US3646201A - Salicylate carbonate compounds - Google Patents

Salicylate carbonate compounds Download PDF

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Publication number
US3646201A
US3646201A US846596A US3646201DA US3646201A US 3646201 A US3646201 A US 3646201A US 846596 A US846596 A US 846596A US 3646201D A US3646201D A US 3646201DA US 3646201 A US3646201 A US 3646201A
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Prior art keywords
carbonate
acetylsalicyloyl
aspirin
dosage
solution
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US846596A
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English (en)
Inventor
Andrew G Kallianos
James D Mold
Melvyn I Simpson
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Liggett Group LLC
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Liggett and Myers Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/90—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl and carboxyl groups

Definitions

  • R is a radical selected from the group consisting of branched and straight-chained, saturated and unsaturated, aliphatic and alicyclic alcohols having from 2 to 30 carbon atoms and polyhydroxy compounds and mixtures thereof.
  • aspirin is a very complex drug in its action and is believed to have three principal forms of action (OReagan, T.: Prolonged Release Aspirin. Drug and Cosmetic Indust., 98 (1966) 35-36, 164); an analgesic one, which appears to be primarily related to blood or tissue acetylsalicylic acid, since other salicylates are not as eifecti ve on an equivalent weight basis; an antiinflammatory activity, which appears to be related more to the total salicylate blood levels; and an antipyretic activity requiring some of the acetylated derivative as well as total salicylate in the blood. (see also: M. J. H. Smith and Paul K.
  • This invention relates to carbonate anhydride esters of acetylsalicylic acid and more particularly to pharmaceutical preparations of these compounds which permit sustained release of acetylsalicylic acid in the body.
  • the carbonate anhydride esters of this invention have the formula:
  • R is a radical selected from the group consisting of branched and straight-chained, saturated and unsaturated, aliphatic and 'alicyclic alcohols having from 2 to 30 carbon atoms including polyhydroxy compounds.
  • aliphatic alcohols which may be utilized to form the esters of this invention are ethyl, hexyl and cetyl alcohols as well as higher molecular weight alcohols, branched chain, or unsaturated alcohols such as oleyl alcohol.
  • alicyclic alcohols such as menthol, cholesterol and the like may be employed.
  • polyhydroxy compounds which may be utilized are compounds such as diisopropylidene glucose and isopropylidene glycerol.
  • the mixed carbonate anhydride esters of acetylsalicylic acid are generally prepared by reacting acetylsalicylic acid dissolved in a solvent such as acetone and a cooled solution of the chloroformate of the hydroxy compound.
  • the reaction preferably involves the use of a catalyst such as pyridine, triethylamine, etc.
  • the reaction of the acetylsalicylic acid with the chloroformate of the hydroxy compound generally takes place by first dissolving the chloroformate in a solvent such as ethyl ether.
  • the chloroformate is then added to a cooled flask containing a catalyst and solvent.
  • the flask is generally maintained at a temperature of about l to +5 C.
  • the chloroformate is added over a period of about 50 to 60 minutes.
  • a solution of the acetylsalicylic acid in acetone is then slowly added over a period of 30 to 35 minutes while the temperature of the reaction is maintained at about 0 C.
  • the mixture is then stirred for about to 60 minutes and the solid residue is removed from the reaction mixture which is then worked up by conventional techniques.
  • the reaction may be run by addition of a solution of the chloroformate in tetrahydrofuran to a solution of triethylammonium acetylsalicylate, prepared in situ, at 40 to -l0 C., preferably at C.
  • the preparation of the chloroformate takes place at reduced temperatures and involves a reaction between the appropriate alcohol in a solvent such as tetrahydrofuran.
  • a solvent such as tetrahydrofuran.
  • the alcohol is slowly added to phosgene over a period of from about 1 to 3 hours and upon completion of the addition the reaction mixture is allowed to reach room temperature where it is agitated over a period of 8 to 24 hours (generally overnight is satisfactory) until the reaction is complete.
  • the carbonate anhydride esters of this invention have been found to be relatively stable in acidic pH media but will decompose at a rate which can be controlled by adjustment of the pH. Thus, by proper selection of the hydroxyl compound it has been found that carbonate anhydride esters may be maintained in a relatively stable condition to the acidic pH found in the stomach.
