US2161358A - Therapeutic agents - Google Patents

Description

5 their systemic efiects.

Patented June .193 9 Hynson, Westcott &-' Dunning, Incorporated, Baltimore, Md., a corporation of Maryland No Drawing.

Application June 1'1, 1938, Serial No. 214,344

3 Claims. (01. 167 65) This invention relates to alkyl nitrites having pharmacological and clinical activity andbeing otherwise suitable for use as therapeutic agents, particularly as vaso dilators. Certain alkyl nitrites such as ethyl nitrite and amyl nitrite are'known and have been used as vaso dilators. nitrites of alkyls having less than six carbon atoms, are quite unstable chemically, uncertain ill in their physiological action and unpleasant and unsafe to use therapeutically. I have found that they are relatively more toxic and irritating than the higher alkyl nitrites and produce undesired effects on the oxy-hemoglobin when used in anii5 mals. On the other hand I have found that alkyl nitrites in which the alkyl group contains more than twelve carbon 'atoms have practically no vapor pressure and for this reason are not suit.-

able for therapeutic use because they cannot be 20 administered by inhalation.

In the course of my investigation I have foun that alkyl nitrites containing from six to twelve carbon atoms in the alkyl group and more especially those containing from six to ten carbon atoms are pharmacologically active and. give results of quite a difierent character from those produced by the lower alkyl nitrites, exemplified by a' striking lack of toxicity and absence of detrimental effect on oxy-hemoglobin; The

compounds tend tobecome less active pharmacologically as the number of carbon atoms in the alkyl group increases above eight and, as indicated above, twelve carbon atoms in the alkyl group represents a practical upper limit.

35 The properties of the alkyl nitrites having six to twelve carbon atoms which are believed to be principally responsible for their clinical utility are their low but .substantial volatility, their chemical'stability and their lipoid solubility. If

40 the compounds were not volatile theyqould not be administered by inhalation. 0n the other hand, if the compounds were too volatile they would be too readily and quickly exhaled from the lungs and would have less chance to exert Moreover high volatility favors high concentration in the blood which is objectionable. Their lipoid'solubility insures that they will be removedfrom the blood stream by absorption into the fatty tissue and lipoid- 50 like substances in the body thereby producing their effects, for example, on the walls of the blood vessels. If they were not soluble in or absorbed by the tissue ofthe body, they would concentrate in the blood stream and exert their 55 toxic effect and detrimental action on the blood These lower alkyl nitrites, i. e.,

1 nor more than twelve.

and they would be lost by exhalation more quickly. Their chemical stability, of course, is associated with their low toxicity. Owing to their low volatility and high lipoid solubility, their sojourn in the blood stream is shortened, their toxicity is reduced and their depressor action is prolonged. Shortening thesojourn of the compounds in the blood stream obviates the formation of toxic by-products such as met-hemoglobin.

The compounds embraced by my invention may be represented by the general formula:

in which nis a whole number not less than six l5 They are generally characterized as straw colored oily liquids possessing a characteristic odor and a specific gravity somewhat less than that of water. They are chemically stable at atmospheric temperatures but decompose slowly under the influence of direct sunlight presumably liberating nitric oxide. They are very slightly soluble in water, soluble in the common organic solvents and readily soluble in lipoidal material.

The following example illustrates the preparation of the octyl nitrite:

172 cc. of 2-ethyl hexanol-lis added to a mixture of 1100 cc. of water and 110 cc. of concentrated hydrochloric acid and cooled at 0 C. A solution of 110 grams of sodium nitrite in 500 cc. of water is added to this mixture drop by drop with mechanical stirring and at such a rate that the temperature is. kept below 10f C. After all the solution has been addedpstirring is continued until practically all the blue' color has disappeared from the lower layer. The two layers are separated and the octyl nitrite is dried with anhydrous sodium sulfate or other suitable drying agents. It is then filtered and distilled under reduced pressure. The boiling is plus or minus 55 C. at 8-10 mm. Analysis of the finished product from several batches has shown it to vary from 94% to 96% octyl nitrite.

The nitrites of other alkyls may be similarly prepared.

The properties of the compounds have been determined by pharmacological and clinical tests. Their efiect on coronary vessels has been determined by (1) perfusion of the coronary vessels of the isolated rabbits heart (2) use of the coronary rings of the steer and (3) the Moravitz and Zahn experiment on the dog in situ. 'By

these" methods various compounds were compared and their degree of prolonged depressor activity and the rapidity of the return subjects to normal was ascertained.

In addition, the acute toxicity by inhalation and injection was determined using white male rats. Subacute toxicity was also determined by both of these methods on rats. Furthermore, the eifect upon hemoglobin was studied in the living animal. All o'fthese experiments withnitrites of the group defined above, and particularly octyl nitrite, have demonstrated their unusual pharmacological properties. I have proved that they possess the properties of rapid and prolonged action coupled with low toxicity. I have found,

or the furthermore, that they produce no deleterious action on the blood and do not form met-hemoglobin as do alkyl nitrii'es of low molecular weight. Experimental observation with human subjects has demonstrated that duration of the depressor response produced by these compounds, particularly octyl nitrite, is six to seven times that obtained with amyl nitrite, even though much smaller doses are used. Clinical experimentation by others has proved that these compounds are useful in conditions where depressor activity or lowering of the blood pressure is indicated, such as asthma, angina pectoris paroxysmal hypertension, or otherspams associated with the constriction of blood vessels. I have found that the most suitable method of application of these compounds is by inhalation,

I claim:

l. A vasodilator comprising an alkyl nitrite the formula CaHrzNOz.

2. 'A vasodilator comprising octyl nitrite.

3. A vasodilator comprising-ethyl hexyl nitrite.

JOHN C. KRANTZ, JR.