DE1792764C3 - Coronary drugs - Google Patents

Description

COOR '

CH ₃

in which

R 'for alkyl radicals with 1 to 4 carbon atoms

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

25th

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

1,4-Dihydropyridines and process for their preparation have already become known. Their suitability as a medicinal product, especially as a coronary drug, was but 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)

R'OOC

H, C

COOR '

CH ₃

So in most cases one was still on Ni'rite, whose effect a.o. on a heart relief 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. These have a strong effect, their rapid onset of action and their long duration of action 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 of the reference substances. So put These coronary active compounds represent an enrichment of the pharmaceutical industry because once they are a Show superiority over known substances and on the other hand another remedy with a different one 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 (11)

30th

35

(D «

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 shown.

HC = O

in which

R "has the meaning given above,

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

H ₃ C-CO-CH ₂ -COOR '

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), column 1689h-1690c, without their Usefulness as coronary therapeutics would be described there.

pharmacology

The following are the most important pharmacological data of the method of Example 1 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-di- "carbmethoxy-1,4-dihydropyridine produced specified. The pharmacological tests change under the general one Compounds falling in the formula lead to similar, albeit gradually different values.

In the mouse, this compound has an LD50 of 375 mg / kg p. o. (solvent! polyglycol) and 202 mg / kg p. o. (Solvent Lutrol). It is i. v. application around 26 mg / kg.

Rat blood pressure:

At 0.125 mg / kg L v. slight decrease during the injection.

Coronary effects on dogs:

Flow rate:

Anesthesia: urethane chloralose.
At 0.005 mg / kg iv increase of 40%, exit after 10 minutes. At ö.01 nag / kg Lv. 60% increase, exit after 20 minutes. At 0.02 mg / kg iv increase of 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 20 to 60 mm Hg in these experiments.

Oxygen saturation:

At 0.005 mg / kg i.v. v. slight to strong increase in 6 attempts, exit after 30 to 60 minutes.

(Glycobarbital anesthesia)

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

(1 attempt) sharp increase, exit after 1.5 to 2 hours.

At 0.05 mg / kg L v. (3 attempts) clear increase in 2 attempts, exit after approx. 3 hours. In 1 attempt temporarily slight increase.

At 0.1 mg / kg i.p. v. sharp increase after 30 minutes canceled, still 23% over exit.

Oxygen pressure:

Anesthesia: urethane chloralosi ;.
0.5 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 L v. significant reduction of different duration.

At 0.1 mg: kg i. v. sustained strong reduction. At 0.5 and 1 mg / kg i.p. v. very strong depression.

Anesthesia: urethane chloralose. 0.005; 0.01 and 0.02 mg / kg i.p. v. slight decrease. 0.5 mg / kg p. O.

strong depression.

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

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

Frequency:

Anesthesia: CyclobarbitaL

Different light effects (L v. Application).

Anesthesia: urethane chloralose.

0.5 mg / kg p. o. strong different we & ung.

10 mg / kg p. o. sharp increase.

50 mg / kg p. o. sharp increase.

The oxygen consumption is after substance administration of 1 mg / kg p. o. by 20%, after 20 y / kg L v. by approx. 50% lowered Simultaneously with the greatly increased Cbronar blood flow, a lowering of blood pressure takes place, which leads to leads to a relief of the heart. Such a peripheral drag reduction has a measurable one Reduced oxygen consumption as a result. In this respect, the substance is similar to the known clinically very effective Nitrites, which also cause a noticeable decrease in oxygen consumption.

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

The superiority of the coronary drugs with a content of the above. 1,4-dihydropyridines compared to the im Commercially available coronary therapeutic dipyridamole can be seen from the following tables.

Table 1 contains the ED ₅ C based on the increase in oxygen saturation in the coronary sinus venous blood of the dog and the LD 50 of the compound of Example 1 and the reference substance dipyridamole.

