JPS59225170A - Aminopropanol derivative, its preparation, and cardio- selective agent for blocking beta-adrenalin action containing said compound - Google Patents

Abstract

NEW MATERIAL:N-[3-( 2-Flourophenoxy )-2-hydroxypropyl-N'-(1, 3-dimethy1-2, 4- dioxopyrimidyl(6)]-ethylenediamine of formula I and its acid addition salt. USE:A cardioselective beta-adrenaline-action blocking agent having extremely strong beta-blocking activity, remarkably high cardioselectivity and wide safety. PREPARATION:The objective compound of formula I can be prepared by reacting the compound of formula II with the compound of formula III optionally in an inert organic solvent. The starting compound of formula III can be obtained easily in high yield in crystalline form, by reactiong ethylenediamine with 1,3- dimethyl-6-chloropyrimidinedione(2,4) in dioxane at 10-100 deg.C.

Description

[Detailed description of the invention] TECHNICAL FIELD The present invention relates to minopropertool derivatives.

More specifically, it relates to an aminopropanol derivative having β-adrenergic blocking properties and a method for producing the same.

Aminopropanol derivatives provided by the present invention are compounds of the formula CD Hs and pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention have asymmetric carbon atoms and therefore occur as racemates as well as in the form of optical antipodes; the optical antipodes can also be resolved from the racemates using known methods.

The aminopronognol derivatives of formula (1) according to the invention can be made into physiologically compatible acid addition salts. Suitable acids include, for example, hydrochloric acid, arsenic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid,
These are lactic acid and tartaric acid.

Conventionally, 1-phenoxy-6-alkylamino-2-propatol derivatives having a substituent such as an isopropyl group or a kushari-butyl group at the N-position have been shown to have β-adrenergic neuroblocking action (hereinafter referred to as β-blocking action). ) is known (e.g. Austrian Patent No. 252)
No. 217, Belgian Patent No. 641133), and compounds in which the N-position is substituted with an arylalkyl group or an alkyl group having a heterocycle instead of the alkyl group are known (for example, JP-A-55-120559, Japanese Patent Publication No. 5
No. 0-95283, JP-A-53-141285). In addition, compounds in which various functional groups are incorporated into the phenyl nucleus at the 1-position of the phenoxy bond at the 1-position of propanol are also known (for example, IF, Bunsaku No. 44-26097, Japanese Patent Publication No. 5).
5-18700) Furthermore, f-hi compounds in which the compound=1 so group is exalted in place of the phenyl group are also known (for example, Japanese Patent Publication No. 42-9954, Japanese Patent Application Laid-Open No. 56-951/7).

Various derivatives of aminopropanol such as those mentioned above are β-
It was developed as a stimulant with anti-inflammatory effects and has been clinically used, and has been shown to be effective in treating angina pectoris, hypertension, and certain arrhythmia diseases. However, blocking the β-receptors in the heart (hereinafter referred to as β1 blockade)
It is known that it not only blocks β-receptors in blood vessels and bronchi (hereinafter referred to as β2-blocking), but is therefore effective for heart disease patients with diseases such as bronchial asthma and emphysema, and obstructive arterial disease. It is said that administration of known β-blockers to patients should be avoided. For these reasons, it has been desired to develop so-called cardioselective β-blocking drugs. Furthermore, there is a need for a drug with a large difference between β-blocking activity and the dose at which toxicity (side effects) occurs, that is, a drug with a wide safety margin.

Given the current situation, the present inventors have conducted repeated research with the goal of developing a β-blocker that has cardioselectivity and a wide safety margin, and have found that the f-blocker shown in formula It has been found that it has excellent β1 blocking activity and selectivity for the heart, and also has an extremely wide safety margin. The compound of the present invention is β
It is a compound with β-blocking activity that is among the strongest among -blocking agents, and no compound with such strong activity and high cardioselectivity has been known up to now. Furthermore, although the compound of the present invention has an extremely wide safety margin, no β-blocker having such a wide safety margin has been known up to now.

