US3726913A

US3726913A - Derivatives of aminoalkanoic acids

Info

Publication number: US3726913A
Application number: US00050331A
Authority: US
Inventors: A Garzia
Original assignee: Istituto Chemioterapico Italiano SpA
Current assignee: Archimica SpA
Priority date: 1970-06-26
Filing date: 1970-06-26
Publication date: 1973-04-10
Anticipated expiration: 1990-04-10
Also published as: DE2131675A1; FR2100832B1; CA919697A; BE768814A; FR2100832A1; IL37142A0; GB1313837A; ZA714175B

Abstract

(3,4,5-trialkoxy benzoyl) amino alkanoic acids and their pharmaceutically-acceptable salts for prophylaxis and treatment of cardiac disorders.

Description

United States Patent Garzia 1 Apr. 10, 1973 DERIVATIVES OF AMINOALKANOIC [56] References Cited ACIDS UNITED STATES PATENTS Inventor: Aldo Gama, Lodi Italy 3,489,793 1/1970 Bertelli ..260/5l9 [73] Assignee: Istituto Chemioterapico Italiano Primary Examiner-Lorraine A. Weinberger S.p.A., Milan, Italy Assistant Examiner-L. Arnold Thaxton AttorneyMorton, Bernard, Brown, Roberts & [22] June 1970 Sutherland, Eugene L. Bernard, John W. Behringer, [21] Appl. No.: 50,331 Martin J. Brown, James N. Dresser, W. Brown Morton, Jr., John T. Roberts and Malcolm L. Sutherland [52] US. Cl. ..260/519, 260/404, tat/$31189, [57] ABSTRACT 51 Int. Cl ..C07c 103/30 y y amino alkanoic acids and 5s Field of Search ..260/519, 404 their phamaceutically-acceptable Salts for P p y and treatment of cardiac disorders.

6 Claims, No Drawings 1 DERIVATIVES OF AMINOALKANOIC ACIDS BACKGROUND OF THE INVENTION This invention relates to a method of prophylaxis and treatment of cardiac disorders. In a particular aspect, 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 aminoalkanoic acid derivative.

The prevention and treatment of cardiac disorders, such as ischemia, thrombosis, cardiac infarction and disorders of rhythm and stimulus transmission, is a serious problem. 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 blood cholesterol 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 hear muscle, and other rhythm and transmission disorders respond to installation of the pacemaker device.

While the use of these methods has greatly improved the prognosis of cardiac patients, the problem of cardiac disorders generally still remains a severe one and in particular the problems caused by infarction are still grave.

SUMMARY OF THE INVENTION It is an object of this invention to provide a method of prophylaxis and treatment of cardiac disorders.

It is another object of this invention to provide novel pharmaceutical compositions suitable for the prophylaxis and treatment of the cardiac disorders.

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 the derivatives of aminoalkanoic acids.

' Other objects of this invention will be readily apparent to those skilled in the art from the disclosure herein.

It has been discovered that administration of compounds corresponding to the following formula where each of R, R and R is methyl, ethyl or propyl, A is a saturated aliphatic hydrocarbon radical containing three to eight carbon atoms, and the carboxylic acid group is linked to A at a position other than terminal, or their phannaceutically-acceptable salts, is effective in the prophylaxis and treatment of cardiac disorders such as cardiac ischemia and infarction, disorders of rhythm and disorders of stimulus transmission. The compound is administered at a dosage of 2-8grams per day per average 60-70 kg. individual. When administration is by intravenous or intraperitoneal injection, soluble, pharmaceutically acceptable salts 200 the compounds of this invention are preferred.

DETAILED DISCUSSION The compounds of the present invention are prepared by reacting the appropriate 3,4,5-trialkoxy benzoyl chloride with the corresponding amino-alkanoic acid at a temperature of about 5 to +5C. According to the process of this invention, the free amino acid is slurried in about an equal weight of water and is neutralized with sodium hydroxide solution. (about 30 percent by weight). Excess sodium hydroxide is added to promote the reaction. The mixture is chilled to within 5C to +5C, and the tri-substituted benzoyl chloride is gradually added with agitation, maintaining the temperature at below 5C. The mole ratio of amino acid to the acid chloride is generally about i 1.5:1. The resulting solution is stirred for from two to four days and when the reaction is complete can be treated with char to decolorize it. It is then neutralized with dilute I-ICl or H to about a pH of 3 or a Congo red indicator endpoint. The resulting precipitate is separated, e.g. by filtration or centrifugation, washed with water, dried, then recrystallized from water or ethanol, separated by filtration, centrifugation or decantation and dried.

