US3051623A - Codeine and 2-methyl-3-o-tolyl-4-quin-azolone analgesic composition - Google Patents

Description

Aug. 28, 1962 E. E. HAYS ETAL 3,051,623

000mm: AND Z-METHYL-3-0TOLYL-4-QUINAZOLONEZ ANALGESIC COMPOSITION Filed April 24, 1959 Q CODEINE SULFATE, 5o MG/KG Q CODEINE SULFATE, 5o M K PLUS ,20 METHYL ATROPINE, 5 MG/KG 5% CODEINE REsIN COMPLEX, 75 MG/KG 13 [I] CODEINE REsIN coMPLEx, 75 MG/KG 3 PLUS METHYL ATROPINE RESIN CD coMPLEx, s MG/KG SI0 r [N FIGI- POTENTIATION OF CODEINE ANALGESIA BY METHYL ATROPINE 5 4O I I 30- E] cooEINE AS RESIN coMPLEx, Ioo MG/KG (j I 33 7 Q CODEINE AS REsIN COMPLEX, I00 MG/KG q PLUS QUINAZOLONE REsIN COMPLEX, 2o MG/KG S cooEINE AS RESIN COMPLEX, I00 MG/KG Iw PLUS QUINAZOLONE REsIN coMPLEx, 66 MG/KG F|G.2- POTENTIATION OF CODEINE ANALGESIA BY UIN ZOLONE Q A .Zfiz/nfors.

521051157 22 Leonard M20 elsorz.

United States Patent l 3,051,623 (ZGDEDJE AND 2-METHYL-3-G-TOLYL-4-QUIN- AZGLONE ANALGESHC COMPGSHIGN Edwin E. Hays and Leonard Michelson, Rochester, N.Y.,

assignors to Wallace and Tiernan inc, a corporation of Delaware Filed Apr. 24, 1950, Ser. No. 808,622 1 Claim. (Cl. 16767) This application is a continuation-in-part of our copending application, Serial No. 706,252, filed on December 31, 1957, now abandoned.

This invention relates to therapeutic compositions, and more particularly to therapeutic compositions containing codeine and codeine-like drugs which produce a longeracting and potentiated response. More particularly, the compositions of the present invention contemplate the inclusion of codeine, and codeine-like compounds which are potentiated by the addition of quinazolones, which are described and claimed in our co-pending application, Serial No. 706,252. The invention relates to compositions including codeine, and codeine-like compounds per se, with the above mentioned quinazolones per se, and also includes such compounds in the form of resinate complexes, as will be more fully described hereafter.

Codeine has long been used in the medical field for its analgesic properties. While it has only moderate oral analgesic properties, it has been employed, particularly in combination with aspirin, phenacetin, and caffeine compounds. Such mixtures, however, must be administered every few hours in order to provide a patient with any prolonged release from pain. As a result, the medical profession has long sought a preparation which would produce a long-acting and potentiated response.

An object of the present invention is to provide therapeutic compositions which have a longer-acting and more powerful analgesic etfect than codeine alone.

It is another object of the present invention to provide compositions which are delayed in their absorption with the resulting reduced toxicity and prolongation of the drug action, such compositions being obtained by combining codeine and the quinazolones mentioned above in the form of a resin complex or resinate.

in accordance with the present invention, the above and other objects which will become apparent hereinafter, are accomplished by a composition comprising codeine, or a codeine-like drug, and one or more of the quinazolones of the type mentioned below.

We have also found that methyl atropine will potentiate the analgesic activity of codeine.

Suitable quinazolone compounds are 2-methyl-3-o-tolyl-4-quinazolone, 2-rnethyl-3-phenyl-4-quinazolone, 2-ethyl-3-phenyl-4-quinazolone, 2-ethyl-3-o-tolyl-4-quinazolone, Z-ethyl-3m-tolyl-4-quinazolone, 2-n-pro-pyl-3-phenyl-4-quinazolone, 2-n-propyl-3-o-tolyl-4-quinazolone, 2-methyl-3-lauryl-4-quinazolone.

