US3265575A - Antinflammatory salicyl morpholide - Google Patents

Description

United States Patent 3,265,575 ANTIINFLAMMATORY SALICYL MORPHOLIDE Alfred Halpern, Great Neck, N.Y., assignor to Synergistics, Inc., New York, N.Y., a corporation of New York No Drawing. Filed Sept. 30, 1963, Ser. No. 324,595 20 Claims. (Cl. 167-65) The present invention relates to the utilization of salicyl morpholide as an antiinflammatory agent and also to its use in combination with substances capable of exerting an antiinflammatory effect, as for example, corticoid steroids and butazolidin, and antimitotic agents such as colchicine, in the therapy of humans.

This application is a continuation-in-part of applicants copending application, Serial No. 174,358, filed February 14, 1962, and now abandoned, which in turn was a continuation-in-part of application Serial No. 107,281, filed March 9, 1961, and now abandoned, which in turn was a continuation-in-part of application Serial No. 744,503, filed June 25, 1958, which in turn was a continuation-inpart of application Serial No. 671,563, filed July 12, 1957, and now abandoned.

In response to stress, the activity of the adrenal cortex is greatly increased and this response is mediated through the anterior pituitary gland and more specifically, by the adrenocorticotropic hormone (ACTH). Although the exact mechanism by which discharge of ACTH is regulated, however, has not been completely established, we know that its physiologic and therapeutic effects depend upon the secretion of corticoid steroids. The adrenocorticotropic hormones of the anterior pituitary gland and the steroids of the adrenal cortex as well as their synthetic derivatives are frequently considered together, since their effects involve a common site of action. However, it should be recognized that the adrenocorticotropic hormone has a different physiology, chemistry, absorption and metabolism and, except for its ultimate therapeutic effect, is a unique and separate entity.

All known adrenal hormones are typical steroids resembling both the estrogenic and androgenic compounds in structure. Approximately 30 such steroid substances have now been isolated from the adrenal glands of animals and man, but only a few have any demonstrable activity. The corticoid steroids both naturally and synthetically derived, of present medical use as antiinflammatory agents are: desoxycorticosterone, cortisone, cortisone acetate, hydrocortisone, hydrocortisone-tert-butyl acetate, hydrocortisone 21 B-cyclopentanepropionate, hydrocortisone-Zl-sodium succinate, prednisolone, prednisolone sodium phosphate, prednisolone 21 acetate, prednisolone-tert-butyl acetate, prednisone, prednisone- 2l-acetate.

Hydrocortisone is believed to be the true adrenal glucocorticoid of man; cortisone being either a precursor or metabolite thereof. The more recent synthetic modifications of hydrocortisone have the same qualitative pharmacologic properties, but show individual quantitative differences from the parent compound. Thus, the pharmacologic therapeutic use and side reactions of these compounds are essentially the same, but variations exist from compound to compound in connection with potency duration of activity and dosage required.

Patients with adrenal or pituitary suppression, or both, cannot tolerate stress, as for example, surgery, trauma or infection. Thus, special caution in steroid therapy must be utilized if emergency surgery is necessary and particular treatment is necessary during the immediate post-operative phase, until functioning endogenous adrenal cortical activity is restored. Even in minor surgical procedures, minor injuries or minor infections, where little if any added hormonal protection is necessary, the patient with a depressed level of adrenocortical 3,265,575 Patented August 9, 1966 hormones may suddenly evidence shock or circulatory collapse. The administration of the corticoid steroids inhibits the inflammatory process and during prolonged therapy infection may develop without previous signs and symptoms. Thus, the utmost caution is necessary in order to initiate appropriate antibiotic and chemotherapeutic procedures before the infection proceeds to uncontrollable limits.

In addition to'these generalized noxious properties of the overall effect of continued administration of corticoid steroids, many serious side-effects in their ordinary use have been observed and these pose a serious and special problem to the physician. Psychiatric changes may be induced by the administration of these compounds, which range from simple euphoria to severe psychotic episodes. In children especially, convulsive seizures may occur, in fact, brain wave changes may occur in practically all patients receiving these drugs whether or not clinical abnormalities develop.

Disturbances in electrolyte metabolism involving sodium retention and potassium loss are most frequently encountered. In certain individuals, as for example, those predisposed to congestive heart failure or in overt congestive heart failure, the retention of the sodium ion poses a serious threat to their continuing cardiac status. The concomitant potassium loss may proceed to a hypokalemia, with consequent symptoms of fatigue, muscular weakness and electrocardiographic changes.

An alteration in carbohydrate tolerance has been observed in some patients who may develop glycosuria, fasting hyperglycemia and a tendency for the glucose tolerance curve to approach that seen in diabetes. On an infrequent occasion, a patient will develop diabetes mellitus during corticoid steroid therapy but this is reversible when the therapy is stopped.

Induced hypercorticism alters tissue reaction to injury, infection and toxemia. This modification of the tissue response may mask such cardinal signs of infection as fever, increased erythrocyte sedimentation rate and the C-reactive protein level. Hypercorticism increases susceptibility of individuals to infections.

In the course of conventional therapy with corticoid steroid substances, peptic ulceration may develop and prolonged hypercorticism may be accompanied by the eventual development or aggravation of osteoporosis, with the subsequent predisposition to fractures. This latter pathologic state is especially important to patients with rheumatoid arthritis and women in the postmenopausal state. Physiologic changes may also be expressed in the form of acne and hirsutism as well as moon face and menstrual disturbances. Thus, it will be recognized that while these potent compounds have resulted in much benefit, their use is fraught with serious limitations and the side reactions observed limit the therapeutic benefits.

There remains a recognized need to counterbalance the therapeutic advantages of this important class of compounds with the occurrence of side effects, in order to make this mode of therapy available to those chronically ill patients who need it most.