According to the method of the present invention, 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. According to one embodiment of the present invention, the method is employed in veterinary medicine, principally in the treatment of household pets, especially dogs, where cardiac problems are frequently encountered.

Cardiac infarction frequently occurs without prior symptoms or before the patient has sought treatment for the relief of symptoms However physicians are frequently able to detect symptoms of an approaching crisis and the administration of the compounds of this invention can be started promptly to obtain prophylactic effects.

The products of the present invention are of a loworder 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 can 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 2-8g per day per person, preferably about 6g 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 1000 mg. dose, six times daily, is preferred.

Administration of the compounds of this invention can be oral, subcutaneous, intravenous or intraperitoneal. When 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. For oral administration 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. According to one suitable method, the free acids can be administered mixed with a molar equivalent of sodium or potassium bicarbonate. in the examples, 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. When administered orally, 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.

EXAMPLE 1 To a 500 cc flask in an ice bath is added 18.5 grams of L-isoleucine (0.14 mole) and 40 cc of water. A solution of 10 grams of sodium hydroxide in 40 cc of water is added to solubilize the acid and an additional 9 grams of sodium hydroxide in 30 cc of water is added. Then at l0C are added 27 grams of 3,4,5-trimethoxybenzoyl chloride in about 30 minutes, and 75 cc of water. After one night at room temperature the reaction mixture is decolorized with charcoal and acidified with 20 percent hydrochloric acid to the end-point 1 shown by Congo Red. The sticky precipitate is washed by decantation, and more water is added. After standing two days at room temperature, the solid is ground in a mortar under fresh water. This gives a white crude product.

Five grams of the crude product was recrystallized from 600-700 cc of boiling water to give 3 grams of product with a melting point of l55-157C and a purity of 98.81 percent. The remainder of the crude product was recrystallized from boiling water to give 21.9 grams.

The product is N-( 3,4,5-trimethoxybenzoyl)-L- isoleucine having the structure 0 H O i O OH omo-Q-o 0NH(.HCHGH2CH3 o H; o (11H;

' EXAMPLE 2 DL-Norvaline l 1.7 grams (0.1 mole) water 8 grams Sodium hydroxide (10%) 200 milliliters Sodium carbonate 16 grams The above mixture is cooled to 0C. and 23.5 grams of 3,4,5-trimethoxybenzoyl chloride and 150 cc of diethyl ether are added slowly at O5 C. The mixture is stirred at 0C. for one hour then allowed to warm to room temperature overnight. The ether is removed and the aqueous layer is acidified to Congo Red end-point with dilute hydrochloric acid after adding 600 ml. of water. Filtration followed by washing with cold water gives 25 grams of crude product.

Ten grams of crude product was dissolved in 50 cc of chloroform and mixed with 45 cc of ligroin to precipitate 9.9 grams of purified product melting at l64-l65 C. and assaying 99.73 percent pure.

The product is N-(3,4,5-trimethoxybenzoyl)-DL- norvaline -DL-n0rvaline having the structure COOH EXAMPLE 3 To 40cc of water is added 18.5 grams of L-leucine. This is neutralized with 10 percent sodium hydroxide (40 cc) and then an additional 9 grams of sodium hydroxide in 30 cc of water is added. The solution is cooled to 0-5 C and 27 grams of 3,4,5-trimethoxybenzoyl chloride and cc of water are added at 05 C in 30 minutes. After one night at room temperature, the reaction mixture is acidified to Congo Red endpoint but it does not crystallize at once. After about 3 days it is crystallized by grinding with ice water and ligroin while cooling in an ice bath. The yield of crude product is 17.5 grams and the melting point is 7375 C.

