IL35200A - Pharmaceutical compositions containing dicarboxylic acids possessing serum triglyceride-lowering activity - Google Patents

Description

35200/2 'opvaip'T msom o' 'aa mnpn-i »τ©3ή ■'! 01103 Pharmaceutical compoeitiona containin dioarboxylio aoids possessing serum triglyceride- lowering activity PARKS, DAVIS & COMPANY Q.33386 35200/2 ,The present invention relates to pharmaceutical Compositions possessing aerum triglyceride-lowering activity, which comprise certain alkanedioio acids and salts and alkyl e stern thoreof.

More particularly, the invention relates to pharma-ceutlcal compositions and methods employing compounds which , can be represented by the formula in which n represents 6, 7· 8, 9» or 10; and each of R and R*- represents hydrogen, a salt-forming cation, or a lower alkyl radical. The lower alkyl radicals are those containing not more than 8 carbon atoms. The salt-forming cations are preferably the pharmaceutically-acceptable cations of alkali metals, alkaline earth metals, ammonium, and substituted ammonium.

In accordance with the invention, pharmaceutical compositions are produced by formulating a compound of the foregoing formula (as an active ingredient) in dosage uni form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, lozenges, and pills; as well as powders and aqueous and non-aqueous solutions and suspensions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses by such means as measurement into a teaspoon or other standard container. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxy-methyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol; glycerine, sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline; and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions of the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents.

The percentage of the active ingredient in the foregoing compositions can be varied within wide limits but for practical purposes it is preferably present in a concentration of at least 10$ in a solid composition and at least 2 in a primarily liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present. The compositions of the invention preferably contain from 20 to 1,000 mg. of the active ingredient per dosage unit so that the entire amount to be administered during a day can be made up from a reasonable number of dosage units.

—Also in aooocdance with the invontion} tho oompoundc of tho forogoing formula aro admlnis orod for tho purpooo of lowering oorum triglyoorido levels u. The aforementioned compounds and compositions containing the same can be administered either orally or parenterally, in dosage unit form, with the dose adjusted to the needs and tolerances of the individual patient. Oral administration is preferred. The usual human dosage range is from 50 to 2,000 mg. per day, preferably 100 to 500 mg. per day, optionally in divided portions.

Treatment is continued while satisfactory control of the serum triglyceride level is maintained without undesired side-effects. compositions The mefahods- of the invention, as explained above, produce a lowering of the serum triglyceride level. In many cases the aforementioned compounds and compositions, especially when they are administered at a relatively high dosage, also produce a lowering of the serum cholesterol level. The lowering of serum triglycerides is a characteristic feature of the invention and the lowering of serum cholesterol is an incidental feature.

The effectiveness of the aforemen ioned compounds and compositions in lowering serum triglycerides can be demonstrated by standard methods. For example, male rats weighing 200-250 g. are maintained on a normal pellet diet. Each animal in a treatment group is given a daily oral dose of a test compound for 7 days. An untreated control group is also maintained. At the end of the 7-day test period the animals are weighed and sacrificed, and the serum cholesterol and serum triglycerides are determined from blood samples taken from the vena cava. The methods used are described in "Journal of Laboratory and Clinical Medicine", 0 , 318 ( 1957 ) and "Journal of Laboratory and Clinical Medicine", 0 , 152 ( 1957 ) . The test compound is considered to exhibit a side effect if the weight of the animals in the treatment group is significantly less than the weight of the animals in the control group. In a representative determination, 2 ,2,9i9-tetramethyldecane« dioic acid at 5 mg./kg. per day for 7 days produced a k reduction of serum triglycerides with no effect on serum cholesterol or weight of the animals, relative to the untreated control group. 2,2,9,9-Tetramethyldecanedioic acid, diethyl ester at 75 mg./kg. per day for 7 days produced a 7^ reduction of serum triglycerides with no effect on serum cholesterol or weight of the animals, relative to the untreated control group.

The preferred pharmaceutical compositions-actd— methods of the invention are those employing an α,α,α',α'-tetramethylalkanedioic acid of the formula or a cationic salt thereof; where n is as defined before and consequently represents 6, 7, 8, 9> or 10.

