US3789070A - Prophylaxis and treatment of cardiac 3,4,5-trialkoxyphenylalkanoic acids and salts thereof - Google Patents

Prophylaxis and treatment of cardiac 3,4,5-trialkoxyphenylalkanoic acids and salts thereof Download PDF

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Publication number
US3789070A
US3789070A US00050327A US3789070DA US3789070A US 3789070 A US3789070 A US 3789070A US 00050327 A US00050327 A US 00050327A US 3789070D A US3789070D A US 3789070DA US 3789070 A US3789070 A US 3789070A
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cardiac
treatment
prophylaxis
compound
acid
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US00050327A
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G Aldo
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IST CHEMIOTERAPICO ITALIANO S
IST CHEMIOTERAPICO ITALIANO S P A IT
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IST CHEMIOTERAPICO ITALIANO S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups

Definitions

  • This invention relates to a method of prophylaxis and treatment of cardiac disorders.
  • it relates to a method of treating ischemic cardiopathy prior to or following a cardiac infarction, disorders of rhythm, and disorders of stimulus transmission by the administration of an alkanoic acid derivative.
  • cardiac disorders such as ischemia, thrombosis, cardiac infarction and disorders of rhythm and stimulus transmission
  • cardiac disorders such as ischemia, thrombosis, cardiac infarction and disorders of rhythm and stimulus transmission
  • Many studies have been conducted in an effort to ascertain the underlying causes and to develop a suitable method of preventing or treating these serious problems, particularly cardiac insufficiency and cardiac infarction.
  • the pharmacological methods which have been proposed for preventing cardiac infarction include lowering of bloodcholesterol levels, relaxation of the arteries and administration of anticoagulants.
  • Ventricular fibrillation is a highly dangerous condition which is treated by electric shock administered to the heart muscle, and other rhythm and transmission disorders respond to installation of the pacemaker device.
  • Another object of this invention is to provide a method of prophylaxis and prevention of ischemic cardiopathy, cardiac infarction and disorders of rhythm and stimulus transmission by the administration of derivatives of alkanoic acids.
  • the article specifically describes the preparation of 'y-(3,4,5-trimethoxybenzoyl)-butyric acid by the reaction at ethyl 3,4,5-trimethoxybenzoylacetate with methyl B-bromopropionate in the presence of sodium in absolute ethanol at low temperature, i.e., 0 C, fol lowed by hydrolysis of the crude ester with sulfuric acid.
  • the 'y-(3,4,5-trimethyoxybenzoyl)-butyric acid is then hydrogenated to produce 8-(3,4,5-trimethoxyphenyl)-valeric acid.
  • compounds corresponding to the formula given hereinbefore are administered for the treatment of cardiac ischemia, either prior to or following a cardiac infarction, disorders of the rhythm whether related to the infarction or not, and disorders of stimulus transmission.
  • Administration of these compounds is an effective prophylaxis in cases of an impending cardiac infarction and an effective treatment after infarction has occurred.
  • the method is employed in veterinary medicine, principally in the treatment of household pets, especially dogs, where cardiac problems are frequently encountered.
  • the products of the present invention are of a low order of toxicity and no side effects are observed in clinical trials.
  • Pharmacological studies indicate that the principal effect of the compounds of the invention is on the heart.
  • the only observed effect on the circulatory system is an increase in the static blood pressure with no significant change in mean arterial pressure.
  • the dosage in which the compounds of the present invention can be given vary widely within rather broad limits. Good results have been obtained with as little as 25 mg/kg/day and as much as 500 mg/kg/day. In human clinical cases, all of the disorders cited above generally respond to a dosage of 2-8 grams per day per person, preferably about 6 grams per day. This dosage is intended for an average 60-70 kg individual equivalent to a dosage generally within the range of about 25-200 mg/kg/day. A dosage in the range of about 40-100 mg/kg/day is preferred.
  • the treatment can consist of a single daily dose, or the above dosages can be given fractionally at periodic intervals. A single daily dose is generally preferred for a treatment of cardiac infarction and associated disorders but for prophylaxis, smaller periodic doses, e.g., a 500 mg dose, 6 times daily, is preferred.
  • Administration of the compounds of this invention can be oral, subcutaneous, intravenous or intraperitoneal.
  • the compounds of the present invention are by subcutaneous, intraperitoneal or intravenous injection, they are administered as their water-soluble neutral salts.
  • Any soluble, pharmaceutically-acceptable salt is suitable and the sodium and potassium salts are preferred.
  • the sodium salt is particularly preferred.
  • the compounds are preferably administered as the free acids but they can also be pharmaceutically-acceptable salts, e.g., as the ammonium, sodium, potassium, magnesium or calcium salt.
  • the free acids can be administered mixed with a molar equivalent of sodium or potassium bicarbonate.
  • the compounds were administered intraperitoneally as the sodium salt because of its ease of handling as an aqueous solution, but the weights given are for the free acid.
  • the compounds are conveniently administered as tablets containing 500 mg with a suitable binder, many of which are known.
  • Suitable tablets for human or animal use can conveniently be prepared containing 50-500 mg of the compounds of the present invention, either as the free acid or as a pharmaceutically acceptable salt thereof. Tablets containing as little as 50 mg are suitable for oral administration, especially for infants and small children, and in veterinary medicine, for small animals. Tablets containing less than 50 mg can be prepared, and in special cases may be useful, but generally a dose smaller than 50 mg is too small to be practical because in the average patient the number of tablets required per day would be excessively high for convenience. Tablets containing more than 500 mg can also be prepared, but large tablets are difficult for most patients to swallow.
  • the crude ester was refluxed with 250 ml. of 20 percent sulfuric acid for 45 hours.
  • the mixture was chilled and the partly gummy crude acid treated with 200 ml. of 5 percent sodium hydroxide. Neutral material was removed by filtration and the filtrate acidified to yield 23 g. (8 lpercent) of almost colorless crystalline material. Recrystallization from water gave colorless plates, m.p. ll8-l20.
  • the product is 8(3,4,5-trimethoxyphenyl)-valeric acid having the structure CHaO CHaO
  • EXAMPLEQ The effect of the compound prepared according to the procedure of Example 1 on the heart is determined in rats by intravenous injection of 1 unit per kilogram of vasopressin (Pitressin, marketed by Parke, Davis Co.), an antidiuretic pituitary hormone.
  • vasopressin Protressin, marketed by Parke, Davis Co.
  • the administration of vasopressin results in variations of the voltage and the morphology, or shape, of the T- wave. It also causes arrhythmia and produces ischemia of the myocardium. It is determined that these electrocardiographic alterations normally produced by the administration of Pitressin are prevented by the administration of the compound of Example 1.
  • EXAMPLE 3 EXAMPLE 4 'y-(3,4,STriethoxyphenyl-a-isopropyl butyric acid is prepared in accordance with the procedure of Example 1 except that ethyl 3,4,5-triethoxybenzoylacetate and methyl-a-bromo isovalerate are employed.
  • EXAMPLE 5 e-(3,4,5 -tripropoxyphenyl)-a-dimethyl caproic acid is prepared in accordance with the procedure of Example 1 except that ethyl 3,4,5-tripropoxybenzoylacetate and methyl-a-dimethyl-y-bromobutyrate are employed.
  • EXAMPLE 6 'y -(3,5-dimethoxy-4-ethoxyphenyl)-a-isopentyl butyric acid is prepared in accordance with the procedure of Example 1 except that ethyl 3,5-dimethoxy-4- ethoxybenzoyl acetate and methyl-a-bromo isoenanthate are employed.
  • EXAMPLE 7 3 4,5-trimethoxyphenyl -a-isopropyl enanthic acid is prepared in accordance with the procedure of Example valerate is employed.
  • EXAMPLE 8 A pharmaceutical composition in tablet form was prepared by mixing 500 mg of the compound of Exam- 1 except that methyl-S-bromo-a-isopropyl' ple l with 50 mg of corn starch and 50 mg of sucrose. This mixture was compressed in a tableting machine to make a durable tablet. It is suitable for oral administration to humans or other animals suffering from cardiac disorders. It is particularly suitable for prophylaxis of a suspected impending coronary occlusion resulting in an infarction.
  • Caproic acid is available in commercial quantity and the commercial grade materials are suitable for preparing the products of this invention.
  • the corresponding valeric, butyric, heptanoic, octanoic and nonanoic acids together with their isomers are prepared by known methods.
  • each ampoule containing 1 or 2 grams of the so- I claim: 1.
  • R R and R is methyl, ethyl or propyl, provided that at least one of R R and R is other than methyl, and pharmaceutically-acceptable salts thereof.
  • R R and R are propyl and A is a-dimethyl caproic acid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
US00050327A 1970-06-26 1970-06-26 Prophylaxis and treatment of cardiac 3,4,5-trialkoxyphenylalkanoic acids and salts thereof Expired - Lifetime US3789070A (en)