The product is N- (3,4,5-trimethoxybenzoyl) -L-leucine having the structure COOH CIT;

EXAMPLE 4 The effect of the compound prefered according to the procedure of Example I 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. As is known, 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 5 The effects of the compound of Example 1 is determined on chloroform-epinephrine induced arrhythmias in rats. In the procedure employed, the rats are anaesthetized with urethane. Chloroforrn is administered for one minute by inhalation and then 100 micrograms/kg of epinephrine hydrochloride is ad ministered intravenously. Electr'ocardiograms are taken and the extent of the arrhythmia in terms of number of beats per minute is determined. The effect of the compound of Example 1 is substantially to reduce the extent of the arrhythmia when administered intraperitoneally in the amount of 700 mg/kg.

EXAMPLE 6 (3,4,5-Triethoxybenzoyl)-a-aminoisovaleric acid is prepared in accordance with the procedure of Example 1 The resulting compound is tested for anti-Pitressin activity in rats as described in Example 4 and similar results are obtained.

EXAMPLE 7 (3,4,5 Tripropoxylbenioyl)-L leucine is prepared in accordance with the procedure of Example 1. The resulting compound is tested for anti-Pitressin activity in rats as described in Example 4 and similar results are obtained.

EXAMPLE 8 (3,4-Dipropoxy-S-ethoxybenzoyl)-L-isoleucine is prepared in accordance with the procedure of Example 1. The resulting compound is tested for anti-Fit ressin activity as described in Example 4 and similar results are obtained.

EXAMPLE 9 A pharmaceutical composition in tablet form was prepared by mixing 500 mg of the compound of Example 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.

The above examples are representative. For example, the 3,4,5-trialkoxy benzoic acids are well known to the art. See, for example, US. Pats. Nos. 3,234,276; 3,364,249 and 3,485,865. Amino acids other than those utilized in the examples can be prepared by means known to the art. For example, thefollowing amino acids can be utilized:

2-amino- Z-ethyl butyric acid 2-amino- Z-methyl hexanoic acid 2-ammo- 2,4-d1methylpentano1c acid alpha methyl norvaline 3-methyl- 2-amino- 2-n-propyl butyric acid l-aminol-n-propyl pentanoic acid 2-amino- 2-n-butyl hexanoic acid 2-amino- 2-n-butyl- 4-methyl pentanoic acid I claim:

1. A compound represented by the formula wherein each of R R and R is methyl, ethyl or propyl, A is a saturated aliphatic hydrocarbon radical containing three to eight carbon atoms and the carboxylic acid group is linked to A at a position other than terminal, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 where R R and R are methyl and (A )COOI-l is 3. The compound of claim 1 where R R and R are methyl and (A)COOH is 4. The compound of claim 1 where R R2 and R are methyl and (A)COOH is 5. The cqrppgnmd of claim 1 wherein the pharmaceutically acceptable salts are the s odiumoi' potassium salts of the compound.

6. A compound represented by the formula wherein each of R R and R is methyl, ethyl or propyl, A is a saturated aliphatic hydrocarbon radical containing three to eight carbon atoms and the carboxylic acid group is linked to A at a position other than terminal.

UNITED STATES FATE QFMQE CERTHEQATE G REQ'HQN Patent 5, 3,726,913 Dated May 7, 1973 lnvehtor(s) ALDO GABZIA It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected 'as shownibelow:

Column 1, line 23, the word "hear" should read -'heart-.

Column line lii henum i be deleted and of inserted t hefefoie Column 2, line 15, the numerals "1 1.5:1" should read -lln5:l-.

sighed and sealed this 26th day of March 197M...

(SEAL) Attest:

EDWARD MFLETGHER,JRa. 0., MARSHALL DANN Attesting Officer Commissioner of Patents USCOMM-DC 60376-1 69 ORM PO-105O (10-69) u.s. GOVERNMENT PRINTING OFFICE 1959 o-sss-aan

Claims

2. The compound of claim 1 where R1, R2 and R3 are methyl and (A)COOH is
3. The compound of claim 1 where R1, R2 and R3 are methyl and (A)COOH is
4. The compound of claim 1 where R1, R2 and R3 are methyl and (A)COOH is
5. The compound of claim 1 wherein the pharmaceutically acceptable salts are the sodium or potassium salts of the compound.
6. A compound represented by the formula wherein each of R1, R2, and R3 is methyl, ethyl or propyl, A is a saturated aliphatic hydrocarbon radical containing three to eight carbon atoms and the carboxylic acid group is linked to A at a position other than terminal.