US3439091A - Method of treatment with modified tetracycline compounds and composition therefor - Google Patents

Description

United States Patent M Int. Cl. A61k 21 /00; C07g 11/00 US. Cl. 424177 7 Claims ABSTRACT OF THE DISCLOSURE Method of treating a patient suffering from an infectious process sensitive to tetracycline comprising administering to the patient effective doses of a compound of the formula ACH -P wherein A is selected from the group consisting of tetracycline, oxytetracycline and chlortetracycline, and wherein P is a carnosine residue.

The invention also embraces a pharmaceutical preparation comprising a compound of the type indicated in a pharmaceutically acceptable carrier therefor.

Cross-references to related applications This application is a division of application of the same inventors Ser. No. 487,573 filed Sept. 15, 1965 for New Tetracycline Derivatives.

Background of the invention Tetracycline type antibiotics have a specific limited blood level. The blood level rises only after a not quite insubstantial period of time and goes down again comparatively soon. Attempts have been made to form compositions incorporating the antibiotic together with a modifying agent. However, it was found that with these modifying agents usually the effectiveness of the antibiotic was impaired or completely destroyed.

Summary of the invention It is therefore an object of the invention to provide for a treatment of patients affected with a disease that is responsive to an antibiotic of the tetracycline type wherein the tetracycline antibiotic is administered in a form which causes the blood level of the antibiotic in the patient to rise rather soon after administration and to go down only after an adequate period of time at which it remains at or substantially close to the high-peak performance point.

It is a further object of the invention to provide for such treatment wherein together with the improvement of the blood level in the patient the antibiotic action proper is not in any way impaired.

It is a further object of the invention to provide for a pharmaceutical composition for administration to a patient in the method just outlined.

These objects are accomplished by a method of treating a patient suffering from an infectious process sensitive to tetracycline wherein there is administered to the patient an eifective dosage of a compound of the formula wherein A is selected from the group consisting of tetracycline, oxytetracycline and chlortetracycline, and wherein P is a carnosine residue.

The invention also embraces pharmaceutical preprations comprising a compound as just indicated together with a pharmaceutically acceptable carrier therefor for administration in the method indicated.

3,439,091 Patented Apr. 15, 1969 Description of the preferred embodiments By way of example, the tetracyclinemethylene-carnosine compound of the invention has a m.W. of 682.67 and the following structural formula:

To prepare this compound, suitable amounts of tetracycline and carnosine are reacted in an aqueous methanol medium and are boiled in the presence of formaldehyde in solution.

The solution is then subjected to gradual cooling and dilution with pure methanol. It is maintained at 0 C. A hydrated crystalline complex then precipitates (this reaction is known as Mannichs reaction). Precipitation may also be effected by lyophilization.

The product is made anhydrous by phosphoric dessication.

The analysis confirms the formula above given. The rotatory power of the product is diiferent from that of its components; it is -174 :10 at the concentration of 30 0.725 in a N solution of hydrochloric acid.

A more specific example of the method of making the tetracyclinemethylene-carnosine composition is as follows:

Example To 111.1 g. of anhydrous pure tetracycline were added 1500 ml. of pure methanol. The product was rendered soluble by heating and stirring.

A solution of 56.5 g. of pure carnosine in 560 ml. of 50% methanol was separately prepared.

To the tetracycline solution a formaldehyde solution corresponding to 0.25 mol was added followed, after homogenization, by addition of the carnosine solution.

The temperature of both the tetracycline and carnosine solutions was maintained at about 50 to 60 C.

After mixing both solutions, the mixture was boiled for 10 to 15 minutes.

After cooling, 350 ml. of pure methanol were added.

The cooling was continued at 0 C. for several hours, and the precipitate obtained was separated and dried at a. low temperature.

The product was purified by redissolution is distilled water and subsequent precipitation by pure methanol.

The same could be accomplished by lyophilization.

The significant properties of the product were:

It was highly soluble in water.

The aqueous solutions were stable for at least 24 hours at a broad pH range. The aqueous solutions prepared in a sterile form retained their inhibitive power against the Bacillus cereus after being kept for 6 days at +40 C.

The toxicity in case of parenteral (intravenous) or oral administration was similar to that of tetracycline.

The bacterial spectrum was practically identical with that of tetracycline.

The tetracycline blood levels were higher with the prod- 65 not than with tetracycline, as was evidenced by the following tests:

Tetracycline-methylene-carnosine of the present invention, on the one hand, and straight tetracycline base on the other hand, were administered respectively to diflerent 70 rabbits in the following way: on the day before the test, two doses by oral way, of a quantity equivalent to 25 mg./kg. of tetracycline; on the day of the test, at zero BLOOD-PLASMA CONCENTRATION OF TETRACYOLINE- CARNOSINE (T-C) AND TETRACYCLINE, IN '1 PER ML.

The product of the invention may be used for antibiotic treatment of all infectious processes that are responsive to tetracycline irrespective where the germs may be located in the body. Specific examples are diseases of the cardiovascular, respiratory, nervous, digestive, sensory, excrete-urinary, glandular or locomotor systems as well as afilictions of the skin, mucosae or in the otorhinolaryngologic area.

What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims.

We claim:

1. A method of treating a patient suffering from a bacterial infections process sensitive to tetracycline, comprising administering to the patient an effective dosage of a compound of the formula A-CH -P wherein A is selected from the group consisting of tetracycline, oxytetracycline and chlorotetracycline, and wherein P is a carnosine residue.

2. The method of claim 1 wherein A is tetracycline.

3. The method of claim 1 wherein A is oxytetracycline.

4. The method of claim 1 wherein A is chlortetracycline.

5. The method of claim 1 wherein the compound is administered to a patient in an amount to contain between 25 and mg. of tetracycline type compound per kg. of body weight.

6. An antibiotic preparation comprising an effective amount of the compound of the formula given in claim 1 and a pharmaceutically acceptable carrier therefor.

7. An antibiotic preparation of claim 6 which is in the form of an aqueous solution of the tetracycline type compound in the carrier.

References Cited UNITED STATES PATENTS 3,042,716 7/1962 Blackwood et al. 260-519 3,228,962 1/1966 McGregor et a1.

3,247,250 4/ 1966 Tamorria.

3,272,817 9/ 1966 Gordon.

OTHER REFERENCES Chemical Abstracts p. 15502=(b) (1966).

FRANK CACCIAPAGLIA, JR., Primary Examiner.

J. D. GOLDBERG, Assistant Examiner.

US. Cl. X.R.