The acid addition salts of these compounds are also included within the present invention. of the acid addition salts of the free base with inorganic or organic acids which may be prepared by the methods hereinafter described are the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, maleate, acetate,

than the resinates made with carboxylic acid cation exchange resins.

Some examples sodium o-nitrobenzoate in acetone.

65 citrate, oxalate, succmate, benzoate, tartrate, phthalate,

I .Of benzene.

3,051,623 Patented Aug. 28, 1962 To facilitate a fuller and more complete understanding of how the principles of this invention may be applied, certain specific examples follow herewith. It is clearly to be understood, however, that these examples are provided by way of illustration only, and that they are not to be construed as imposing any limitations upon the invention as defined in the subjoined claims.

PREPARATION OF QUINAZOLONES Example 1.2-Methyl-3-Ph enyl-4-Quinaz0l0ne 135 gms. of N-phenyl-acetamide were refluxed for 4 hours with gms. of thionyl chloride and one liter of benzene. The benzene and excess thionyl chloride were stripped oil under vacuum. The residue was dissolved in 350 cc. of acetone and added to 210 gms. of sodium o-nitro-benzoate in acetone. After an hour at room temperature, the reaction mixture was concentrated and the residue extracted with hot water to give 250 gms. of N- phenyl 1 N-acetyl-onitrobenzamide. The N-phenyl-N- acetyl-o-nitrobenzamide was dissolved in 2500 cc. of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in 5500 cc. of water was added dropwise. The alcohol was stripped off, and the residue poured into water, filtered, washed with hot water, and the product was extracted with warm concentrated HCl. The free .base was obtained by neutralizing with HCl solution in alkali. Yield200 gms.

Example 2.-2-Ethyl-3-Phenyl-4-Quinazolone 149 gms. of N-phenyl propionamide were refluxed for 4 hours with 120 gms. of thionyl chloride and one liter of benzene. The benzene and excess thionyl chloride were stripped ofi under vacuum. The residue was dissolved in 375 cc. of acetone and added to 210 gms. of sodium o-nitrobenzoate in acetone. After one hour at room temperature, the reaction mixture was concentrated and the residue extracted with hot water to give 270 gms. of Nphenyl-N-propionyl-o-nitro benzamide. This was dissolved in 2700 cc. of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in 5500 cc. of water was added dropwise. The alcohol was stripped off and the residue poured into water, filtered, washed with hot water and the product was extracted with warm concentrated HCl. The free base was obtained by neutralizing the HCl solution with alkali. Yield220 gms.

Example 3.-2-Ethyl-3-0-T0lyl-4-Quinazolone 173 gms. of N-o-tolyl-propionamide were refluxed for 4 hours with 120 gms. of thionyl chloride and one liter of benzene. The benzene and excess thionyl chloride were stripped ofi under vacuum. The residue was dissolved in 400 cc. of acetone and added to 210 gms. of sodium o-nitrobenzoate in acetone. After one hour at room temperature, the reaction mixture was concentrated and the residue extracted with hot water to give 280 gms. of

N-o-tolyl-N'propionyl-o-nitrohenzamide. This was dissolved in 2800 cc. of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in 5500 cc. of water was added dropwise. The alcohol was stripped off and the residue poured into water, filtered, washed with hot water and the product was extracted with warm concentrated HCl. The free base was obtained by neutralizing the HCl solution with alkali. Yield230 gms.

Example 4.2-Ethyl-3-m-Tolyl-4-Quinazolone 173 gms. of N-m-tolyl-propionamide were refluxed for 4 hours with 120 gms. of thionyl chloride and one liter The benzene and excess thionyl chloride were stripped off under vacuum. The residue was dissolvedin 400 cc. of acetone and added to 210 gms. of After one hour at room temperature, the reaction mixture was concentrated oxychloride.

will depend on the nature of the reactants.

and the residue extracted with hot water to give 280 guns. of N-m-tolyl-N-propionyl-o-nitrobenzamide. This was dissolved in 2800 cc. of alcohol and heated to reflux. A solution of 1750 gms. of Na S O in 5500 cc. of water was added dropwise. "Ihe alcohol was stripped off and the residue poured into water, filtered, washed with hot water and the product was extracted with warm concentrated HCl. The free base was obtained by neutralizing the HCl solution with alkali. Yield230 gms.

