pressure decrease such as burns, sepsis, bee or snake venom, anaphylaxis, organophosphorus poisoning, or side effects of various cytokine therapies. It can also be used as an effect enhancer such as a cardiotonic agent.

[0023]

EXAMPLES Next, the present invention will be specifically described with reference to examples.

Example 1 (2- (4-Carboxyphenyl) -4,4,5,5-tetramethylimidazoline-
Synthesis of 1-oxyl-3-oxide (C-PTIO)) 24.6 g of 2,3-bis- (hydroxyamino)-
After dissolving 2,3-dimethylbutane sulfate in 100 ml of water and neutralizing with 1 M KHCO ₃ under ice cooling, 15.
0 g of p-formylbenzoic acid was added, and the mixture was stirred at room temperature overnight. The precipitate formed is dried and 16.9 g of 1,3-dihydroxy-4,4,5,5-tetramethyl 2- (4-
Carboxyphenyl) imidazole (I) was obtained.

This intermediate (I) was analyzed by ¹ H-NMR, FAB
The results of identification by -MS (fast atom collision mass spectrum) are as follows, and were confirmed to be the above intermediate (I).

(1) ¹ H-NMR (DMSO-d ₆ ) δ: 7.73 (dd, 4H, Ar-H) 4.57 (s, 1H, C-H) 4.10 (broads, 2H) , NOH) 1.05 (s, 6H, CH ₃ ) 1.09 (s, 6H, CH ₃ )

(2) FAB-MS m / z 279 (MH) ^-

Then, 14.0 g of (I) was dissolved in 100 ml of N, N-dimethylformamide, and 23.5 g of P was added.
After adding bO ₂ and reacting at room temperature for 3 hours, PbO ₂
Was filtered off. The concentrated residue of the filtrate was dissolved in water and freeze-dried to obtain 12.5 g of C-PTIO. The results of identifying the product by infrared absorption spectrum, mass spectrum, ¹ H-NMR, and ESR were as follows.

(1) IR (KBr disk): 136
0 cm ^-1 (N-O)

(2) FAB-MS m / z 276 (MH) ^-

(3)¹H-NMR (D _TwoO)  δ: 2.90 (d, 12H, CH_Three) 7.90 (s, 4H, Ar-H)

(4) ESR (0.25M phosphate buffer,
pH 7.5) a _N ^1.3 = 0.81 mT

From the above analysis results, the product is 2- (4-
Carboxyphenyl) -4,4,5,5-tetramethylimidazoline 1-oxyl-3-oxide (C-PTI
O) was confirmed.

Example 2 (2- (4-Carboxymethoxyphenyl) -4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CM-PTI)
Synthesis of O)) 24.6 g of 2,3-bis- (hydroxyamino)-
After dissolving 2,3-dimethylbutane sulfate in 100 ml of water and neutralizing with 1 M KHCO ₃ under ice cooling, 18.
0 g of p-phenoxyacetic acid was added and stirred at room temperature overnight,
The resulting precipitate was dried.

This was dissolved in 100 ml of N, N-dimethylformamide, 45 g of PbO ₂ was added, and the mixture was reacted at room temperature for 3 hours. After removing PbO ₂ by filtration, the filtrate was concentrated. Dissolve the residue in water and lyophilize to 1
5.1 g of CM-PTIO was obtained. The analysis results are as follows.

(1) IR (KBr disk): 136
0 cm ^-1 (N-O)

(2) FAB-MS m / z 306 (MH) ^-

(3)¹H-NMR (D _TwoO)  δ: 1.35 (d, 12H, CH_Three) 1.65 (s, 2H, CH_Two) 7.10 (d, 2H, Ar-H) 8.05 (d, 2H, Ar-H)

(3) ESR (0.25M phosphate buffer,
pH 7.5) a _N ^1.3 = 0.82 mT

From the results of this analysis, the product was found to be 2- (4-carboxymethoxyphenyl) -4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (C
M-PTIO) was confirmed.

[Example 3] (Production of C-PTIO injection) C-PTIO was dissolved in 800 ml of distilled water for injection, sodium chloride was added, and the total amount was 1000 ml with distilled water for injection.
And This solution was sterilized by a filtration method to obtain a C-PTIO injection having the following components and composition.