Many of the compounds employed in the compositions and methods of the invention are old. They ca all be prepared in a number of different ways. The alkane-dioic acids and a method of preparation have been described in "Journal of the American Chemical Society", 22.» (1951) The alkanedioic acids, their salts and esters can also be prepared by reacting isobutyric acid or an ester thereof with a polymethylene dihalide in the presence of a strong base in an anhydrous medium, optionally followed by acidification, as illustrated in greater detail hereinafter. The alkanedioic acid esters can also be prepared by esterifying the alkanedioic acids, typically by reaction with a lower alkanol in the presence of a mineral acid or strong organic acid. The alkanedioic acid salts can be prepared from the alkanedioic acids by reaction with any of a large number of bases.

The invention is illustrated by the following examples.

Example 1; Ingredient Quantity 2 ,2 ,9,9-Tetramethyl- decanedioic Acid 1,000 g.

Lactose 960 g.

Magnesium Stearate 40 g.

The mixture is blended in a twin-shell blender and filled into No. hard gelatin capsules. Each capsule is filled with 200 mg. of the powder mixture and contains 100 mg. of 2,2,9,9-tetramethyldecanedioic acid. Yield equals approximately 10,000 capsules.

Example 2; Ingredient Quantity 2,2,11,11-Tetramethyl- dodecanedioic Acid 1,000 g.

Lactose 960 g.

Magnesium Stearate 40 g.

The mixture is blended and filled into No. 4 hard gelatin capsules, filling each capsule with 200 mg. of the powder mixture. Yield equals approximately 10,000 capsules, each containing 100 mg. of 2 ,2 , 11, 11-tetramethyl dodecanedioic acid.

Similarly, filled gelatin capsules are obtained by substituting 1,000 g. of any of the following substances for the 2,2, 11, ll-tetramethyldodecanedioic acid in the foregoing procedure: 2 ,2,9,9-Tetramethyldecanedioic acid, disodium salt. 2.2.12.12-Tetramethyltridecanedioic acid. 2.2.13.13-Tetramethyltetradecanedioic acid.

Example 3: Ingredient Quantity 2 , 2 , 9, 9-Tetrameth 1- decanedioic Acid 1,000 g.

Lactose 800 g.

Magnesium Stearate 35 g.

The mixture is blended and filled into No. 3 hard gelatin capsules, filling each capsule with 367 mg. of the powde mixture. Yield equals approximately 5,000 capsules, each containing 200 mg. of 2 ,2 , 9, 9-tetramethyldecanedioic aicd.

Example : Ingredient Quantity 2 , 2 , 9 , 9-Tetramethy 1- decanedioic Acid 1,000 g.

Propylene Glycol 1,000 g.

The above ingredients are blended and filled into soft gelatin capsules, filling each capsule with 400 mg. of the mixture. Yield equals approximately 5,000 capsules, each containing 200 mg. of 2,2,9,9-tetramethyldecanedioic acid.

Similarly, filled gelatin capsules are obtained by substituting 1,000 g. of either of the following substances for the 2,2,9,9-tetramethyldecanedioic acid in the fore¬ going procedure: 2 ,2,9,9-Tetramethyldecanedioic acid, diethyl ester. 2 , ,9,9-Tetramethyldecanedioic acid, dioctyl ester.

Example 5: Ingredient Quanti y 2 , , 9, 9-Tetramethyl- decanedioic acid 3,000 g.

Lactose 750 g.

Corn Starch 300 g.

Gelatin 120 g.

Water 1,000 cc.

Magnesium Stearate 20 g.

The 2,2,9,9-tetramethyldecanedioic acid, lactose, and I 0 g. of the corn starch are blended and granulated with a solution of the gelatin in the water. The wet granulation is screened, dried, and re-screened. The resulting dried granulation is blended with the magnesium stearate and the remaining I50 g. of corn starch, and the mixture is compressed into 698 mg. tablets using I5/32 inch standard concave punches. Yield equals approximately 6 , 000 tablets, each containing 500 mg. of 2 , 2 , 9, 9-tetramethylde-canedioic acid.