The compound represented by formula [I] of the present invention is disclosed in JP-A-56-1
Claim 1 of Specification No. 41285: General formula (1)
As a result of the investigation, it was discovered that Kokichi is a f-compound that can be said to be of great value, but the patent specification not only does not contain any specific description of the compound of formula [I] of the present invention, but also 1
From page 7, line 12 to page 18, line 4, the compound of formula (11) or its acid addition salt is (generally preferred -1) (omitted)
, or substituents R1 and r (one of 2 is not a hydrogen atom and is located at the para position of the phenyl nucleus, or R
1 or R2 is a hydroxyl group, alkoxy, alkoxyalkyl-1 or hydroxyalkoxy group. Particularly clever ones have two or more of the above-mentioned properties, i.e. n 2, R= CR3, R2 is hydroxyl in the para position, hydroxyalkoxy, alkoxy, It means an alkoxyalkyl-1 or hydroxyalkoxy group.'' In the compound of formula [I] of the present invention, the para position of the phenyl nucleus is unsubstituted, and the ortho position is substituted with a fluorine atom. However, extensive pharmacological experiments have shown that the f compound of formula [I] of the present invention has extremely strong β-blocking activity and extremely high cardiac selectivity. However, this was not expected from the description of the cited patent application.Therefore, the present inventors discovered that the compound described in JP-A-53-141285 had a broader safety profile. An r compound (f compound-person) in which the ortho position of the phenyl nucleus is substituted with a chlorine atom (f compound-A) and a compound in which the phenyl nucleus is substituted at the nC4H00- position (compound-
As a result of synthesizing B) and measuring the β-blocking activity of each (see test results below), no compound with strong β-blocking activity and cardioselectivity was found. Furthermore, from among these compounds, para ("4 nC4) 1gO- was substituted [
Compound-B (cited in t3iJ) Patent application JP-A-1987-
Among commercially available β-blockers, pindolol and propranolol were selected from among commercially available β-blockers, and the safety margin (LD, ./ED) of the compound of the present invention was determined. .

(Pindolol) (Propranolol) Means one of the parameters indicating the degree of safety) As a result (see test results below), the compound of the present invention (racemic suspension) is a nc4Hgo-substituted product, and the compound-B is 20
10 times more than pindolol, 100 times more than propranolol
It was found that there is a safety margin of ~200 times. These effects were completely unexpected from the descriptions of the cited patents, and were discovered for the first time by the present invention. Furthermore, no β-side agent with such a wide safety margin has been known until now.

Therefore, the compound of the present invention has a high possibility of becoming a drug with fewer side effects in clinical practice, and while most of the commercially available β-blockers are prescribed as powerful drugs, the compound of the present invention has a high possibility of becoming a drug with fewer side effects. It is expected that it will be possible to administer the drug as a drug. The compound of the present invention has a long duration of action.
It has also been shown that it has pharmacological properties such as anti-arrhythmia and no local anesthetic effect [9].

Next, we will discuss the pharmacological effects of the fl:X compound of the present invention.

[Experimental materials and methods].

1. Beta-blocking effect After an adult mongrel dog was anesthetized with ventoparvitarna II, both IE vagus nerves were cut at the head. Blood pressure and heart rate were measured from the left femoral artery using an electric sphygmomanometer. Membrane surface 1. Blood flow was measured in mice. 1. After treatment with heparin to prevent blood clots, an extracorporeal circuit was created in the right femoral artery, and a probe was placed in this circuit to measure blood flow.

The test drug was dissolved in physiological saline and injected into the femoral vein or extracorporeal circuit.

l5oproterenol O, 5 μy/nori (i,
■,) ED of βl blocking effect, the dose of the test drug that suppresses the increased heart rate by 50%. value and also 0
, 5 μl/animal (i, a,) of gD, which has a β2-blocking effect, is administered at a dose that suppresses the increased femoral artery blood flow by 50% by intracorporeal administration. (I fixed it.