  • EXAMPLE 1 Acetylsalicyloyl cetyl carbonate (a) Cetyl chloroformate.-In a 500 milliliter, 3-neck round-bottom flask fitted with a magnetic stirrer, Dry-Ice condenser, dropping funnel, and cooling bath, was placed approximately 25 g. (0.25 mole) of phosgene at a bath temperature of --10 to -20 C. A solution of g. (0.124 mole) of cetyl alcohol in 120' milliliters of tetrahydrofuran was added with stirring at 0 to -10 C.
  • reaction mixture was then allowed to reach room temperature and to stir overnight.
  • the product when measured in CCL, solution, had infrared absorption bands at 5.71 and 5.52 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type (D. S. Tarbell and E. I. Longosz, J. Org. Chem, 24 (1959) 774), and exhibited bands at 5.64 and 8.41 microns characteristic of the acetate group present in acetylsalicylate.
  • Mass spectrum m/e 404 (M+CO the parent peak was not observed because of the high temperature required to volatilize the sample), 163, 138, 121, 120, 43.
  • EXAMPLE 2 Acetylsalicyloyl cholesteryl carbonate To a solution of 8.98 g. (0.02 mole) of cholesteryl chloroformate in milliliters of dry tetrahydrofuran was added, dropwise with stirring at 0 C., a solution of 2.02 g. (0.02 mole) of triethylamine in 15 milliliters of tetrahydrofuran. The mixture was stirred for an additional 1-0 minutes and a solution of 3.6 g. (0.02 mole) of acetylsalicylic acid was added with stirring while the reaction mixture was maintained at 0 C.
  • the product when measured in G01 solution, had infrared absorption bands at 5.70 and 5.52 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.60 and 8.4 microns characteristic of the acetate group present in acetylsalicylate.
  • EXAMPLE 3 Acetylsalicyloyl methyl carbonate To a solution of 8.5 g. (0.039 mole) of methyl chloroformate in 70 milliliters of dry tetrahydrofuran was added, dropwise with stirring at C., a solution of 3.94 g. (0.039 mole) of triethylamine in 20 milliliters of tetrahydrofuran. To the cooled solution was added with stirring 7.0 g. (0.039 mole) of acetylsalicylic acid in 50 milliliters of tetrahydrofuran. After addition was complete, the cooling bath was removed and stirring was continued for one hour. The triethylamine hydrochloride was removed by filtration.
  • the product when measured in CCl solution, had infrared absorption bands at 5.71 and 5.56 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.61 and 8.41 microns characteristic of the acetate group present in acetylsalicylate.
  • the product when measured in CCl, solution, had infrared absorption bands at 5.71 and 5.53 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.62 and 8.43 microns characteristic of the acetate group present in acetylsalicylate.
  • Mass spectrum m/e 308 (M+), 163, 138, 121, 120, 43.
  • the product when measured in CCl, solution, had infrared adsorption bands at 5.71 and 5.52 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.63 and 8.42 microns characteristic of the acetate group present in acetylsalicylate.
  • Mass spectrum m/e 252 (M+), 163, 138, 121, 120, 43.
  • Acetylsalicyloyl 1,2-isopropylideneglyceryl carbonate (a) 1,2 isopropylideneglycerol.1,2 isopropylideneglycerol was prepared according to the procedure of Hibbert and Morazain (H. Hibbert and J. G. Morazain, Can. J. Res., 2 (1930) 35); BR 8990/25 mm. The infrared spectrum of the compound, when measured in CCL, solution, showed peaks at 2.77, 2.86, 8.23, 9.38, 9.53, and 11.29 microns.
  • Mass spectrum m/e 181, 179 (ratio 3/1) M+, 101 85, 59, 43, 41.
  • Mass spectrum m/e 338 (M+), 323, 163, 138, 121, 120.
  • EXAMPLE 7 Acetylsalicyloyl oleyl carbonate (a) Oleyl chloroformate.0leyl chloroformate was prepared according to the procedure set forth in Example 6 for the synthesis of 1,2-isopropylideneglyceryl chloroformate. Approximately 20 g. (0.0746 mole) of oleyl alcohol in 65 milliliters of anhydrous tetrahydrofuran was added to approximately g. (0.15 mole) of phosgene at 10 to After workup the reaction mixture yielded g. of a yellow oil (quantitative yield). The infrared spectrum of the product, measured in CCl showed peaks at 3.31, 5.60, 8.66, and 14.49 microns.
  • the product when measured in CCl solution, had infrared absorption bands at 5.76 and 5.53 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxyliccarbonic anhydrides of this type, and exhibited bands at 5.61 and 8.42 microns characteristic of the acetate group present in acetylsalicylate and at 3.27 microns, characteristic stretching vibrations of the vinyl protons.
  • Mass spectrum m/e 474 (M+), 430 (M+CO 250, 163, 138, 121, 120.
  • mice All rats were assigned numbers and randomized as to the dosage each would receive. Animals were housed individually in wire cages and fasted overnight with only water available prior to oral dosage. Control samples of plasma were collected from each animal 24 hours prior to dosage. During the test period a minimum of 0.5 milliliter of pooled plasma was collected from the orbital sinus at 0, 2 (1, 2, 3), 4, and 8 hours, and about 2 milliliters from the inferior vena cava at sacrifice 12 hours after dosage. About equal quantities of blood were pooled from each of the 3-6 rats comprising a test group.
