DE2131677A1 - 3,4,5-trialkoxyphenylalkanecarboxylic acids and their salts and medicinal preparations - Google Patents

Description

DfPL-CHEM. DR. ELISABETH ΜϋΝσ'υΟΟΡβΙ " ¹⁸ MDNCHEN 23.

DJiPL-CHEM. DR. VOLKER VOSSIUS Clemensstrasse 30 QIPL-PHYS. DR. JÜRGEN SCHIRDEWAHN Telegram address, invent / monchen PATENT LAWYERS

, Darts cannot be f-ridden

u.z .: G 133 C (Vo / kä) June 25, 1971 3

Case 50 327 "[■

ISTITUTO CHEMIOTERAPICO ITALIANO S.ρ.Α., ι *

Milan, Italy - [

"3,4,5-Trialkoxyphenylalkanecarboxylic acids and their salts as well as. ^

- Medicinal products "5

Priority: June 26, 1970, V.St.A., Mr. 50 327

The prophylaxis and treatment of heart diseases, such as ₍ >

Ischemia, thrombosis, myocardial infarction, rhythm and irritation disorders,

is an important task. Numerous investigations * hired to look for the causes of the disease and one

Appropriate prevention or treatment method for these i |

Find diseases, especially for heart failure and '"Jf

Heart attack. For the prophylaxis of myocardial infarction, up to now

Medicines to lower blood cholesterol, for. ^; ; ί

Relaxation of the arteries and anticoagulants administered. ^

Ventricular fibrillation is a very dangerous condition caused by,, i * Electroshock the heart muscle is treated. Other rhythm and stimulus disorders are treated with the use of pacemakers.

2 0 9 8 2 A / 111 3 8

Although these procedures improve the prognosis of heart disease patients

to have, .

largely improved /. remain heart diseases in general and the heart attack in particular continues to cause serious problems.

The invention relates to new 3 * 4,5-trialkoxyphenylalkanecarboxylic acids of the general formula I.

(D

in which R ,, Rp and R. ,, which are identical or different, methyl, Ethyl or propyl groups and A is one with a carboxyl '; group-substituted alkyl radical having 4 to 9 carbon atoms, and their salts.

The compounds of general formula I can according to the in The Journal of the American Chemical Society, Volume 75 (1953), pages 720 to 723; j See also U.S. Patents 3,234,276, 3,364,249 and 3 485 865-

The invention also relates to medicinal preparations which contain a compound of the general formula I or a pharmacologically acceptable compound thereof Contain salt. The pharmaceutical preparations of the invention are used to treat cardiac ischemia, either before or after a heart attack, Arrhythmias that may be related to the infarct, and disorders of the conduction administered. The administration of the medicinal preparations of the invention is an effective one

same. Prophylaxis in cases of impending heart attack and effective Behaldung after an infarction has occurred. The medicinal preparations'. .2098247 1 1-3 8 "

ORiQSNAL INSPECTED

Te of the invention can also be used in veterinary medicine, mainly used in the treatment of pets, especially dogs, where heart disease is common will.

The heart attack often occurs without any prior symptoms or occurs before the patient requests treatment has taken care of eliminating the symptoms. However, doctors are often able to diagnose the symptoms of an impending one To establish a crisis. The administration of the medicinal preparations of the invention can then be started immediately in order to obtain a to achieve prophylactic effect.

Clinical studies have shown that the toxicity of the compounds of general formula I is low and no side effects appear,. Pharmacological research shows that the main effects of the compounds are on the heart. The only effect observed on the circulatory system is an increase in static blood pressure with no significant change of the average arterial pressure.

The dosage of the pharmaceutical preparations of the invention can vary widely. Good results have been achieved with drug doses of 25 mg / kg / day to 500 mg / kg / day. In humans, for all of the disorders mentioned, a daily dose of. ^; 2 to 8 g / day, preferably about 6 g, is effective. This dosage refers to "an average body weight of"; 60 to 70 kg and thus corresponds to a dose of 25 to 200 mg / kg / day. Doses in the range of about 40 to 100 mg / kg / day are preferred. The treatment may consist of the administration of "a single physical dose or in partial doses which"

20982A / 1 1 38

COPY

ORfGiNAL INSPECTED

\
ι

at time intervals distributed over the day, administered v / ground, · \
For the treatment of heart attacks and related disorders, a single daily dose is generally preferred, '*'