Example 6: Ingredient Quantity 2 , 2 , 9 , 9-Tetramethy 1- decanedioic Acid (micronized) g.

Polyoxyethylene Sorbitan Monostearate 0. 1 cc.

Sodium Carboxymeth l Cellulose 0.3 g.

Complex Magnesium- Aluminum Silicate 0.5 g.

Sugar 10 g.

Glycerin 2 cc.

Sodium Benzoate 0.5 g.

Sodium Citrate 0.2 g.

Approved Red Dye 1 mg.

Imitation Cherry Flavor 0.02 cc.

Citric Acid, to make pH 4 . 0 Distilled Water, to make 100 cc.

The polyoxyethylene sorbitan monostearate can be a product such as polysorbate 60 or Tween 60. The complex magnesium-aluminum silicate is a gel-forming agent. A product such as Veegum H.V. can be used. This substance is hydrated overnight in 10 cc. of distilled water. A mixture is prepared from the polyoxyeth lene sorbitan monostearate, imitation cherry flavor, 30 cc. of distilled water, and the 2 ,2 , 9, 9-tetramethyldecanedioic acid and passed through a homogenizer. With vigorous stirring, the sugar, glycerin, sodium citrate, sodium benzoate, and sodium carboxymethyl cellulose are added, followed by hydrated complex magnesium-aluminum silicate and a solution of the red dye in 2 cc. of water. The resulting suspension is homogenized, adjusted to pH 4 .0 with citric acid, and diluted to a final volume of 100 cc. with distilled water. A 5 cc. oral dosage unit of this suspension contains 200 mg. of 2 ,2 , 9, 9-tetramethyldecanedioic acid.

If desired, the red dye and imitation cherry flavor can be omitted or replaced by other coloring and flavoring agents.

By the foregoing procedure, with the substitution of 4 g. of micronized 2 ,2 , 10 , 10-tetramethylundecanedioic acid for the 2 ,2 , 9, 9-tetramethyldecanedioic acid, a suspension containing 200 mg. of 2 , 2 , 10 , lO-tetrame hylundecane-dioic acid per 5 cc. oral dosage unit is obtained.

Example J: Ingredient Quantity 2 ,2,9,9-Tetramethylde- canedloic Acid 20 g.

Polyethylene Glycol 50 cc.

Benzyl Alcohol 4 cc.

Sodium Hydroxide 10$ Solution, to make pH 8.0 Hydrochloric Acid 10# Solution, to make pH 8.0 Sterile Distilled Water, to make 200 cc.

The polyethylene glycol used in this formulation can be a material such as polyethylene glycol 400. A solu¬ tion is prepared by dissolving 2 ,2 ,9,9-tetramethyldecane- dioic acid in 100 cc. of 10% sodium hydroxide solution. The polyethylene glycol and the benzyl alcohol are added and the pH is adjusted to 8.0 using 10# sodium hydroxide and IO96 hydrochloric acid. The solution is sterilized by filtration using a sterilized millipore filter membrane and a microfiber glass pre-filter disc. Equipment suitable for this purpose is a type SS (0.22 micron pore size) millipore filter membrane and a type AP-20 microfiber glass pre-filter disc. The filtrate is collected in a sterile receiving vessel and aseptically filled into round amber glass vials, filling each vial with 2 cc. of the solution and sealing the vial. The resulting solution for parenteral administration contains 100 mg. of 2,2,9,9-tetramethyl- decanedioic acid per cc.