  • Free salicylic acid in the plasma samples was determined by a modification of published methods (Routh, J. L, et al.: Method for the Determination of Acetylsalicylic Acid in the Blood, Clinical Chemistry, 13 (1967) 734-743; Williams, L. A., Linn, R. A., and Zak, B.: Differential Ultraviolet Spectrophotometric Determination of Serum Salicylates, J. Lab and Clinical Medicine, 53 (1969) 156-162). Briefly, this entailed acidification of the collected plasma with a small amount of concentrated hydrochloric acid, extraction with chloroform, back extraction of the chloroform phase with sodium bicarbonate solution and UV spectrophotometric analysis of the aqueous phase.
  • Each value represents the free salicylic acid (SA) in one pooled plasma sample from number 01 rats indicated (3-6). Ind ependent values are corrected for apparent SA levels in blanks (Time 0) and for recovery of control SA levels. Values in mg. percent can be converted to ug./ml. by multiplying by 10.
  • the free salicylic acid recovery of the method was determined as follows: a weighed amount of salicylic acid is added to a volume of rat plasma. This plasma is then submitted to the analytical procedure and the recovery of salicylic acid determined. A control recovery experiment, which serves as a check on the method, was included with each set of plasma samples resulting from the treatment of rats with each dose of the compounds tested. The values of the experimental results shown in Table II are corrected for apparent salicylic acid levels in blanks (time and for recovery which averaged 97.4% (standard deviation, 3.5).
  • mice Male, Sprague-DaWley (Charles River- CD) strain rats weighing about 93.3 grams (88.5-97.5) were administered a single oral dosage of each compound at a level of 300 mg. per kilogram of body weight based on acetylsalicylic acid content.
  • Free salicylic acid in the plasma samples was determined by the differential ultraviolet spectrophotometric method described above. The results of these analyses are shown in Table IV below. The values are corrected for apparent salicylic acid levels in blanks (time 0) and for By comparison with the other materials tested, the 54) recovery of control salicylic acid levels.
  • a major shortcoming of free aspirin medication is that free aspirin produces a very high peak in the concentration of plasma salicylate in about 2 hours after administration and a rapid fall thereafter.
  • the compounds of this invention reduce to a minimum this overdosing peak and sustain a slower decline in plasma salicylate with time.
  • the preparation of this invention would allow good control of a sustained dosage level. This would have the added advantage in that it would eliminate high initial concentrations of free salicylate at any one locale and thereby effect a reduction in irritations of the mucosa with a concomitant reduction in gastrointestinal bleeding.
  • the therapeutic efficacy of the preparations of this invention was demonstrated by their ability to reduce yeastrange 20 on the Sanborn Polygraph. After the normal foot volume of each rat had been determined, 0.1 ml. of Brewers yeast (20% in sterile H O) was injected into the foot pad. Exactly one hour later the volumeof the now swollen foot was again determined and the predetermined dosage of test compound was administered orally. Subsequently, the foot volume of each animal was monitored at 1, 2, 3, 4, 6, 8, 1'0, 12, 14, 16, 18, 20, 22 and 24 hours after treatment.
  • Cetyl aeetysalicyloyl carbonate (600 rug/kg.) a l6 0. 6 -17. 0 l0. 9 Test 11 r. Ethyl ecetylselicyloyl carbonate (600 mg.[kg.) r. 16 6. 4 17. 8 -20. 9
  • Foot volumes were determined and recorded as follows: a rats foot was immersed in a 10 ml. mercury bath to a previously inscribed line on the ankle. The bath was connected to a pressure sensitive transducer which in turn was connected to a recording galvanometer. The displacement of the foot was translated into a deflection from the base line tracing.
  • a standard of known The sustained release agents of this invention may be used alone or mixed with other conventional binders and fillers, such as starch, gelatin and sugars.
  • the active ingredient will be formed into waters or tablets in unit dosage forms.
  • compositions comprising a pharmaceutical carrier and as the active ingredient thereof an effective oral dosage amount, for sustaining an effective dosage level in plasma salicylate, of carbonate anhydride esters of acetylsalicylic acid having the general formula:
  • R is a radical selected from the group consisting of branched and straight-chained, saturated and unsaturated, aliphatic and alicyclic alcohols and polyhydroxy compounds having from 2 to 30 carbon atoms and mixtures thereof.