Example 5 .2-n-Propyl-3-Phenyl-4-Quinazolone 163 gms. of N-phenyl butyramide were refluxed for 4 hours with 120 gms. of thionyl chloride and one liter of benzene. The benzene and excess thionyl chloride were stripped oil under vacuum. The residue was dis solved in 400 cc. of acetone and added to 210 gms. of sodium o-nitro-benzoate in acetone. After one hour at room temperature, the reaction mixture was concentrated and the residue extracted with hot water to give 280 gms. of N-phenyl-N-butyryl-o-nitrobenzarnide. This was dissolved in 2800 cc. of alcohol and heated to reflux. A solution of 1750 gms. of Na S O4 in 5500 cc. of water was added dropwise. The alcohol was stripped off and the residue poured into Water, filtered, washed with hot water, and the product was extracted with warm concentrated HCl. The free base was obtained by neutralizing the HCl solution with alkali. Yield-230 gms.

Example 6 .2-n-Pr0pyl-3-0-T0lyl-4-Quinazolone 177 gms. of N-o-tolyl butyramide were refluxed for 4 hours with 120 gms. of thionyl chloride and one liter of benzene. The benzene and excess thionyl chloride were stripped off under vacuum. The residue was dissolved in 430 cc. of acetone and added to 210 grns. of sodium'o-nitro-benzoate in acetone. After one hour at room temperature the reaction mixture was concentrated and the residue extracted with hot water to give 290 gms. of N-o-tolyl-N-butyry l-O-nitrolbenzamide. This was dissolved in 2900 cc. of alcohol and heated to reflux. Added dropwise was a solution of 1750 gms. of Na S O in 5500 cc. of water. The alcohol was stripped off and the residue poured into water, filtered, washed with hot water, and the product was extracted with warm concentrated HCl. The free base was obtained by neutralizing the HCl solution with alkali. Yield240 gms.

In general, the compounds of the present invention may be prepared by either of two methods. The first, in general, involves the heating of N-acyl-o-amino-cyclic carboxylic acid with a primary amine in a suitable solvent in the presence of phosphorus trichloride or phosphorus The phosphorus chloride, preferably diluted with a small amount of the solvent employed, is added slowly and portionwise to the solution of the other components. The degree of heating to efiect the reaction Preferably, the temperature is one at which the reaction mixture refluxes, although lower temperatures may be employed.

The second method involves the preparation of the compounds, such as shown in Examples 1-6, by the reaction of the corresponding amide with thionyl chloride in a suitable solvent, and the addition of a benzoate to form the corresponding amide, which is then converted to the desired quinazolone.

In general, it has been found that doses between 10 and 400 mgs. are effective for producing the therapeutic results set forth above. In particular, it has been found that the above compounds, when absorbed upon and ionically bound with a sulfonic acid cation exchange vresin, produce a long acting effect for a period of at least 8 to 12 hours.

An example of dosage form. of 2-rnethyl-3-ortho-tolyl- 4 (3H)-quinazolone bound on a sulfonic acid ion exchange resin is as follows:

To 370 gms. of moist Amberlite IR120 resin (225 gms. of dry resin) suspended in distilled water was added for reaction with the compounds disclosed herein to provide the pharmaceutically effective adsorption compounds. The term sulfonic acid cation exchange resin is intended to include the phenol-sulfonic acid cation exchange resins and the carboxylic-sulfonic acid cation exchange resins, as well as the ordinary sulfonic acid cation exchange resins. However, particularly satisfactory result-s have been obtained with the sulfonic acid cation exchange resins disclosed in DAlelio Patent No. 2,366,- 007, such resins being sulfonated polymerizates of polyvinyl aryl compounds. Other suitable cation exchange resins are disclosed in US. Patents Nos. 2,204,539; 2,338,- 159; and 2,729,607.