This need is of particular importance to patients wherein an inflammatory tissue response is the predominant factor. Among the many attempts to modify the inherent limitations of the steroid group of compounds and to preserve the antiinflammatory activity, has been the synthesis of new derivatives or partial replacement of the more potent agent with a less potent compound. Thus, phenylbutazone, a syntheticagent, without steroid or hormonal properties, has been proposed as an antiinflammatory agent for use in the rheumatic patent. Its toxicity is virtually the same as the corticoid steroids it was intended to replace.

Thus, it will be readily appreciated that the replaceby either the oral or parenteral route is both its insolubility in aqueous and physiologic fluids and the high incidence of local tissue irritation resulting after its use.

Alkali metal salts of salicylic acid are water soluble but these pose the problem of the corrosive alkaline pH of these compounds, which is not compatible with normal tissue physiology. Another problem which arises after the utilization of the alkali metal salts of salicylic acid is the interference with mineral ion balance as a result of the large dosages of salicylate required.

While the use of organic salts of salicylic acid have been resorted to in order to circumvent the alkalinity of the inorganic salicylate salts, as well as the physiologic effects of the excess of metallic ions, this approach'has been found to be unsatisfactory. The acidity of the stomach soon decomposes these labile compounds into their component parts.

We have found that salicyl morpholide possesses none of these disadvantages since it is not a salt of salicyclic acid and is stable over the entire pH range encountered physiologically in both the human and animal. Salicyl morpholide is not broken into an amine or salicyl moiety in the gastrointestinal tract but passes through the mucosal wall as an intact molecule.

Salicyl morpholide is a well defined crystalline compound which analyzes in excellent agreement with its theoretical requirements. It has the empirical formula C H NO a melting point of 174176 C. and a solubility at 20 C. in terms of grams per 100 cc. as follows: water, 0.41; ethanol, 3.3 and ether, 0.22. The pH of a 1 saturated aqueous solution is pH 6.2.

Salicyl morpholide is stable under the ordinary conditions of storage and does not hydrolyze in the gastrointestinal tract. It is absorbed into the blood stream as a single entity in contrast to salicylic acid salts. When salicyl morpholide is administered orally it does not cause local irritation to the gastrointestinal mucosa as do salicylic acid salts and is of relatively low toxicity, thereby permitting a flexibility of dosage, to meet the requirements of clinical medicine.

Salicyl morpholide is obtained by causing a salicylic acyl halide (chloride or bromide) to react with an equimolar quantity of morpholine in an inert medium. The reaction is substantially instantaneous and the desired compound is obtained by evaporating the inert solvent. The dried residue is crystallized from methanol or ethanol to yield the desired amount in a high state of purity.

A method of preparing this compound is to cause the reaction between an alkyl or aryl ester of salicylic acid and morpholine in order to effect the formation of the amide. This process has the advantage of eliminating the gaseous hydrogen halides resulting from the reaction between an acyl halide and morpholine and may be carried out without cumbersome traps for noxious gases or the use of special equipment.

Another method of preparing salicyl morpholide is to react salicylic acid anhydryde with morpholine in an inert medium, containing a dehydrating agent. This method of preparation is a preferred one. The compound obtained as a result of this procedure, is in a high degree of purity and compares in every respect to those obtained by the previous methods.

It has been found that when salicyl morpholide is administered in animals a demonstrable blood level of this agent appears in the circulation within fifteen minutes after administration, although maximum levels occur about one hour afterward. Pharmacologic evidence of these facts is established by the data reported in Table I, which was obtained in the following manner: A group of six rabbits of mixed sex were fed a slurry of salicyl morpholide and water by intragastric intubation. Blood samples were obtained from the marginal ear vein at periodic intervals of 15 minutes, one-half hour, one hour, two hours, three hours, four hours, five hours, and twentyfour hours, and the concentration of salicyl morpholide in the blood sample determined.

TABLE I.AVERAGE BLOOD LEVELS OF SALICYL MORPHOLIDE FOLLOWING INTRAGASTRIC INTUBATION IN RABBITS Mg. percent of Time: salicyl morpholide 15 minutes 16.5

30 minutes 16.1

1 hour 17.4

2hours 14.3

Shours 6.5 24 hours 5.7

An excess of 16 mg. percent of salicyl morpholide was achieved within fifteen minutes and a peak of 17.4 mg. occurred at sixty minutes, after which time the concentration steadily decreased although a level of approximately one-third of the peak value was found at the end of twenty-four hours.

It is important to note that in the course of these experiments, it was demonstrated that salicyl morpholide is not hydrolyzed within the gastrointestinal tract but is absorbed into the circulation as an intact molecule and that it is not decomposed into its component parts in the blood stream. This resistance to hydrolysis is further demonstrated by the absence of free salicylic acid ions in the blood stream after the administration of even high doses of salicyl morpholide. Experimental confirmation of the lack of hydrolytic cleavage of salicyl morpholide in aqueous and physiologic fluids was obtained by a special study. It was determined that no free salicylic acid was found in the blood of rabbits after the administration of salicyl morpholide by intragastric intubation. However, when a sample of the blood of these rabbits who were fed salicyl morpholide was treated with 10 N potassium hydroxide solution, and autoclaved at 15 lbs. pressure for one hour and 15 minutes, cleavage of the com-pound was observed. It is obvious that such drastic chemical treatment is far in excess of what Would be encountered in the living human and that under the ordinary physiologic conditions, salicyl morpholide is absorbed intact and does not decompose into its component parts.

When salicyl morpholide is administered to a patient suffering from an inflammatory disease process, as for example, rheumatoid arthritis, or bursitis, or to those patients having an inflammatory tissue response, such as would be present after surgery or infection, a prompt antiinflammatory action is observed. This antiinflammatory action is demonstrated by the lowering of the C-reactive protein blood level, in addition to other changes.