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US5032770A 1970-06-26 1970-06-26

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US (1) US3789070A (enExample)
BE (1) BE768811A (enExample)
CA (1) CA919686A (enExample)
DE (1) DE2131677A1 (enExample)
FR (1) FR2100828B1 (enExample)
IL (1) IL37138A0 (enExample)
ZA (1) ZA714114B (enExample)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036365A3 (en) * 1999-11-17 2002-11-07 Karobio Ab Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2580459A (en) * 1946-11-27 1952-01-01 Schering Corp Production of halogenated aryl fatty acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2580459A (en) * 1946-11-27 1952-01-01 Schering Corp Production of halogenated aryl fatty acids

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Gardner et al., Chem. Abst. 49 950i (1955). *
Haworth et al., Chem. Abst., 43 3403h. *
Horning et al. Chem. Abst., 45 2959e. *
Koo, J. Am. Chem. Soc., 75 720 (1953). *
Merck Index, Merck & Co. Inc. (1960), pages 277 278. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036365A3 (en) * 1999-11-17 2002-11-07 Karobio Ab Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
US20050267206A1 (en) * 1999-11-17 2005-12-01 Johan Malm Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
US7005538B1 (en) 1999-11-17 2006-02-28 Karo Bio Ab Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
US7319163B2 (en) 1999-11-17 2008-01-15 Karo Bio Ab Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders

Also Published As

Publication number Publication date
CA919686A (en) 1973-01-23
BE768811A (fr) 1971-11-03
FR2100828A1 (enExample) 1972-03-24
DE2131677A1 (de) 1972-02-17
ZA714114B (en) 1972-03-29
IL37138A0 (en) 1971-08-25
FR2100828B1 (enExample) 1975-06-06

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