The cross linkage of the sulfonic acid resins is suitably between 3 percent and 17 percent, and preferably between 5 percent and 10 percent, to obtain the most effective slow rate of diffusion of stomach and intestinal juices into the resin. The particle size of the resins is of lesser importance, but improved slowing down efiect is obtained with a particle size between 20 to mesh over that of finer particle, such as 200 mesh.

An illustrated formula of a suitable cation exchange resin adsorption product of an amine is given below, A representing a resin nucleus:

The resin adsorption compounds of this invention are preferably substantially saturated with the amine. Saturation will generally run from about 30 percent to 50 percent, depending upon the amine and the time of contact with the sulfonic acid cation exchange resin. However, the resin does not necessarily have to be saturated, and as little as 10 percent and less of the adsorption amine can be used.

The resin adsorption products can be readily made by agitating the ingredients suspended in water until the reaction is complete.

In the examples, IR-120 refers to a sulfonic acid cation exchange resin, 7 percent to 8 percent cross-linked, having a particle size such that substantially all particles pass through a 20 mesh screen and are retained on a 50 mesh screen, and made in accordance with Example 1 of US. Patent No. 2,366,007, except that 7.5 parts of divinyl benzene are used instead of the 10 parts. XE-69 refers to the same resin as I-R120 except that substantially all particles pass through an 80 mesh screen and are retained on a mesh screen.

PREPARATION OF CODEINE RESIN COMPLEX Example 7 Place 34.66 lbs. of Amberlite Resin XE-69 in sack in the reaction tank. 35 gallons of deionized water is added and then hydrochloric acid, 'C.P. conc., is added to bring pH to one to 2 under agitation. Continued agitation for 30 minutes, drain tank, add 25 gallons of deionized water and drain tank; add 35 gallons of deionized water. Next, 11.82 lbs. of codeine is added and then is agitated for 3 hours and allowed to stand overnight. Supernatant liquid is removed and 35 gallons of water added and agitated for 15 minutes, allowed to stand, and supernatant decanted. Repeat 3 more times. The cake is sucked to dryness, transferred to trays, and dried at 128 F. overnight. Cake is then fed through Fitzpatric with No. 2 screen.

PREPARATION OF METHYL ATROPINE-RESIN- COMPLEX Example 8 Add 220 gms. of XE-69 resin to one liter of 3 percent hydrochloride in water and mix for 30 minutes. Decant, wash, and resuspend in 3 liters of water. Add 95 gms. of methyl atropine nitrate and stir slurry for 3 hours. Allow to stand overnight, then stir for additional 2 hours. Decant, wash, and oven dry at 60 F.

50 nag/kg. of codeine sulfate showed efiective analgetic response (greater than 3 Asec.) at 30 minutes but not after 90 minutes. At 75 nag/kg. potency was similar but efiective analgesia lasted 90 to 180 minutes.

75 mg./kg. of codeine resinate (sulfuric acid cation exchange adsorption compound) produced efiective analgesia equal in intensi-ty to that of 50 mg./kg. of codeine as sulfate, but of much longer duration (4-12 hrs.) than that of even 75 mg./kg. of codeine as sulfate. Hence, prolongation of effect is attained.

FIGURE 1 shows the potentiation of codeine analgesia by the addition of methylatropine, and methylatropine as the resin complex. Methylatropine at 5 and mg./kg. as the nitrate enhanced the analgetic action of 50 mg./kg. of codiene as sulfate. 9 mg./kg. of methylatropine as resinate potentiated the analgetic effect of 75 mg/kg. of codiene as resinate. Methylatropine, itself, has substantially no analgesic activity.