Thus, when the blood level of C-reactive protein was determined for a group of 5 patients, whose principal complaint was bursitis or rheumatoid arthritis, it Was found to range from plus 2 to plus 4, which value is an indication of the presence of tissue inflammation. [For C-reactive protein determinations see, Selman, D., and Halpern, A., Angiology, 7: 292, (1956).] Salicyl morpholide was then administered to these patients at a dos-age level of from 40 to 60 grains per day, and the C-reactive protein levels re-determined after 48 hours, 96 hours and one Week, of therapy. At the end of 48 hours of therapy, the C-reactive protein blood level had fallen to 0 lill one patient, to plus 2 in two patients, with no change in the other two patients. At the end of 96 hours, the C-reactive protein level test was negative in two patients, plus 1 in two patients, and plus 2 in one patient. A comparable control group, who did not receive any medication, continued to maintain a C-reactive blood level of from plus two to plus four during the same period. The results of this study establish that salicyl morpholide is capable of exerting an anti-inflammatory reaction to a degree which is suitable for therapy.

In another study, salicyl morpholide was administered to patients with chronic, inflammatory disease in order to evaluate the anti-inflammatory properties of this compound. The group of patients studied consisted of 30 patients; 12 males and 18 females of from 46 to 74 years of age, and presented the following complaints: rheumatoid arthritis patients); bursitis (7 patients); myositis (5 patients); and scleroderma (3 patients). The dose of the drug administered to these patients ranged from 40 to 60 grains per day. All previous medication was stopped except for antibiotics, when indicated.v The overall duration of study was from three to four months of therapy.

A comparable group of patients receiving no therapy were used as a control. The results were evaluated as excellent, if there was a relief of accompanying pain and a remission of the objective signs of the disease; good, if there was partial relief of pain and minimal remission of objective symptoms; and poor, if there were no changes observed when compared to the control group.

Twenty-two patients manifested an excellent response while on salicyl morpholide therapy, reporting relief of pain and greater flexibility of joint motion (where this was previously limited) and also a diminution of local edema. Four patients reported fair relief of pain, with persisting restriction in limb motion and also no appreciable diminution in local tissue sensitivity. Four patients showed no change to the dosage levels of salicyl morpholide administered.

There were no incidents of gastrointestinal distress, allergic reactions or any other side effects observed during the period of therapy and the conclusion of the investigator was that a satisfactory anti-inflammatory response was obtained after the administration of salicyl morpholide to these patients.

Intermittent C-reactive protein blood level determinations were carried out with the entire group of 30 patients described above, utilizing the office technique according to the standard method (for methods utilized in C-reactive protein determinations see, Selman, D., and Halpern, A., Angiology, 7: 292, [1956]). At the start of the study, one patient had plus 4 C-reactive protein level; 15 patients had plus 3 C-reactive protein levels; 1 exhibited a plus 2 level; three patients had a plus 1 and in one patient the test was negative. The C-reactive protein blood level was determined during the period of therapy and this test was utilized as an objective criterion of the effects of the drug. A lowering of the C-reactive protein level while the patient was on drug therapy was considered a positive demonstration of an antiinflammatory effect. The C-reactive protein levels for the group were determined after one week of therapy and the following results Were obtained.

No. patients: C-reactive protein blood level 8 Plus 3 10 Plus 2 6 Plus 1 6 0 After two weeks of therapy the C-reactive protein level was determined to be No. patients: C-reactive protein blood level 2 Plus 3 12 Plus 2 9 Plus 1 7 0 After one month of therapy, the C-reactive protein level ratios were within comparable limits.

No. patients: C-reactive protein blood level 2 Plus 3 10 Plus 2 10 Plus 1 8 0 The effect of salicyl morpholide on the C-reactive protein values determined in the 30 patients with inflammatory disorders, was statistically analyzed for significance.

TABLE II.-RAW DATA FOR STATISTICAL ANALYSIS Number of Patients with Time Observed CRP Level Test Interval Treatment Start None 1 3 7 15 1 One week 40 gr. SA*/day G 6 10 8 O Two weeks. 40 gr. SA*/day 7 9 12 2 0 One or two 40 gr. SA*/day 8 10 10 2 0 months.

*Salicyl morpholide.

C-reactive protein serum level observations during therapy periods were compared with results observed during the period of no therapy. Differences between serum levels without treatment and under treatment with salicyl morpholide generate chi-square values which quantify the likelihood that these results could have occurred by chance and therefore are indicative of the significance of the results. The details of the procedures used are described in: Cochran, W. G., and G. M. Cox, Experimental Design, pp. 100403, 407-411, John Wiley & Sons, New York, 1950".

The probabilities for the comparison of the test results were found to be as follows:

TABLE IlL-SUHMARIES OF THE SIGNIFICANCE OF TEST RESULTS OF THE EFFECT OF SALIGYL MORPHOLIDE ON C-REACTIVE PROTEIN FLUCTUATIONS These results establish that the chi-square value for all treatment periods combined when compared with the control periods exceeds the fractile value. This would occur on the basis of chance only 5 times in 10,000 trials. This establishes the view that salicyl morpholide produces changes in the serum levels of C-reactive proteins which would occur on the basis of chance less than 5 times in 10,000 experimental trials which are highly statistically significant changes. The changes in the serum C-reactive protein levels are also highly significant for individual treatment periods when compared with control. At the end of the second week the observed changes in these serum levels would only occur by chance 5 times in 1,000 experimental trials and at the end of one month, the changes observed in these serum levels would occur by chance only 1 time in 1,000 trials. Only those changes in serum levels recorded in the first week generate chi-square values which have border-line significance at the 5% level.