2. Oral absorption and persistence After anesthetizing an adult mongrel dog with thiobental, insert silicone tubes filled with henochlorinated fluid into the thoracic aorta and thoracic vena cava, and expose the ends of each under the skin of the scapula through the neck. did. At least 6 days after the surgery, blood pressure was measured using a silicone tube inserted into the artery, and a tachometer was driven from the pulse wave to measure heart rate.

Additionally, l5oprot was administered via a tube inserted into the vein.
After administering erenolO, 7 to 5μb and observing changes in blood pressure and heart rate, the test drug was orally administered and how the changes in blood pressure 2 and heart rate due to l5oprotereno+ administration were affected by the test drug over time. I watched it to see if it changed.

The animals used were fasted for 18 hours before the start of the experiment.

3. Antiarrhythmic effect After anesthetizing an adult mongrel dog with bentoparbital sodium, intravenously inject 0uahain 40 tt 17Kg, and then administer 0uahain 10a at 20 minute intervals.
f/9 was administered until arrhythmia appeared. 0u
The total amount of abain is 60μf/Ky or 70μy7
A persistent arrhythmia developed when xg was reached. After the appearance of arrhythmia, the test drug was injected at a rate of 4 μ/Ky/min until the arrhythmia disappeared, and the dose of the test drug required to eliminate the arrhythmia was determined as EDlo.

I asked for it as.

4. Local anesthetic effect After stimulating the 14F guinea pig cornea with a 1/4 mandoline wire for injection and confirming that a flicker reflex occurred, 0.2 ml of the test drug at various concentrations was instilled into one eye.

Physiological saline was instilled into the eye on the other side, and after 5 minutes, the cornea was stimulated 6 times at 5 minute intervals and the number of blink reflexes was counted.

The total number of blink reflexes for 30 minutes after instillation was determined and compared with that on the side in which the saline solution was instilled.

The concentration of the test drug that caused a 50% reduction in the number of blink reflexes in the control eye was defined as EC,o.

5. Acute toxicity Five week old ddY male mice were used per group.

The administration volumes of the test mulberry were p, o, i, and v, all of which were 0.
1 me/101. After administering the test drug, observe the symptoms of toxicity and count the number of deaths to determine the estimated LD5. The value was calculated.

6. Safety margin, LD, which means one index of safety. /
E D a o values were calculated and compared.

〔Experimental result〕

1. β-blocking effect β1 and β when each test drug was cumulatively administered.

Table shows the results of ED5° value S of i-blocking activity and cardiac selectivity.
Shown in 1.

Table-1 Compounds of the present invention 3 90 Ro○ Compound-A 5 3 0.6 Compound-Rdo
2,500 6'), 5 pin roll
3.4 4. t6 1.4 Propranolol 70 80 1.1 The β-blocking activity of the compound of the present invention was the same as that of pindolol, which is said to be the strongest among existing β-blocking agents, and was extremely high compared to other compounds. . The cardiac selectivity was about 1/2 of that of r-hybrid compound-B, but it was clearly higher than other compounds. l1f
D) The compound of the present invention is a highly cardioselective compound-B.
It exhibited β-blocking activity comparable to that of Compound-B in the /1o wall, making it the most well-balanced and useful β-hlocker among these compounds.

2. Oral absorption ε and duration of action The β-blocking activity and duration of oral administration of the compounds of the present invention were clearly superior to Compound-B8 and propranolol. The maximum effect of the compound of the present invention appeared 2 hours after administration, and the β-blocking effect was completely maintained even for 8 hours. Other compounds lost activity within 8 hours. (Table 2) Table 2 Isoproterenol (0,
Table 6 shows the results of the antiarrhythmia effect. The compound f of the present invention exhibited almost the same activity as Compound B and propranolol.

Table - Compound of the present invention 6.96 Ratio Compound - B429 Propranolol 615 4. The local anesthetic effect results are shown in Table 4. 1% of the compound of the present invention did not exhibit any surface anesthetic effect.

Table 4 Compounds of the present invention 〉1.0 Compound-B > 1.0 Pindolol 068 Propranolol 0.17 The strong local anesthetic effect may lead to blockage of the cardiac impulse conduction system, so it is not a desirable effect.