4 while for prophylaxis smaller dosfr

sen, e.g. 500 mg six times a day, are preferred »^

The administration of the medicinal preparations of the invention can be orally, ■.%

be done subcutaneously, intravenously or intraperitoneally. With sub-. , * .-

cutaneous, intraperitoneal or intravenous injection \

the compounds of general formula I in the form of their water i * soluble neutral salts are used. Everyone is suitable for this

soluble pharmacologically acceptable salts. Preferably. · Ί

the sodium and potassium salts are used. Particularly appealing <>

The sodium salts are preferred. The free acids are preferably used for oral administration, but they can
also pharmacologically acceptable salts, e.g. the ammonium,

Sodium, potassium, magnesium or calcium salts, used j will. The free acids can optionally with an, equi- "'ί.

molar amount of sodium or potassium bicarbonate. |

For intraperitoneal administration, the drugs are · · ■%

used as sodium salts because they are easy to handle in aqueous> solution. In the case of oral administration, the usual - Ί

Usually tablets with 500 mg of active ingredient, which have a common 4 contain dematerials, used.

* Tablets for administration to humans or animals may Ub- ί licherweiee 50 to 500 mg of a compound of allgomeinen ■; Formula I either in the form of the free acid or a pharmaceutically A, ecologically acceptable salt contain · Tablets with 50 mg

209824/1138

_L. ORlGtNAt INSPECTED

Active ingredients are suitable for oral administration, in particular

for children and infants and in veterinary medicine for £

Small animals. Tablets with less than 50 mg of active ingredient can. ·. ' Λ

are produced 'and are valuable in special cases, but in the _; |

In general, a dose of less than 50 mg is too low, because ·. '**

the number of t required for the average patient

Tablets per day would be too high. Tablets with more than 500 mg |

-i active ingredients can also be produced, but large ta- *

Bletten make swallowing difficult for most patients. ', V

The examples illustrate the invention.

For example.

CT (3 "4" 5-trimethoxyphenyl) valeric acid was prepared by the in ■ '"\

'■) Journal of The American Chemical Society, Volume 75 (1953), Se- ^: \

te 722 described procedure »>

A solution of 3> 5 g sodium in 250 ml anhydrous ethanol & was at 40 ⁰ C with 28.2 g 3,4,5-trimethoxybenzoyl acetic acid}

The mixture was stirred for 10 minutes. 2.17 g of methyl β-bromopropionate were then added dropwise with constant stirring, the temperature being kept below ⁰ ° C. Between the addition of the first 0, 17 g of the ß-bromopropionic acid methyl ester and the remainder was

ispension 16 to 18

stirred tere 3 to 4 hours at 5 to 10 ⁰ C / hour to stand at 10 ⁰ C, then diluted with Biswasser and acidified with dilute acetic acid. The hydrochloric acid solution was extracted with ether, the ether extract was washed, dried and

209824/1138

03E ^ ¹ W ^; - ·. '"^ -— ORfQtNAL INSPECTED

a break of 1 hour was observed. The suspension became white

evaporated. 40 g of a pale yellow oil remained.

The crude ester was refluxed with 250 ml of 20 percent sulfuric acid for 45 hours. After cooling, the mixture was treated with 200 ml of 5% sodium hydroxide solution. Neutral substances were filtered off and the piltrate was acidified. 23 g (81 percent of theory) of almost colorless crystals were obtained. By recrystallization from water / water, K- (3,4,5-trimethoxybenzoyl) butyric acid was obtained ⁱⁿ colorless platelets with a melting point of 118 to 120

C.

A solution of 30 g JF (3,4,5-trimethoxybenzoyl) butyric acid in 160 ml of acetic acid for 4 hours at 60 ⁰ C in the presence of 12 g 5prozentigem palladium on charcoal and at a pressure from 1.4 to 2 , 8 atm. Hydrogenated. The catalyst is then filtered off, the piltrate is evaporated to 100 ml and 300 ml of ice water are added while stirring. The precipitated crystals are filtered off after 2 hours. Yield 25 g (90 percent of theory) (f- (3> 4 »5-trimethoxyphenyl) valeric acid from P. 66 to 68 ⁰ C.