In still another study, a group of ten patients presently receiving hydrocortisone therapy for rheumatoid arthritis and presently maintained on the dosage schedule of from 20 to 30 mg. per day were studied for the effects of salicyl morpholide as a partial replacement for this steroid drug in their therapeutic regimen. The dosage of hydrocortisone was reduced to 5 mg. per day and 40 grains per day of salicyl morpholide was administered concomitantly. The patients were observed at weekly follow-up visits and the effect of this therapeutic regimen evaluated. At the end of two weeks, six patients of the group of ten, were satisfactorily maintained on this regimen, and in the remaining four, the dosage of salicyl morpholide was increased to 60 grains per day. After two weeks of treatment at the elevated dosage of salicyl morpholide, only one of this latter group of four patients appeared to be satisfactorily maintained. The dosage of hydrocortisone was then increased to 10 mg. per day for these three patients and the amount of salicyl morpholide reduced to 40 grains per day. After two weeks of therapy at this dosage level, the patients status appeared to indicate that satisfactory maintenance regimens had been achieved in two patients of this group and no benefit in one. This latter patient required a return to the original maintenance dosage of 30 mg. per day.

Hence, it was observed that for six patients a replacement of approximately 75 percent to 80 percent of the daily hydrocortisone requirements could be achieved by the substitution of 40 grains of salicyl morpholide per day. Three patients required 60 grains of salicyl morpholide to effect a reduction in hydrocortisone dosage of from 50 to 75 percent of their previous daily maintenance requirement, and there was no response in one patient. Thus, the anti-inflammatory properties of salicyl morpholide appear to be mediated through the adrenal gland and the effect of salicyll morpholide on the adrenal gland would appear to be to increase the endogenous hydrocortisone activity.

Statistical analysis was carried out again by standard chi-square tests for which results of treatments of the 10 patients with rheumatoid arthrtis are classified according to the supportive level attained.

TABLE IV.RAW DATA FOR STATISTICAL ANALYSIS (b) 40 grains salicyl morpholide plus mg. hydrocortisone. (e) 60 grains salicyl morpholide plus 5 mg. hydrocortisone. (d) 40 grains salicyl morpholide plus mg. hydrocortisone.

A series of three analytical comparisons were made: (1) hydrocortisone vs. control; (2) combined therapy vs. control; (3) hydrocortisone vs. combined therapy.

TABLE V.RESULTS OF THE STATISTICAL ANALYSIS Comparison Chi-squares Probabilities 16. 20 Less than 0.0005 (1 d.f.). 12. 93 Less than 0.0005 (1 d.f.).

0. 85 Greater than 0.30 (1 d.f.).

Comparison 1Treatment with hydrocortisone, 20 mg. to 30 mg.-The chi-square exceeds the fractile value, this would occur by chance only 5 times in 10,000 experimental trials, indicating that the heavy dosage of hydrocortisone for the patients with these inflammatory disorders produces highly significant supportive effects related specifically to the large dose levels of hydrocortisone used.

Comparison 2Treatment with varying doses of salicyl morpholide with a sharply reduced intake of hydrocortisone.-The chi-square value again exceeds the fractile value which occurs by chance 5 times in 10,000 trials, indicating that combined therapy of salicyl morpholide and a lowered dosage of the steroid produce highly significant supportive effects related specifically to the employment of this combination of the drugs. This positive effect is obtained despite the drastic reduction in the amount of steroid dosage.

Comparison 3-C0mparis0n between tre atments.The chi-square value is smaller than the fractile value which occurs by chance 30% of the time, indicating that there is no detectable difference between the supportive effects '8 of combined therapy and that of heavy dosages of hydrocortisone, upholding the view regarding the steroid-enhancing antiinfiammatory activity of salicyl morpholide.

A further advantage of salicyl morpholide for lOngterm use in the treatment of patients with chronic inflammatory disease is its lack of local gastrointestinal irritation which permits a high dosage of the drug to be ad ministered. There was no tolerance observed to continued administration of the drug and there was no interference with the acid base balance of the blood after the administration of the large doses in these studies.

In recent years pyrazolidone derivatives, namely 3,5-diozo-l,2-diphenyl-4-n-butyl pyrazolidine, have been utilized in the treatment of various arthralgic states, despite a number of inherent limitations. The commonly accepted name for this substance is phenylbutazone. Phenylbutazone has been demonstrated to have a marked capacity to raise the pain threshold in laboratory animals as well as exerting an antipyretic effect. Phenylbutazone exhibits antiinflammatory properties in animals similar to steroids, although it has been shown that this action is not mediated through the pituitary-adrenal cortex axis. Phenylbutazone causes sodium retention, which leads to edema. Tissue respiration studies have shown that oxygen consumption of brain tissue is lowered during phenylbutazone therapy, as is the utilization of glucose by the tissues. Phenylbutazone is slowly metabolized in man. The rate of bio-transformation varies with different subjects although the range in biometabolism has been postulated to be from 10 percent to 40 percent per day. The use of large doses of this drug, which is necessary to achieve the therapeutic effect desired, has resulted in serious toxic manifestations. The use of the drug has been enjoined with careful constant follow-up of the patients blood status, since severe blood dyscrasias have been reported after its use and liver damage has also been observed after its use. When salicyl morpholide is administered concomitantly and simultaneously with phenylbutazone or pyrazolidone derivatives exerting a similar effect, either in combination as a single dosage form or by co-administration, the anti-inflammatory properties of salicyl morpholide permit the reduction in the dosage of phenylbutazone so that the noxious toxic effects may be avoided without modifying the therapeutic effects of the regimen. Thus, the full therapeutic spectrum of phenylbutazone may be obtained without the occurrence of liver damage or blood dyscrasias, since the administered dose may be greatly reduced. Thus, while the initial daily dosage ranges from 300 to 600 mg. of phenylbutazone, and a maintenance dosage of 100 to 200 mg. per day is utilized in therapy, this dosage may be reduced from 50 percent to 75 percent by the addition of from 0.2 to 3.2 gins. of salicyl morpholide per day, administered concornitantly.