[0042]

Example 4 (Production of PTIO Tablets) PTIO, lactose and starch were mixed and wet granulated with an aqueous polyvinylpyrrolidone solution. After drying and sieving, the granules were kneaded with magnesium stearate and compressed to give tablets of 500 mg / tablet having the following components and compositions.

[0044]

[Example 5] (Production of CM-PTIO suppository) The following components were mixed and mixed to give 10 suppositories. CM-PTIO 5.0g Macrogol 4000 2.0g Macrogol 1500 9.0g

[Example 6] (Inhibition of EDRF-dependent relaxation of vascular smooth muscle by the blood pressure-maintaining agent of the present invention) A rabbit aorta with vascular endothelium was prepared in a ring shape and filled with Krebs-Ringer solution in an organ bath. It was hung inside and its tension was recorded continuously. The aorta was contracted with 0.15 μM phenylephrine and then completely relaxed by adding 3 μM acetylcholine. This relaxation of vascular smooth muscle by acetylcholine is caused by EDRF (ie, N
O) known to be dependent. At this time, PTIO and phenylephrine and C-PTIO or CM-PTIO prepared in Examples 1 to 2 were added to 30, 1
In addition to concentrations of 00 and 300 μM, the extent of PTIO inhibition of acetylcholine-induced relaxation was measured. As a control, the NO synthase inhibitor N ^G -methylarginine was used at the same concentration. The results are shown in Table 1.

[0047]

Table 1 Inhibition of EDRF-dependent vascular smooth muscle relaxation by PTIO, C-PTIO, CM-PTIO and N ^G -methylarginine (Note 1) The vascular smooth muscle contracted by 0.15 μM phenylephrine was 100% relaxed by 3.0 μM acetylcholine. The relaxation rate at this time was 0%. (Note 2) The measured value is the average value ± standard deviation of 10 experiments.

As is clear from the results in Table 1, PTI
O, C-PTIO and CM-PTIO suppressed EDRF-dependent relaxation of vascular smooth muscle in a concentration-dependent manner. PTI
The strength of inhibition by O and CM-PTIO is almost the same as or slightly stronger than that of N ^G -methylarginine, and C-P
The strength of inhibition by TIO was about twice that of these substances.

[Example 7] (Inhibitory effect of PTIO on blood pressure decrease by intravenous injection of NO aqueous solution) [0049] A rat anesthetized with Nembutal was cannulated into the tail vein for use as a drug administration route. An average blood pressure and a heart rate were monitored by measuring a tail artery pressure wave using an automatic blood pressure measuring device (PS-200) manufactured by Riken Development Co., Ltd. To the rats of the first group, 2.0 mg / ml PTIO injection prepared according to Production Example 1 was intravenously infused at a rate of 6.0 ml / hour for 10 minutes, and then 4 minutes later, 1 NO saturated physiological saline solution was added. 0.0 ml was intravenously injected. Rats in the second group were similarly administered NO without PTIO. A physiological saline solution was continuously infused at a rate of 6.0 ml / hour except when the drug was administered. During this period, the blood pressure and heart rate were continuously monitored, and the blood pressure and heart rate values for 5 minutes after NO administration were N
The ratio to that for 5 minutes before the O administration was measured. The results are shown in Table 2.

[0050]

[Table 2] Effect of PTIO on changes in blood pressure and heart rate by NO administration Experimental group 1: 10 mg of 2 mg / ml PTIO at 6 ml / hour
Group administered for 3 minutes (3 animals). Experimental group 2: a control group (3 animals) not administered with PTIO. Each measured value shows an average ± standard deviation.

According to the results shown in Table 2, the blood pressure was lowered by about 40% and the heart rate was about 20 by the administration of the NO-saturated saline solution.
% Increase (Group 2), but preadministration of PTIO showed little change in blood pressure and heart rate (Group 1).

Claims (2)

[Claims] 1. An imidazoline derivative represented by the following general formula (1): [Chemical 1] (In the formula, R ¹ is a carboxyl group or a pharmaceutically acceptable salt thereof, or a carboxymethoxy group or a pharmaceutically acceptable salt thereof.) 2. A blood pressure-maintaining drug containing an imidazoline derivative represented by the following general formula (2) as an active ingredient. [Chemical 2] (In the formula, R ² is a hydrogen atom, a carboxyl group or a pharmaceutically acceptable salt thereof, or a carboxymethoxy group or a pharmaceutically acceptable salt thereof.)