5 Mouse Acute Toxicity Estimated LD by oral administration 2 and intravenous injection. The values are shown in Table-5. Although the compounds of the present invention exhibit strong β-blocking activity, they exhibit extremely low toxicity.

Table-5 p, 0° Compound of the present invention 6.000 350 ratio compound-1
3〒1.000 220 Pindolol 350 40 Propranolol 551 686, safety margin L1) 5°/
E.D. are shown in Table-6. The safety margin of the compounds of the present invention is much wider than that of Deco-B, pindolol and brobranolol.

Table 6 p, 0 Compound of the present invention 1000 117f compound-B
>25 5.5 pin roll
10ro 11,8 propranolol
7.9 0.54 When using the r-H compound of the present invention in medicine, it is possible to use it as a free base as a pharmaceutical raw material, but stability, ease of formulation, etc. should also be taken into consideration. Furthermore, in cases where water solubility is required, such as in the case of injections, it may be used as a pharmaceutically acceptable salt such as hydrochloride, citrate, phosphate, etc. It is preferable to use it for.

The medicament of the present invention can be used in the same dosage form and administration method as conventional β-blockers.

For example, tablets, capsules, etc. can be used as oral preparations. As an injection, an intravenous drug or the like can be used.

The β-blockers of the present invention are suitable for the treatment or prevention of heart diseases such as angina pectoris and arrhythmia, and are also suitable for the treatment of hypertension.

It is desirable that the administration method 8 and dosage form of the medicament of the present invention be appropriately selected depending on the type of disease, patient's condition, etc. The appropriate dosage is 0.1 to 60 mg per day. Furthermore, depending on the type of disease and the patient's condition, the therapeutic effect of the active ingredient of the present invention can be increased by using other mowing agents as necessary.

Next, a method for producing the compound of the present invention will be explained.

The present invention provides ro-(2-fluorophenoxy)-1゜2- represented by the formula (ID).
If epoxypropane and N-[1,3-dimethyl-2,4-dioxopyrimidyl(6)]-ethylenediamine of the formula (II FI3) are required, they are reacted in an organic solvent inert to this reaction. The present invention also includes a method for producing an aminopropatur derivative represented by formula (1), which is characterized by It was found that two manufacturing routes have been described.

E+] One of them is the route [Al shown below formula or triethylamine, and the other one (Ma-JB) is shown below formula H
3 OOH Y is a hydrogen atom or a residue that can be separated by hydrogenolysis. However, most of the Examples described in the same specification are the A route (Examples 1 to 4), and the B route is only Example 5, and the compounds of Examples 6 to 47 listed in Table 1 It is also described that these were manufactured according to Examples 1 to 5 (see page (44) of the specification of the same application). Therefore, according to the description in the same specification, the manufacturing route F
There is only Y at 8 in T'31, and when Y is a hydrogen atom, there is no specific description of ζ. This is because the reactivity of the two amino groups of ethylenediamine is equivalent to that of ethylenediamine, as the inventors believe.
6←Dimethyl-6-chloropyrimidinedione (2,4)
In the reaction with , it reacts with both amino groups to form the so-called bis-form (N,
N'-disubstituted product) or N, N-disubstituted product and even N
, N, N', N'-tetra-substituted products, etc., to form a complex mixture. Therefore, in order to avoid this side reaction, N-benzylethylenediamine, which has been retained with a benzyl group in advance, is used. Ro-dimethyl-6-chloropyrimidinedione (
2,4) to produce N-benzyl-N'-(1,3-dimethyl-2,4-di''-xopyrimidyl (6))]-ethylenediamine and using this as the starting product] Note B It is thought that the manufacturing method of the route was adopted.

However, the present inventors reacted ethylenediamine and 1゜6-dimethyl-6-chloropyrimidinedione (2゜4) in an inert solvent, particularly dioxay, at room temperature or with gentle warming, and then allowed to cool to room temperature. N-(1) readily crystallises in good yield.

6-dimethyl-2,4-dioxopyrimidyl (6)]-
It has been found that ethylenediamine can be obtained.