Another drug which has been used with therapeutic benefit for the relief of the symptomatology of inflammatory bone and tissue disease is colchicine. Here we find that the drug, because of the quantities necessary to exert a therapeutic effect, cause severe gastrointestinal distress. However, when colchicine is combined with salicyl morpholide in the therapeutic regimen, the dosage of colchicine may be greatly lowered without impairing its therapeutic efficacy. A reduction in the effective dosage of colchicine may range from 25 percent to percent when administered with 0.2 to 3.2 gm. of salicyl morpholide per day. Thus, the noxious gastrointestinal effects may be avoided and the drug which is capable of exerting great benefit may now be administered to patients who were formerly denied desirable pharmacologic effects because of the onset of local gastrointestinal irritation. This is of particular significance when it is recognized that colchicine is considered the drug of choice in the treatment of gout and the unilateral arthridites, pathalogic states which are common and present a crippling phenomena to our aging population.

'is added one mol of phenyl salicylate.

9. Example 1 To one-tenth mol of salicylic acid in'a three-necked round bottom boiling flask, fitted with a reflux condenser (attached to a gas absorption trap), a mechanical stirrer and a delivery funnel, is added two-tenths mol of thionyl chloride. The mixture is refluxed until no further evolution of hydrogen chloride occurs (approximately one-half hour), and the excess thionyl chloride distilled. To the resulting salicylic acyl chloride is added exactly one-tenth mol of morpholine, dissolved in 200 cc. of dry benzene. The reaction mixture is stirred at room temperature for one hour and the benzene is slowly distilled over a period of one to one and one-half hours. The dry residue comprising salicyl morpholide is mixed with 250 cc. of 1 percent sodium bicarbonate solution and warmed for fifteen to twenty minutes at a temperature of about 40 C., cooled and filtered. The insoluble material is dried and then dissolved in just sufficient hot methanol to achieve solution and the whole set aside to crystallize. On cooling overnight in an ice-chart, crystals of salicyl morpholide, melting at 174-176 C. are obtained in a yield of better than eighty percent which analyzes for carbon, hydrogen and nitrogen in excellent agreement with theoretical values.

To three mols of morpholine in a round-bottom, boiling flask fitted with a reflux condenser and a stirring device, The mixture is heated to approximately 130 C. and the stirring started. The reaction mixture is maintained at this temperature for two hours and the excess morpholine distilled under reduced pressure (2-3 mm. Hg). The residue is dissolved in one liter of methanol with the aid of gentle heat and crystallized overnight in an ice-box. Salicyl morpholide is obtained in better than 90 percent yield and conforms in every respect with the product isolated as a result of Example 1, above.

Example 3 To 0.5 mol of salicylic acid anhydride dissolved in one liter of dry benzene is added 0.5 mol of morpholine dissolved in 500 cc. of dry benzene. The mixture is warmed to reflux for two hours and the solvent distilled. The residue is crystallized from hot methanol to yield salicyl morpholide, M.P. l74176 C. in better than 95 percent yield.

Example 4 Tablets or capsules for oral administration should be prepared to contain not less than 50 mg. and not more than 400 mg. of salicyl morpholide per unit dose. Because the active ingredient is relatively not toxic, such tablets or capsules may be administered up to a total daily dosage of 5 grams, dependentupon the patients requirements. Preferably, it will be found that pharmaceutically desirable tablets and capsules may be prepared to contain about 350 mg. of the therapeutically active compound. Besides salicyl morpholide, the tablet may contain the usual carrier ingredients, as well as a disintegrating agent.

In preparing a tablet, it is first necessary to make up a carrier base granulation containing powdered sucrose,

powdered lactose or powdered corn starch. If desired, the coloring agent may be incorporated with the base granulation by either mixing it with the dry powder or incorporating it into the granulating solution, which consists of either 5 percent gelatin, or 5 percent acacia solution. The dried powder is uniformly moistened with this granulating solution and then screened coarsely through No. 4 to No. 12 mesh screen, depending on the properties of the dampened mass and then spread on trays, in thin layers, to dry. granulation, then the temperature must not exceed 65 C. When dry, the mass is further sieved through a No. 16 or No. 20 screen.

The salicyl morpholide is then mixed with a lubricating agent, such as calcium or magnesium stearate, and a disintegrating agent, as for example, powdered corn starch, and the whole intimately mixed. The salicyl morpholide mixture is then added to the base granulation and the mixture blended so as to form a uniform composition, which is then compressed into tablet form. A typical formulation for tablets may be as follows (all parts are by weight) 350 parts of salicyl morpholide parts of powdered lactose 3 parts of magnesium stearate 2 parts of powdered corn starch For the preparation of capsules, the salicyl morpholide may be filled directly into the appropriately shaped gelatin capsule of the proper size or it may be mixed with a diluent as, for example, powdered lactose, powdered sucrose or powdered starch, and then filled into the gelating capsules.