Example 2

The effect of the compound prepared by the method of Example 1 on the heart was determined in rats by intravenous injection of 1 vasopressin unit per kilogram (Pitressin, Parke Davis Co.), an antidiuretic pituitary hormone. It is known that the administration of vasopressin causes changes in the tension and shape of T-waves. It also causes arrhythmia and ischemia of the myocardium. It was found that this im

209824/1 1 38 ΟΟΡΪ

ι,

Electrocardiogram detectable changes that are more normal: -, wisely caused by administration of pitressin, by the administration of the compound from Example 1 'prevented. -

Example3

The effects of the compound from Example 1 were determined on rats in which there were arrhythmias caused by chloroform-epinephrine had been generated. In the procedure used, the rats were anesthetized with urethane. The animals were left 1 hour of chloro «· inhale form and then administered 100 ug / kg epinephrine hydrochloride intravenously, electrocardiograms were recorded, and the extent of arrhythmia was expressed as the number of heartbeats determined per minute. The effect of the compound from Example 1 is that the extent of the arrhythmia at intraperitoneal administration of 700 mg / kg is substantially reduced. .

-Example 4

Jf- (3 _f 4,5-triethoxyphenyl) -Ä -isopropy! Butyric acid was according to. Example 1 prepared from 3i4,5-2riäthoxybenzoylessigsäureäthylester and Ct-bromoisovaleric acid methyl ester.

-Example

£ - (3,4,5-0? Ripropoxyphenyl) -of-dimethylcaproic acid was prepared in accordance with Example 1 from 3,4,5-Tripropoxybenzoylessigsäureäthylester and U-dimethyl-i-bromobutyric acid methyl ester.

ORIGINAL! NSPEGTED

COPY 209824/1138

B e i s ρ i e 1 6

/ - (3,5-Dimethoxy-4-ethoxyphenyl) -o6-isopentyrbutyric acid was obtained for example 1 from 3,5-I ⁾ imethoxy-4-ethoxybenzoyl acetic acid- '\

ethyl ester and methyl bromoisoönanthate produced. |

Example 7

f- (3,4,5-Trimethoxyphenyl) -o (-isopropylönanthic acid vairde according to Example 1 from 3,4,5-trimethoxybenzoyl acetic acid ethyl ester and,

^ -Bromo-rt-isopropylvaleric acid methyl ester.

'" ί

^ψ examples

590 ^m S <^ ^he mg of compound of Example 1, 50 mg of corn starch and _50; Sucrose was mixed and compressed into a tablet in a tablet machine. It is suitable for oral administration to humans or animals suffering from cardiac disorders. It is particularly suitable for the prophylaxis of heart attacks. $.

The following dosage is used for the first 24 hours after a |; Infarct recommended; . \

ψ 2 to 4 g for Phleboklysef 1 to 2 ampoules (each ampoule contains *; contains 2000 mg sodium salt of the compound of Example 1, dissolved / in sterilized, distilled water with a total volume of 10 ml)

dissolved in 400 to 600 ml of physiological saline solution. |

'Φ 2 to 4 g for intravenous administration; 2 to 4 ampoules for '.; 2 to 4 injections, (each ampoule contains 1000 mg sodium salt

the compound of the example!, dissolved in sterilized, |

distilled water with a total volume of 10 ml). ^l .

209824/1138

• "· -J

2 g for intramuscular administration; 8 ampoules for 4 injections (Each ampoule contains 250 mg sodium salt of the compound '- |

of example 1 and sterilized, distilled water at *

3 ml total volume) '. · · |

4 to 6 g for oral administration; 8 to 12 tablets (each '^ Tablet contains 500 mg of the sodium salt of the compound of Example 1 and a sufficient amount of vehicle).

On the third or fourth day after the start of treatment, the Do- |

can be reduced to half of the stated amounts. %

Therapy should not be started before the third week after the onset

of the infarct are discontinued. ?

Both during the attack and in the subsequent stage ^

therapy using one or more administration. ·. * forms of delivery are carried out.

209 82 4/1138 _{0RlaiNAL INSPECTED}

Claims (1)

- ίο - Claims 1) 3,4,5-Trialkoxyphenylalkanecarboxylic acids of the general Formula I. R ₂ O- ff \ -A in which R ₁ , R ₂ and R- ,, which are identical or different, represent methyl, ethyl or propyl groups and A represents an alkyl radical having 4 to 9 carbon atoms substituted by a carboxyl group, and their salts. 2) O- (3,4,5-trialkoxyphenyl) valeric acids and their salts of general formula II X N. (CH ₂ ) ^ - COOH (H) in which R ₁ , R ₂ and R ,, which are identical or different, represent methyl, ethyl or propyl groups and at least one of these radicals is a group other than the methyl group. 5) Medicinal preparations containing a compound according to claim 1 or 2 or their pharmacologically acceptable salt. ORIQINAL INSPECTED