This fact could not have been predicted at all from the technical standpoint described in the cited patent application. Even when this reaction was carried out in a solvent such as toluene, benzene, ethyl alcohol, dimethylformamide or diglyme, the desired product was not obtained in the form of crystals from the reaction solution.

Next, N-(1,3-dimethyl-2,
4-dioxopyrimidyl (6)]-ethylenediamine (
! : By heating and reacting 3-(2-fluorophenoxy)-1,2-epoxypropane in an inert solvent such as ethyl alcohol, the compound of the present invention, that is, N-[3-(2-fluorophenoxy) phenoxy)-2-hydroxyproyl-N'-(1,3-dimethyl-2,4-
Dioxopyrimidyl (6)]-ethylenediamine is obtained as crystals.

On the other hand, in the case of the cited patent application, the starting product N-benzyl-N'-(1,3-dimethyl-2
,4-dioxopyrimidyl(6)]-ethylenediamine is 1,5-dimethyl-6-chloropyrimidinedione(2)
, i) and N-benzylethylenediamine in boiling doluol, but there is no description of the yield, and the product obtained is hydrochloride, which is further converted into a free base with an aqueous soda solution. This is then 2-n-
When it is reacted with butoxyphenyl glycide ether, it is not obtained as a crystal but only as an impure resinous state. Moreover, in the above-mentioned cited patent application, this is P
Hydrolysis using d/C must be carried out in several steps using extremely complicated means. Furthermore, it is also known that the process for producing N-benzylethylenediamine itself, which is the starting material of the cited application, is not necessarily easy.

Compared to this, the production method of the present invention has fewer steps and is simpler, as described above, and can be carried out industrially with great advantage.

The following examples illustrate the preparation of the compounds of the present invention. The present invention is not limited to the following examples.

Example-1 Production of N-45-(2-fluorophenoxy)-2-hydroxypropyl-N'-[:1,3-dimethyl-2,4-dioxopyrimidyl(6)]-ethylenediamine N-[ 4.59 (0,022 mol) of 1,3-dimethyl-2,4-dioxopyrimidyl (6)]-ethylenediamine and 80 ml of ethyl alcohol were placed in a flask equipped with a condenser and heated to 80°C. Let it go and dissolve. In this, 3.8?3-(2-fluorophenoxy)-1,2-epoxypropane? A solution of (0,022 mol) dissolved in 113 ml of ethyl alcohol was added dropwise over about 1 hour. The mixture was continuously stirred at 80°C for 4 hours. The reaction solution was left to cool overnight to precipitate.

The crystals were filtered, washed with a little ethyl alcohol, and then dried. When the P washing solution was concentrated and allowed to cool, crystals (secondary product) were obtained. A total yield of 61% and a yield of 73.5% were recrystallized from ethyl alcohol and then acetone, and the melting point was 141.0-1425°C.

redundancy; analysis i1σ 0%) I[fly N(%
F%) Actual value 55,69 6.67 15
,25 5.10 Calculated value 5・5,73 6.33
15.47 5.19 (C, 71-1□3FN4
04) as IR, vcm"' (Kf3r) 260, 2900, 1690, 16.10° 1550
, 1500 , 1440 , 1360 .

1300.1260,1200,1100°1040.
940.750 N-(i,ro-dimethyl-2
,4-dioxopyrimidyl(6)]-cochenediamine was prepared as NY6 as follows.

Dioxane 3 () 44 g of ethylenediamine was cooled in a flask with a top and stirred to dissolve. Into this, 10 f of 1,6-dimethyl-6-chloropyrimidinedione (2,4) was added to 30 tttl of dioxane. was gradually added dropwise over a period of about 1 hour at 75-80°C. The mixture was further stirred at 80°C for 3 hours. - At night, the precipitated crystals were filtered, washed with dioxane and then methanol, and then dried. Yield: 7.9f, Yield: 70.0
%, melting point 153.5-154.5°C (recrystallized from methanol).