Example 6 Salicyl morpholide may be incorporated into a liquid dose form pharmaceutical preparation through the use of an appropriate non-toxic pharmaceutical carrier such as ethanol, glycerine, propylene glycol or polyoxyethylene glycol, or combinations of these, or utilized as a suspension by dispersing the active material in an aqueous vehicle such as water or sugar syrup with the aid of a dispersing. agent. Any of the pharmaceutically acceptable dispersing agents may be utilized to prepare these suspensions, as for example, the fatty acid esters of sorbitol, or their polyoxyethylene derivatives (these agents are known to commerce as Spans and Tweens); or the.

vegetable gums, as for example, acacia or tragacanth or lecithin. When the fatty acid esters of sorbitol or their polyoxyethylene derivatives are utilized as the dispersing agent, the range in concentration of these agents will depend upon the quantity of salicyl morpholide to be dispersed and the volume used will be from 0.1 percent to 2 percent. When the vegetable gums are utilized to achieve dispersion of the active drug, they range in concentration from 5 to 10 percent. A concentration from 5 to 15 percent of lecithin will be adequate to disperse salicyl morpholide in an aqueous medium.

The range of concentration of salicyl morpholide in the liquid preparation should be formulated so as to contain from 50 to 400 milligrams per unit dose which may be administered several times daily.

In preparing a solution, the appropriate quantity of active material is dissolved with the aid of gentle heat in a pharmaceutically acceptable solvent, as for example, ethanol, propylene glycol, glycerine, or polyoxyethylene glycol. The solution is cooled and filtered. Appropriate flavoring and coloring agents may be added, if desired.

When an aqueous suspension is desired, the appropriate suspending or dispersing agent is mixed with. the salicyl morpholide and a small quantity of the vehicle added to make a base dispersion. This is then diluted under continuous agitation with additional quantities of the vehicle until the proper volumeis achieved. It may If heat is used to dry the:

ll be found desirable to pass the entire suspension through any of the conventional homogenization apparatus for more uniform dispersion.

The solution and dispersions are stable and homogeneous and may be conveniently used in therapy.

Example 7 When it is desired to administer salicyl morpholide by the rectal route, then the active ingredient may be incorporated in a pharmaceutically acceptable suppository base, as for example, cocoa butter, polyoxyethylene glycol of a molecular weight from 1500 to 6000 (compounds which are known in commerce as Carbowax), or glycerine-gelatine mixtures. Suppositories may be made with the aid of conventional molding equipment and each suppository should contain a range in concentration of active therapeutic compound from 50 mg. to 400 mg.

The appropriate quantity of salicyl morpholide is mixed with .the selected suppository base, utilizing the conventional techniques of either milling or dispersion in the molten base-composition. The suppositories are formed by filling the mold with the mixture by either a hot pour or extrusion techniques.

By reason of the extraordinary stability and lack of dissociation into free salicylic acid ions, salicyl morpholide permits the use of large quantities of analgetic agents without the occurrence of local tissue irritation.

Example 8 When it is desired to obtain an antiinflammatory effect, in animals or humans, salicyl morpholide may be administered by intragastric intubation of a slurry of salicyl morpholide in water (concentration of active material, 20 percent, by weight) or by tablet, capsule, or liquid dose form, as for example, elixir, tincture, or suspension or as a suppository for rectal administration. The range in concentration of the active material when administered in either the oral or rectal routes is from 50 mg. to 400 mg. per unit dose. The total quantity of the drug which may be administered to an individual patient per day, may be as high as grams.

Salicyl morpholide will be found in the blood stream within fifteen minutes after administration and will achieve a peak blood level within one hour, after which time it will be eliminated via the normal metabolic pathways. There are no free ions of salicylic acid observed in the blood after the administration of salicyl morpholide, nor is there alteration of the acid-base balance of the blood after its administration even when high dosages are used. The compound may be administered under chronic regimens and no occurrence of untoward noxious side reactions which effect either the liver or the kidneys, have been observed.

Example 9 When it is desired to obtain an antiinflammatory effect in the patient presenting a muscular-skeletal disorder, associated with local tissue or joint inflammatory disease, as for example, rheumatoid arthritis, bursitis or myositis, or to provide an antiinflammatory effect during the postoperative period, salicyl morpholide may be administered by either the oral or rectal routes, utilizing the above described dose forms for a daily dosage level of from 0.5 gram to 5 grams of the active therapeutic compound. An antiinflammatory effect will be observed in the patient as evidenced by a greater degree of joint mobility, lessening of the pain, incidental to the reduction of inflammation, and a reduction in the C-reactive protein level of the blood. Salicyl morpholide may be prescribed as tablets, capsules, teaspoonful or suppository dose-form, at a dosage range of from 100 mg. to 400 mg., to be taken one to eight times per day, depending upon the patients need. The antiinflammatory properties of salicyl morpholide will be observed after the administration of the drug in that an increasing joint mobility as well as a decrease in local inflammation, will result.

12 Example 10 When it is desired to obtain an antiinflammatory effect in the patients presenting those pathologic states requiring long-term administration of conticoid steroids, as for example, such mesenchymal diseases as rheumatoid arthritis, rheumatic fever, disseminated lupus erythematosus, periarteritis nodosa, dermatomyositis, scleroderma, bursitis, and calcific tendonitis or allergic diseases such as acute and chronic bronchial asthma, status asthmaticus, nasal polyps, acute drug reactions, contact dermatitis, and atopic dermatitis, or metabolic diseases such as spontaneous hypoglycemia, or acute gouty arthritis, or diseases of the skin, such as pemphigus, exfoliative dermatitis, drug eruptions, anaphylactoid purpura, chronic eczema, atopic dermatitis or gastrointestinal diseases such as sprue, ulcerative colitis, regional ileitis, and chronic hepatic disease or diseases of the eye, such as allergic conjunctivitis, vernal conjunctivitis, episcleritis, marginal ulcer, uveitis, acute optic neuritis, chemical and thermal burns of the eye, or neoplastic disease, such as leukemia, lymphoma and carcinoma of the breast, of dental and oral diseases, such as rheumatoid arthritis of the temporomandibular joint and allergic stomatitis and glossitis, then a reduced maintenance regimen of the-corticoid steroids may be prescribed together with a supplementation dosage of salicyl morpholide.

