DE1792764B2 - Coronary drugs - Google Patents

Description

CH ₃

in which

R 'for alkyl radicals with 1 to 4 carbon atoms

stands and
R "stands for a nickel radical or stands for 2 substituents, the other substituent being chlorine

R'OOC

COOR '

(D

H ₃ CH CH ₁
in which

R 'for alkyl groups with 1 to 4 carbon atoms

stands and
R "stands for a nitro radical or stands for 2 substituents, the other substituent being chlorine.

Among the diseases of the circulatory system, there are primarily those that affect the coronary artery of the heart more and more in frequency. There has therefore been no lack of attempts to find effective compounds for treatment to find these diseases.

The previously commercially available preparations, however, z. B. Dipyridamole and Carbocromene, which according to animal experiments in the case of intravenous administration, therapeutic hopes appear justified Coronary insufficiency, especially in painful angina pectoris, clinical success is not always certain eezeiet.

The present invention relates to new coronary drugs containing 1,4-dihydropyridines.

',, 4-Dihydropyridines and process for their preparation have already become known. Their suitability as a medicinal product, especially as a coronary drug, was however-not yet described.

There have been coronary drugs for oral, intravenous or intramuscular administration or in the form of Found suppositories which are characterized by the content of at least one dihydropyridine general formula (I)

So in most of the pills you were still on nitrites, their effect on a heart relief, among other things based, instructed.

Nitroglycerin, which is also used as a coronary therapeutic agent, only lasts about 5 times Minutes and is therefore unsuitable for the prophylactic treatment of coronary disease

Surprisingly, the abovementioned 1,4-dihydropyridines show both when administered intravenously as well as a significant and long-lasting coronary enlargement, especially with oral application. Due to their strong effect, their rapid onset of action and their long duration of action, these have become Compounds shown to be superior to known commercial products

In addition, these compounds show very strong musculotropic calcium antagonism. This Mechanism of action differs from the mechanism of action the comparison substances. Thus, these coronary-active compounds are an asset in pharmacy because they once show a superiority over known substances and on the other hand another agent with a different mechanism of action for the treatment of coronary diseases represent.

The compounds used to prepare the corona agents are obtained by adding benzaldehydes of the general formula (II)

HC = O

in which

R "has the above; meaning

with acyl fatty acid esters of the general formula (III)

H ₃ C-CO-CH ₂ -COOR ' m

in which

R 'has the meaning given above,

and with ammonia in an organic solvent, in particular in alcohols

Various of the compounds used in the corona agents are known, see also Journ. Amer. so Chem. Soc. 71 (1949), pp. 4003-4007 and Chem. Abstr. 60 (1964), columns 1689h-1690c, without their Their usefulness as coronary therapeutic agents is described there.

pharmacology

The following are the most important pharmacological data of the 4- (2'-nitrophenyl) -2,6-dimethyl-3 _i 5-diparbmethoxy-1,4-dihydropyridine prepared according to the method of Example 1 are given. The pharmacological testing of the other compounds falling under the general formula leads to similar, albeit gradually different, values.

ei This connection has an LD »of on the mouse 375 mg / kg p. o. (solvent polyglycol) and 202 mg / kg p. o. (Solvent Lutrol). It is included i. v. application around 26 mg / kg.

Rat blood pressure;

At 0.125 mg / kg Lv. slight decrease during the Injection.

Coronary effects of the dog:

Flow rate:

Anesthesia: urethane chloralose.
At OJBlOS mg / kg Lv. 40% increase, exit after 10 minutes. At 001 mg / kg L v. 60% increase, exit after 20 minutes. At 0.02 mg / kg L v. <° increase by 70%, exit after 30 minutes. At 10 mg / kg po increase by 60%, after 8 hours still 30% above the starting point. The minute volume increases by 55%.

The blood pressure decreased by '5 in these experiments 20 to 60 mm Hg.

Oxygen saturation:

At 0.005 mg / kg Lv. slight to strong increase in 6 attempts, exit after 30 to 60 minutes. ^M.

(GiycGbarbitalnarkosc)

At 0.01 mg / kg L v. (3 attempts) and 0.02 mg / kg L v.

(1 attempt) strong increase, exit after 14 to 2 Hours.

At 0.05 mg / kg L v. (3 attempts) in 2 attempts

clear rise, exit after cn. 3 hours. In 1 attempt temporarily slight increase.

At 0.1 mg / kg L v. sharp increase after 30 minutes

canceled, still 23% over exit.

Oxygen pressure: Anesthesia: urethane chloralose. OJS mg / kg po significant increase, exit after approx.

7 hours (2 attempts).

10 mg / kg p. o. (1 attempt) significant increase.

Exit after 9 hours.

50 mg / kg p. o. sharp increase, still after 8 hours above the exit.

Blood pressure:

Anesthesia: CyclobarbitaL At 0.005; 0.01; 0.02 and 0.05 mg / kg Lv. distinct Lowering of different duration. At 0.1 mg: kg L v. sustained strong reduction. at O ^ and 1 mg / kg L v. very strong depression. Anesthesia: urethane chloralose. 0.005; 0.01 and

0.02 mg / kg Lv. slight decrease, 04 mg / kg p.o.

strong depression.