As can be seen from the table, the mentioned compound only about 1/8 of the substance amount of the comparison compound needed to produce the same To achieve effect. This connection is therefore superior to the 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

LD ₅₀ mouse per os, mg / kg
ED ₅₀ dog IV, mg / kg

494
0.0034

2150
0.179

Table 2 shows the relative efficacies of the above 1,4-dihydropyridines in relation to their potency and duration of action. The effectiveness of the dipyridamole was set to 1 in each case and the strength 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 1 mg / kg No. 2 Onset of action 2 min

continuation

I. Resorption per os Coronary agent Dipyridamole ι; With a content of
link i No. 2a Dose 5 mg / kg
Onset of action 1–10 min • y Resorption sublingually ί
\ example 1 Dose 0.5-1 mg / kg
Onset of action 2–3 min no effect I. link Ampoules Capsules

Example 2b ,

-. 4- (3'-nitrophenyl) - 0.2 mg 2.5 mg

! 2,6-dimethyl-3,5-dicarboixo-

Table 3 contains data on the coronary effects of the agents according to the invention on dogs. The appropriate

The dose given causes a clearly visible increase in oxygen saturation (approx. 20%).

S table 3

% Connection coronary effects on the dog

f Example 1

4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbomethoxy- 0.005-0.02 mg / kg i.v. I 1,4-dihydropyridine 0.5-1.0 mg / kg p.o.

I example la

J: 4- <2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbethoxy- 0.01 mg / kg i.v.

I 1,4-dihydropyridine

si example Ib

S 4- {2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbo-isopropoxy-0.01 mg / kg i.v.

I 1,4-dihydropyridine

I example 2

j ^ S'-nitrophenyO ^ jo-dimethyl- ^ S-dicarbethoxy- 0.005 mg / kg i.v.

1,4-dihydropyridine

Example ? .A

; 4- {3'-nitrophenyl) -2,6-dimethyl-3,5-dicarbomethoxy-0.05 mg / kg i.v.

1,4-dihydropyridine

• Example 2b

4- <3'-nitrophenyl) -2,6-dimethyl-3,5-d; carbo-isopropoxy- 0.005 mg / kg i.v. 1,4-dihydropyridine

Example 3

4- (4'-nitrophenyl) -2,6-diethyl-3,5-dicarbethoxy-2 mg / kg i.v.

1,4-dihydropyridine

Example 2d

4- (3'-NitiO - # - c.hlorpVnyl) 2,6-dimethyl- 0.1 mg / kg i.v.

3,5-dicarbmethoxy-1,4-dihydropyridine

Example 2c

4- <3'-nitro-6'-chlorophenyl) -2,6-dimethyl-0.05 mg / kg i.v.

3,5-dicarbethoxy-1,4-dihydropyridine

17th 92 764 30-40%
20-30% Coronary sinus
Duration of action example
No. Increase in 02 saturation in
of the dog
Dose mg / kg effect
iv strength > 60min.
10-60 min. 2d
2e 0.1
0.05

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

Table 4

Dragees, tablets, suppositories and the like generally contain about 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-dicarbomethoxy-0.2 mg 1,4-dihydropyridine per patient

Example la

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

0.2 mg

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-1,4-dihydropyridine

0.2 mg

Example 2a

4- (3'-nitrophenyl) -2,6-dirnethyl-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, namely in Dependence on body weight or the type of application route, but also on the basis of the individual Behavior towards the drug or the type of its formulation and the time or Interval at which the administration takes place. So in some cases it can be sufficient 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 may be advisable to use them in to distribute several individual tasks over the day.

The coronary active compounds mentioned in the description and the examples can used to treat angina attacks and for prophylaxis of angina pectoris.

In addition, it should be noted that the mechanism of action of the 1,4-dihydropyridines mentioned on the mechanism of action of the comparison substance deviates So these compounds show in comparison to Dipyridamol, which no calcium antagonism has, and to all previously known coronary active compounds a very strong muscular tropic Calcium antagonism. So these connections are not just because of their superior effect, theirs 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 £ -dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine

45 g of 2-nitrobenzaldehyde, 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, after suction, receives 75 g of yellow crystals with a melting point of 172 to 74 ° C

In the same way are obtained:

a) 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbäthoxy-1,4-dihydropyridine, mp 122 to 124 ⁰ C.

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

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

After boiling 151 g of 3-nitrobenzaldehyde for an 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 ^0C.;

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-dicarbethoxy-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 of methanol, 260 ecm of 260 ecm of ethyl acetoacetate and 110 ecm of ammonia are heated under reflux for 5 hours and, after cooling and suction, 375 g of yellow crystals are obtained, which melt ^{at 132 to 134 ° C. when recrystallized from methanol.}

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, Mp 152 ° C;

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

Claims (1)

Patent claim: Coronary agents characterized by a content of at least one 1,4-dihydropyridine of the general formula (I) R'OOC H ₃ C 10