When such a dosage regimen is utilized in therapy, the corticoid steroid is combined with the salicyl morpholide into a single dosage form. Thus, hydrocortisone may be combined with salicyl morpholide into a single tablet, capsule, suppository or liquid unit dose form or other dosage form, utilizing a ratio of from 1 to 5 mg. of hydrocortisone for each 50 to 400 mg. of salicyl morpholide contained in the particular unit dosage form selected. The active ingredients are combined and added to the pharmaceutical carrier. The procedures described in Example 5 may be usedto prepare combination tablets and that of Example 7 to prepare suppository medication.

The daily dosage range of the combination of corticoid steroids and salicyl morpholide will depend upon the individual patient, as well as the potency of the corticoid steroid utilized. Thus, the daily dosage requirement of hydrocortisone will be higher than that of prednisolone for the same patient because of the variations in potency of these two compounds. Similarly, the degree of severity of the disease within the patient may require more or less of the corticoid steroid.

However, it will be found that a range of from 4 to 40 mg. of hydrocortisone in combination with from 0.2 to 3.2 mg. of salicyl morpholide per day, will be adequate to treat the patients requiring this form of medication. This same range in daily dosage requirements applies irrespective of whether tablets, capsules, suppositories or liquid dosage form is used. It is preferred that the total daily dose be divided into from 3 to 8 portions, administered throughout the day in order to maintain a uniform blood level.

Example 11 In place of the hydrocortisone used as described in Example 10, above, there may be substituted any of the following corticoid steroid compounds, in the particular ratios described below for each respective compound, to prepare unit dosage forms as described in Example 10, which comprises a combination of corticoid steroid compound and salicyl morpholide:

Mg. Cortisone 1 to 5 Cortisone acetate l to 5 Hydrocortisone-tert-butyl acetate 1 to 5 Hydrocortisone-Zzlfl-cyclopentanepropionate 1 to 5 Hydrocor-tisone-Zl-sodium succinate 1 to 5 Prednisolone 0.1 to 3 Prednisolone sodium phosphate 0.1 to 3 Prednisolone ZI-acetate 0.1 to 3 Mg. Prednisolone-tert-butyl acetate 0.1 to 3 Predni'sone 0.1 to 3 Prednisone-Zbacetate 0.1 to 3 When it is desired to utilize these combinations of this combined form of therapy, it will be found that the daily dosage range for the combination of the corticoid steroid compound, listed below, and salicyl morpholide, to treat patients requiring this form of medication, is:

Cr-tisoneFrom 4 mg. to 40 mg. of cortisone in combination with'from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Cortisone aceta-te--From 4 mg. to 40 mg. of cortisone in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Hydrocortisone-tert butyl acetate-From 4 mg. to 40 mg. of cortisone in combination with from 0. 2 gm. to 3.2 gm. of salicyl morpholide.

Hydrocortisone 21,8 cyclopentanepropionate From 4 mg. to 40 mg. of cortisone in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

HydrocortisoneJrI-sodium succinateFrom 4 mg. to 40 mg. of cortisone in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

PId1liSOlOI1C-IFI'0II1 .4 mg. 'to 25 mg. per day, in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisolone sodium phosphate-4 mm .4 mg. to 25 mg., per day, in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisolone 2 l-acetate-From .4 mg to 25 mg., per day, in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisolone-tert-butyl acetateFrom .4 mg. to 25 mg, per day, in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednisone- From .4 mg. to 25 mg, per day, in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

Prednis-one-Zl-acetateFrom .4 mg. to 25 mg, per day, in combination with from 0.2 gm. to 3.2 gm. of salicyl morpholide.

This same range in daily dosage requirements applies When either tables, capsules, suppositories or the liquid dosage form is used. It is preferred that the total daily dose be divided into from 3 to 8 portions, administered throughout the day in order to maintain a uniform blood level.

Example 12 When it is desired to obtain an antiinflammatory effect in patient-s presenting those pathologic states requiring administration of pyrazolidone derivatives such as 3,5-dix0 1,2 diphenyl 4 n butyl pyrazolidine, which is commonly known as phenylbutazone, for the purpose of treating such disease manifestations such as rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, psoriatic arthritis, painful shoulder syndrome and acute superficial thrombophlebitis, then phenylbutazone in combination with salicyl morpholide may be administered by either the oral, rectal or parenteral routes. The ratio of the combination of phenylbutazone and salicyl morpholide is from 50 to 300 mg. of phenylbutazone to 0.2 to 3.2 gm. of salicyl morpholide, administered in divided doses throughout the day. Thus, it may be desirable to utilize a tablet containing 50 mg. of phenyl butazone and 400 mg. of salicyl morpholide, which would be administered to the patient from 1 to 6 times daily, depending upon the patients needs. The administration of such combination of medication results in a prompt remission of the acute symptomatology.

Should a liquid dosage form be desired, then a suitable elixir may be prepared utilizing from 20 percent to 40 percent of alcohol and the remainder of the vehicle being simple syrup. Suitable flavoring and coloring may be added. The range of phenylbutazone may be from 50 mg. to 300 mg., for each teaspoonful, although it will be found preferable to utilize the lower dosage of between 50 mg. and mg. per teaspoonful. The concentration of salicyl morpholide contained in this liquid preparation is from 200 mg. to 500 mg. per teaspoonful although it will be found preferable to utilize the lower range of from 200 mg. to 300 mg. per teaspoonful dose.

Similarly, when a suppository is desired, the conventional suppository base may be used and the range in phenylbutazone per unit suppository is from 50 mg. to 300 mg. and the concentration of salicyl morpholide per unit suppository is from 200 mg. to 500 mg.