10 mg / kg p. o. 1 attempt significant, 1 attempt so strong reduction.

50 mg / kg p. o. sustained strong reduction.

40 frequency;

Anesthesia; CyclobarbitaL Different light effects (L v.-Appüka-

tion).

Anesthesia: urethane chloralose,

0.5 mg / kg p, o, strong different effects.

10 mg / kg p. o. sharp increase.

50 mg / kg p. o. sharp increase.

The oxygen consumption is according to the substance district of 1 mg / kg p. o. by 20%, after 20 y / kg L v. by approx. 50% lowered Simultaneously with the greatly increased coronary blood flow a decrease in blood pressure takes place, which leads to a relief of the heart peripheral reduction in resistance results in a measurable reduction in oxygen consumption. In this it is similar the substance is known to be clinically very effective nitrites, which also have a noticeable decrease in oxygen consumption cause.

The pharmacological attack of this substance is likely the vascular smooth muscle as such, an effect on the central or vegetative central nervous structure could not be demonstrated.

The superiority of the coronary drugs with a content of the above. 1, ^ dihydropyridines compared to the im Commercially available coronary drug dipyridamole can be seen from the following tables.

Table 1 contains the ΕΓ? >> the compound relative to the increase of oxygen saturation in coronary sinus venous blood of the dog and the LD ₅ O of Example 1 and the reference substance dipyridamole.

As can be seen from the table, the compound mentioned only accounts for about 1/2 of the amount of substance the comparison compound is required to achieve the same effect. So this connection is that Superior to a comparable product, even if it is taken into account that the comparable dose of the comparative compound is about 4 times higher

Table 1 Example 1 Dipyridamole LDj ₀ mouse per os, mg / kg 494 2150 ED ₅₀ dog IV, mg / kg 0.0034 0.179

Table 2 shows the relative efficacies of the above-mentioned 1 ^ -dihydropyridines in relation to their potency and duration of action. The effectiveness of the dipyridamole was set here in each case -1 and the potency of the 1,4-dihydropyridines on this Value calculated

Table 2 Coronary drugs Dipyridamole Resorption per os With a content of link Dose 0.5-1mg / kg Dose 10-20 mg / kg number 1 Onset of action 2-5 min Onset of action from 60min Dose 5 mg / kg No. la Onset of action 20 min Dose 1mg / kg No. 2 Onset of action 2 min

17 92 764
5
continuation 6th 1 no effect Coronary effects on dogs ^: Resorption per os coronary agent Dipyridamole Capsules 0.005-0.02 mg / kg Lv.
0.5-1.0 mg / kg po With a content of
link
No. 2a dose 5 mg / kg
Onset of action 1-lOmii 24 mg 0.01 mg / kg Lv. Resorption sublingually Table 3 contains data on the coronary effects of the agents according to the invention on dogs. The indicated
given dose causes a clearly visible increase in oxygen saturation (approx. 20%). 0.01 mg / kg Lv. Example 1 dose 0.5-1 mg / kg
Onset of action 2-3 min Table 3 0.005 mg / kg Lv. Connection ampoules link 0.05 mg / kg Lv. Example 2b
4- <3'-nitrophenyl) - 0.2 mg
2,6-dimethyl-3,5-dicarboixo-
propoxy-1,4-dihydropyridine example 1
4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbomethoxy-
1,4-dihydropyridine 0.005 mg / kg Lv. Example la
4- (2'-nitrophenyi) -2,6-dimethyl-3,5-dicarbethoxy-
1,4-dihydropyridine 2 mg / kg Lv. Example Ib
4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbo-isopropoxy-
1,4-dihydropyridine 0.1 mg / kg i.v. Example 2
'KS'-NitrophenyO ^ .ä-ditnethylO.S-dicarbethoxy-
1,4-dihydropyridine 0.05 mg / kg i.v. Example 2a
^ '- Nitn ^ henyO ^ .ö-dimethylO.S-dicarbomethoxy-
1,4-dihydropyridine Example 2 b
^ S'-NitrophenyO ^ .o-dimethyl-SS-dicarbo-isopropoxy-
1,4-dihydropyridine Example 3
^ '- NitrophenyO ^ .o-dimethyl- ^ S-dicarbethoxy-
1,4-dihydropyridine Example 2d
4- (3'-nitro-6'-chlorophenyl) -2,6-dimethyl-
3,5-dicarbmethoxy-1,4-dihydropyridine Example 2e
4- (3'-nitro-6'-chlorophenyl) -2,6-dimethyl-
3,5-dicarnethoxy-1,4-dihydropyridine

17th 92 764 30-40%
20-30% Coronary sinus
Duration of action example
No. Increase in Oj saturation in the
of the mouth
Dose mg / kg effect
iv strength > 60min.
10 - 60 min. 2d
2e 0.1
0.05