FIGURE 2 shows the potentiation of codiene analgesia by the addition of quinazolone compounds described herein, both alone and as resin complexes. The quinazolones which have no analgetic properties in doses of mg./kg. increased the analgetic activity of 50 and 100 mg./kg. of codeine as sulfate. When both codeine (100 rug/kg.) and the quinazolones (20 mg./kg.) were given as resinates, the analgesic activity was increased by an average factor of 4.3. Increase of the quinazolone dose to 66 mg. kg. increased tht factor to 6.4.

The specific quinazolone compound shown in FIG. 2 was 2-methyl-3-orthotolyl-4-quinazolone. However, similar potentiation was obtained with other quinazolones above mentioned and the effect is believed to be a general one for analgesic morphine compounds and tranqnilizing quinazolones.

The prolongation of therapeutic activity of a number of drugs has been achieved by reacting them with appropriate synthetic ion exchangers. Where the drug resinate exhibits prolongation of action, it is less toxic than the soluble salt form when compared on a free drug basis.

The above results were obtained by the DAmour and Smith apparatus and technique for aualgesiometn'c measurement in the rat. A 300 watt A.C. projection lamp at 95-100 volts as a heat source was used. Two groups of 10 animals each were placed in the dolorometer and their response time measured. The voltage was adjusted so that mean baseline response time was of the order of 2 sec. The voltage was then kept constant throughout the experimental period. The pre-treatment response time of each animal Was measured 3 times. The average of second and third values was taken as the animals baseline response time. Drugs were given by gavage as aqueous solutions or suspensions at a 5 percent dose volume. Response time was measured minutes after dosing and then at intervals usually one hour apart. Ten seconds was the maximal stimulus time in any measurement. For each animal, baseline response time was subtracted from each post-dose response time (:A see). This value less 3A sec. (the criterion of minimum analgesia) was multiplied by hours elapsed after administration of the dose (:A sec. hr.) and totaled (6A sec. hr.) for each animal. The mean and stand. dev. of eA sec. hr. of test and control groups were calculated. Students t test was used to demonstrate whether the difference of the means was statistically significant. Rat-torat variation is large as evidenced by large stand. dev. Day-to-day variation is greater than dose-to-dose variation (Table 1). Accordingly, a reproducible log doseefiect curve could not be derived. Each test is a 1 x 1 direct comparison.

The active medicaments of the present invention, as described above, may be in dosage-unit form for a single therapeutic dose, in smaller units for multiple doses, or in larger units for division into single doses. Obviously, in addition to the therapeutic effective agents or medicaments, there may also be present excipients, binders, fillers, extenders, and other therapeutically inert ingredients necessary in the formulation of active medicaments into a pharmaceutical preparation in dosage-unit form.

Since various changes and modifications may be made in the invention, certain preferred embodiments of which have been herein described, it is the intention that such changes and modifications as are within the scope of the appended claim shall be considered as part of the invention.

We claim:

Therapeutic compositions having analgesic properties comprising a mixture of a substance of the group consisting of codeine and its pharmaceutically acceptable acid addition salts, with a substance of the group consisting of 2-methyl-3-o-tolyl-4-quinazolone and its pharmaceutically acceptable acid addition salts, said quinazolone compound and codeine compound being present in a ratio 20 to 66 parts by weight of quinazolone to 50 to parts by weight of codeine.

References Cited in the file of this patent J.A.M.A., 168213, Nov. 29, 1958, pp. 52-57.

Lesser: D & C Ind., 75:3, September 1954, pp. 312- 314, 401-404.

Chan: Amer. J. of Med. Sci., 234:2, August 1957, pp. 207-212 and 226.

American Drug Index, I. B. Lippincott, Philadelphia, 1958, p. 166.

J. Ind. Chem. Soc., vol. 33, pp. -142, 1956.

Indian J. Med. Res., vol. 43, 1955, pp. 637-641.

Chemical Abstracts, 46:11210 (1952).

Chemical Abstracts, 50:6662 (1956).

IA. Ph.A., Pract. Pharm. Ed., 18:1, p. 59, January 1957.

Remingtons Practice of Pharmacy, 9th ed., 1948, pp. 814-815.

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