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4595695A (en) * 1983-01-05 1986-06-17 Teva Pharmaceutical Industries Ltd. 1'-ethoxycarbonyloxyethyl ester of valproic acid, its preparation and pharmaceutical compositions containing it
US4851426A (en) * 1982-12-09 1989-07-25 Teva Pharmaceutical Industries, Ltd. Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
US20020177609A1 (en) * 2001-03-23 2002-11-28 Swindell Charles S. Fatty alcohol drug conjugates
US20030065023A1 (en) * 2001-03-23 2003-04-03 Swindell Charles S. Fatty amine drug conjugates
US20040235943A1 (en) * 2002-05-31 2004-11-25 Dongcheng Dai Triptolide derivatives for modulation of apoptosis and immunosuppression
US20060287525A1 (en) * 2003-09-09 2006-12-21 Xenoport, Inc. Aromatic prodrugs of propofol, compositions and uses thereof

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4851426A (en) * 1982-12-09 1989-07-25 Teva Pharmaceutical Industries, Ltd. Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
US4595695A (en) * 1983-01-05 1986-06-17 Teva Pharmaceutical Industries Ltd. 1'-ethoxycarbonyloxyethyl ester of valproic acid, its preparation and pharmaceutical compositions containing it
US20020177609A1 (en) * 2001-03-23 2002-11-28 Swindell Charles S. Fatty alcohol drug conjugates
US20030065023A1 (en) * 2001-03-23 2003-04-03 Swindell Charles S. Fatty amine drug conjugates
US8552054B2 (en) 2001-03-23 2013-10-08 Luitpold Pharmaceuticals, Inc. Fatty amine drug conjugates
US7816398B2 (en) 2001-03-23 2010-10-19 Luitpold Pharmaceuticals, Inc. Fatty alcohol drug conjugates
US20090171103A1 (en) * 2002-05-31 2009-07-02 Dongcheng Dai Triptolide Derivatives for Modulation of Apoptosis and Immunosuppression
US7662976B2 (en) 2002-05-31 2010-02-16 Pharmagenesis, Inc. Triptolide derivatives for modulation of apoptosis and immunosuppression
US7847109B2 (en) * 2002-05-31 2010-12-07 Pharmagenesis, Inc. Triptolide derivatives for modulation of apoptosis and immunosuppression
US20110076293A1 (en) * 2002-05-31 2011-03-31 Dongcheng Dai Triptolide derivatives for modulation of apoptosis and immunosuppression
US20040235943A1 (en) * 2002-05-31 2004-11-25 Dongcheng Dai Triptolide derivatives for modulation of apoptosis and immunosuppression
US7576127B2 (en) * 2003-09-09 2009-08-18 Xenoport, Inc. Aromatic prodrugs of propofol, compositions and uses thereof
US20090312424A1 (en) * 2003-09-09 2009-12-17 Xenoport, Inc. Aromatic prodrugs of propofol, compositions and uses thereof
US20060287525A1 (en) * 2003-09-09 2006-12-21 Xenoport, Inc. Aromatic prodrugs of propofol, compositions and uses thereof

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