The coronary active compounds can be in are usually administered intravenously, orally, intramuscularly, but also in the form of suppositories, the ampoules, capsules,

Table 4

Dragees, tablets, suppositories and the like generally contain approximately the following amounts, as for Ampoules and capsules based on some compounds in the medicinal products are listed in Table 4 as an example:

link

Ampoules

Capsules

example 1

4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarboromethoxy-0.2 mg 1,4-dihydropyridine per patient

Example la

4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbethoxy- 0.2 mg

1,4-dihydropyridine

Example Ib

4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarboisopropoxy- 0.2 mg 1,4-dihydropyridine

Example 2

4- (3'-nitrophenyl) -2,6-dimethyl-3,5-dicarbethoxy-0.2 mg

1,4-dihydropyridine

Example 2a

4- (3'-nitrophenyl) -2,6-dimethyl-3,5-dicarbomethoxy-1 mg 1,4-dihydropyridine

Example 2b

4- (3'-nitrophenyl) -2,6-dimethyl-3,5-dicarboisopropoxy-0.2 mg 1,4-dihydropyridine

2.5 mg
per patient

2.5 mg

2.5 mg

2.5 mg

5 mg

2.5 mg

For application in human medicine, 1 to 2 ampoules / day are required for angina pectoris attacks Capsules, dragees and tablets 3 times a day, provided this information applies to people weighing around 70 kg Refer to body weight. The application of the suppositories can be varied accordingly.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of administration route, but also due to the individual behavior towards the drug or the type of its formulation and the time or interval to which the administration takes place So in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the application of larger amounts, it can be advisable to distribute these in several single doses over the day.

The coronary active compounds mentioned in the description and the examples can for the treatment of angina pectoris seizures and for the prophylaxis of angina pectoris.

It should also be noted that the effect

mechanism of the mentioned 1,4-dihydropyridines of the mechanism of action of the comparison substance deviates So these compounds show in comparison to dipyridamole, which has no calcium antagonism, and to all known coronary agents Connections a very strong musculotrooen Calcium antagonism. So these compounds not only because of their superior effect, their rapid onset of action, their long duration of action and their sublingual resorption, but also due to its novel mechanism of action, in particular the beneficial calcium antagonism, a Enrichment of pharmacy.

Production of 1,4-dihydropyridines

1. 4- (2'-Nitrophenyl) -2,6-dimethyl-34-dicarbmethoxy-1,4-dihydropyridine

45 g of 2-nitrobenzaldehyde and 80 ecm of methyl acetoacetate are heated. 75 ecm of methanol and 32 ecm of ammonia under reflux for several hours, filtered off, cools and receives 75 g of yellow crystals with a melting point of 172 ° to 174 ° C. after suction

In the same way are obtained:

a) 4 (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbetho: <y-1,4-dihydropyridine, Mp 122-124 ° C;

b) 4- (2'-nitrophenyl) -2,6-dimethyl-2,5-dicarbisopropoxy-1,4-dihydropyridine, Mp. 140 to 142 ° C.

2.

ethoxy-1,4-dihydropyridine

After boiling 151 g of 3-nitrobenzaldehyde for one hour, 260 ecm of ethyl acetate, 250 ecm of methanol and 110 ecm of ammonia are 300 g of yellow Crystals with a melting point of 161 ° C. were obtained.

In an analogous manner the following were obtained:

a) 4- (3'-nitrophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine, Mp 206-208 ° C;

b) 4- (3'-nitrophenyl) -2,6-dimethyl-3,5-dicarbisopropoxy-1,4-dihydropyridine, Mp 123 ° C;

c) 4- (3'-nitro-4'-chlorophenyl) -2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine, Mp 133 ° C;

d) 4- (3'-nitro-6'-chlorophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine, mp 190-192 ⁰ C.

e) 4- (3'-nitro-6'-chlorophenyl) -2,6-dimethyl-3,5-dicarbätlioxy-1,4-dihydropyridine, Mp. 202-205 ° C.

Example 3

4- (4'-nitrophenyl) -2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine

151 g of 4-nitrobenzaldehyde, 300 ecm are heated Methanol. 260 ecm 260 cm ethyl acetoacetate and 110 ecm ammonia under reflux and for 5 hours obtained after cooling and suctioning 375 g of yellow crystals, which recrystallized from methanol at 132 bis Melting at 134 ° C.

In an analogous manner the following were obtained:

a) 4- (4'-nitrophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine, Mp 196-197 ° C;

b) 4- (4'-nitrophenyl) -2,6-dimethyl-3,5-dicarbisopropoxy-1,4-dihydropyridine, m.p .: 152 ⁼ C;

c) 4- (4'-nitrophenyl) -2,6-dimethyl-3,5-dicarb-tert-butoxy-1,4-dihydropyridine, Mp. 215 ° C.

Claims (1)

Claim: Coronary agents characterized by a content of at least one 1,4-dihydropyridine of the general formula (I) R'OOC H ₃ C COOR '