Elemental analysis value C(?d H(HiNen actual measurement value 47.60 6.93 28.26 Calculated value 48.4B 7.12 28.49I R
17cm-' (KBr) 3320.2830.1640~1600°1420.
1250,960,760 Example-2 N-C3-C2-fluorophenoxy)-2-hydroxypropyl-N'-[1,3-dimethyl-2,4-dioxopyrimidyl (6)]-ethylenediamine hydrochloride Preparation of the free base 4.07 (obtained by the method described in Example 1)
o, oii mol), 20 trtl of water, and 1.21 mol of 64% hydrochloric acid were mixed to uniformly dissolve. Water was distilled off from this solution under reduced pressure, and 60 ml of acetone was added to the residue and stirred to form crystals. It was filtered and washed with acetone and ethyl ether. Yield 412, yield 94.1%, Ma1 point of recrystallized from methanol is 18Z5-18
The temperature was 8.5°C (foaming decomposition).

Elemental analysis value C
28 6.20 13.81 9.27 Calculated value 50.
68 6.00 13.91 8.80(”+7
H23FN404・Hcb) as 71 (Crn-
'(KBr) ro260.2920.1650.1550.

1450.125[], 1200,110[1°103
0.760 Example-5 N-(ro-(2-fluorophenoxy)-2-hydroxybrobyl-N'-[1,3-dimethyl-2,4-dioxopyrimidyl(6)]-ethylenediamine Tablets as active ingredient N-(3-(2-fluorophenoxy)-2-hydroxypropyl-N'-'[1,ro-dimethyl-2,4-dioxopyricimidyl (6)]-ethylenediamine 1 j 123 y of milk and 20 g of corn starch were mixed well, mixed and granulated with a solution of 5 f of hydroxypropyl cellulose dissolved in 100 ml of water, and then granulated at 50°C.
Dry for an hour. 12 pieces of magnesium stearate are added to the mixture, mixed well, and then compressed using a tablet machine to give tablets with a weight of 150 square centimeters per tablet.

Example-4 N-(ro-(2-fluorophenoxy)-2-hydroxypropyl-N'=(1,ro-dimethyl-2,4-dioxopyrimidyl(6))]-ethylenediamine as an active ingredient Capsule N-(3-(2-fluorophenoxy)-2-hydroxypropyl-N'-[1,3-dimethyl-2,4-dioxopyrimidyl (6)]-ethylenediamine 51. Milk 1
Mix 12O5'g of ffi and 25f of corn starch well. This is filled into hard capsules of 1507 #g using a capsule filling machine to obtain capsules.

Example-3 Effective use of N-(3-(2-fluorophenoxy)-2-hydroxydibropyru-N'-(1,ro-dimethyl-2,4-dioxopyrimidyl 16)]-ethylenediamine hydrochloride Injection N-[3-(2-fluorophenoxy)-2-hydroxypropyl-N'-[1,3-dimethyl-2,4-dioxopyrimidyl (6)]-ethylenediamine hydrochloride 2
Take 100ml of sodium chloride and 085ml of sodium chloride, dissolve it in an appropriate amount of distilled water for injection, and make the total amount 100ml (!) to make an injection. This injection is suitable for intravenous administration.

Agent Patent Attorney 1) Parent Male -n [q

Claims (3)

[Claims] (1) Ryominopropatool derivative 8 represented by formula (1) and a pharmaceutically acceptable acid addition salt. (2) A cardioselective β-adrenergic blocker containing an aminopropanol derivative represented by formula [I] or a pharmaceutically acceptable thallic acid addition salt thereof. (3) Formula [■] c indicates tl, 5-(2-fluorophenoxy)-i
. 2-epoxypropane and formula [1) CH. A method for producing an aminopropanol derivative represented by formula [I] 0 , which comprises reacting N-[1,3-dimethyl-2,4-dioxopyrimidyl (6)]-ethylenediamine represented by . N-Cl, dimethyl-2,4-dioxopyrimidyl (6)]-ethylenediamine represented by (41niJ formula CI) is ethylenediamine and 1. Ro-dimethyl-6-
chloropyrimidinedione (2,4) in dioxane
The method according to the above item (3), which is produced by reaction in a temperature range of 0°C to 100°C.