Example 13 When it is desired to utilize a combination of colchicine and salicyl morpholide in the treatment of the gouty arthridites or gout, then it may be administered in the form of a tablet, liquid or suppository so that each unit dosage form contains from 0.2 to 0.5 mg. of colch-icine and 200 mg. to 500 mg. of salicyl morpholide. A prompt reduction in symptomatology and degree of inflammatory disease present, will be observed soon after administration of this combination without the onset of any of the local gastrointestinal distress usually accompanying the administration of colchicine alone.

It is not desired to be limited except as set forth in the following claims, the above description 'being by way of illustration of the invention.

What is claimed is:

1. A method of achieving an antiinflammatory effect in a human which comprises the step of the administration to such human of salicyl morpholide and a pharmaceutical carrier therefor.

2. A method of claim 1, said salicyl morpholide being administered in unit dosage form to such human containing from 50 to 400 mg. of said compound.

3. An antiinflammatory pharmaceutical preparation in unit dosage form comprising salicyl morpholide and a corticoid steroid compound having an antiinflammatory efiect.

4. An antiinflammatory pharmaceutical preparation in unit dosage form comprising from 50 to 400 mg. of salicyl morpholide and from 0.1 to 5 mg. of a corticoid steroid compound having antiinflammatory effect and a pharmaceutical carrier therefor.

5. An antiinflammatory pharmaceutical preparation in unit dosage form, comprising from 50 to 400 mg. of salicyl morpholide and from 1 to 5 mg. of hydrocortisone.

6. An antiinflammatory pharmaceutical preparation in unit dosage form comprising from 50 to 400 mg. of salicyl morpholide and from 1 to 5 mg. of cortisone.

7. An antiinflammatory pharmaceutical preparation in unit dosage form comprising from 50 to 400 mg. of salicyl morpholide and from 0.1 to 3 mg. of prednisone.

8. An antiinflammatory pharmaceutical preparation in unit dosage form comprising from 50 to 400 mg. of salicyl morpholide and from 0.1 to 3 mg. of prednisolone.

9. An antiinflammatory pharmaceutical preparation in unit dosage form comprising from 50 to 400 mg. of salicyl morpholide and from 50 to 300 mg. of phenylbutazone.

10. An antiinflammatory pharmaceutical preparation in unit dosage form comprising from 50 to 400 mg. of salicyl morpholide and from 0.2 to 0.5 mg. of co'lchicine.

11. The method of obtaining an antiinflammatory effect in a human presenting a tissue inflammatory reaction which comprises the step of the administration to such human in unit dosage form of salicyl morpholide and a compound selected from the group consisting of corticoid steroids having an antiinflammatory effect, phenylbutazone and colchicine.

12. The method of obtaining an antiinflammatory effect in a human presenting tissue inflammatory reaction whichcomprises the step of the administration to such human in unit dosage form of from 50 mg. to 400 mg. of salicyl morpholide and from 0.1 to mg. of a corticoid steroid having anti-inflammatory action.

13. The method of obtaining an antiinflammatory eflect in a human presenting tissue inflammatory reaction which comprises the step of the administration to such human in unit dosage form of from 50 to 400 mg. of salicyl morpholide and from 50 to 300 mg. of phenylbutazone.

14. The method of obtaining an antiinflammatory effect in a human presenting tissue inflammatory reaction which comprises the step of the administration to such human in unit dosage form of from 50 to 400 mg. of salicyi morpholide and from 0.2 to 0.5 mg. of colchic-ine.

15. The method of obtaining an antiinflammatory effect in a human presenting tissue inflammatory reaction which comprises the step of the administration to such human in unit dosage form of from 50 to 400 mg. of saii-cyl morpholide and from 0.1 to 3 mg. of prednisone.

16. The method of obtaining an antiinflammatory effect in a human presenting tissue inflammator eaction which comprises the step of the administration to such human in unit dosage form of from 50 to 400 mg. of salicyl morpholide and from 0.1 to 3 mg. of predn-isolone.

17. The method of obtaining an antiinflammatory effect in a. human presenting tissue inflammatory reaction which comprises the step of the administration to such human in unit dosage form of from 50 to 400 mg. of

salicyl morpholide and from 0.1 to 3 mg. of prednisolone sodium phosphate.

18. The method of obtaining an antiinflammatory eflect in the patient sufieringfrom rheumatoid arthritis, bursitis, myositis, thrombophlebitis, gouty arthritis, osteoarthritis and spondylitis, which comprises the step of the administration to such patient in unit dosage form of from to 400 mg. of salicyl morpholide and a compound selected from the group consisting of hydrocortisone, cortisone, hydrocortone-Zl-sodium sucoinate, prednisone, prednisolone, prednisolone-t-butyl acetate, phenylbutazone and colchicine.

19. The method of obtaining an antiinflammatory effect in a patient suffering from thrombop-hlebitis which comprises the step of the administration to such patient in unit dosage form of from 50 to 400mg. of salicyl morpholide and 50 to 300 mg. of phenylbutazone.

20. The method of obtaining an antiinflammatory effect in a patient suffering from gout and gouty arthritis which comprises the step of the administration to such patient in unit dosage form of from 50 to 400 mg. of salicyi morpholide and 0.2 to 0.5 mg. of colchioine.

No references cited.

JULIAN S. LEVITT, Primary Examiner.

MARTIN J. COHEN, Assistant Examiner.

Claims (1)

1. A METHOD OF ACHIEVING AN ANTIINFLAMMATORY EFFECT IN A HUMAN WHICH COMPRISES THE STEP OF THE ADMINISTRATION TO SUCH HUMAN OF SALICYL MORPHOLIDE AND A PHARMACEUTICAL CARRIER THEREFOR.