Preparation of Tetramethylalkanedioic Acids, Salts, and Esters At 0-10* C, 375 ml. of a solution of n-butyl- lithium in heptane (1.6 millimoles/ml. ) is added with stirring to a solution of 61 g. of diisopropylamine in 300 ml. of anhydrous tetrahydrofuran. The cold mixture is stirred for more minutes and then treated with a solution of 26.4 g. of isobutyric acid in 25 ml. of anhydrous tetrahydrofuran, added over a period of 20 minutes. The mixture is stirred for 10 minutes at 0-10* C, for 30 minutes at room tempera¬ ture, again cooled to 0-10° C, and treated with a solution of 36.6 g. of 1,6-dibromohexane in 0 ml. of anhydrous tetrahydrofuran. It is then stirred overnight at room temperature, cooled to 0° C, and cautiously diluted with 500 ml. of water. The aqueous phase is separated, washed with ether, and acidified with hydrochloric acid. The acidified mixture is extracted with ether and the ether extract is washed with water, dried, and evaporated to give a residue of 2,2,9,9-tetramethyldecanedioic acid; 0 By the foregoing procedure, with the substitution of another polymethylene dihalide for the 1,6-dibromohexane, the following additional products are obtained.

From if0.8 g. of 1,8-dibromooctane, the product is 2 ,2 , 11, 11-tetramethyldodecanedioic acid; m.p. 92.5- 50 C.

From 42.9 g. of 1,9-dibromononane, the product is 2 ,2 , 12 , 12-tetramethyltridecanedioic acid; m.p. 70-72* C.

From .Ο g. of 1, 10-dibromodecane, the product is 2 ,2, 13 , 13-tetramethyltetradecane- dioic acid; m.p. 86-88* C.

With stirring, 12.7 g- of sodium hydride and then 27.8 g. of isobutyric acid are added to a solution of 42 ml. of diisopropylamine in 300 ml. of anhydrous tetrahydrofuran. The mixture is heated at reflux for 4 minutes, cooled to 0* C, and treated with 2I3.5 ml. of a solution of n-butyl-lithium in heptane (1.4 millimoles/ml. ) . The mixture is then stirred for 30 minutes at room temperature, cooled to 0* C, treated with 25.4 g. of 1,7-dichloroheptane, and stirred overnight at room temperature. It is then hydro-lyzed and the product isolated as described above to give 2 ,2 , 10, lO-tetraraethylundecanedioic acid; m.p. 75-77* C. following crystallization from acetonitrile .

Salts with pharmaceutically-acceptable cations are obtained by reacting any of the alkanedioic acids with a base such as sodium hydroxide, potassium carbonate, calcium hydroxide, ammonia, diethylamine, 2-aminoethanol, or choline. For example, a suspension of 5.2 g. of 2,2,9,9-tetramethylalkanedioic acid in 30 ml. of water is treated with 37 ml. of I N sodium hydroxide and then with 20 ml. of methanol. The mixture is concentrated to one-third its original volume, diluted with 100 ml, of water, concentrated to two-thirds volume, and freeze-dried to give a residue of 2,2,9,9-tetramethyldecanedioic acid, di-sodium salt.

A mixture of 50 g. of 2,2,9,9-tetramethyldecanedioic acid, 1.2 g. of £-toluenesulfonic acid mono-hydrate, 5 ml. of ethanol, and 300 ml. of toluene is heated at reflux for 36 hours, with continuous removal of the water formed in the reaction. The mixture is cooled, washed with dilute sodium hydroxide solution and with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give a residue of 2,2,9,9-tetramethyldecanedioic acid, diethyl ester. For purification the product is distilled in vacuo b. . 1 -1 ° C. ¾at 1 mm.

Similarly, with the substitution of 122 ml. of 1-octanol for the ethanol, the product is 2,2,9,9-tetra-methyldecanedioic acid, dioctyl ester; b.p. higher than 180° C. at 0.05 mm.

Claims (4)

H02 CLAIMS:

1. A pharmaceutical composition in dosage unit form possessing serum triglyceride- lowering activity and suitable for internal administration, comprising a pharmaceutical carrier and 20 to 1,000 mg. per dosage unit of a compound of the formula R0— —OR1 where n represents 6, 7> 8, 9, or 10; and each of R and represents hydrogen, a salt-forming cation, or a lower alkyl radical.

2. A composition according to Claim 1 suitable for oral administration.

3. A composition according to Claim 1 suitable for parenteral administration.

4. A composition according to Claim 1 in the form of a capsule or tablet for oral administration and containing 2 , , 9, 9"tetramethyldecanedioic acid . 5· A composition according to Claim containing 100 mg. of 2 ,2 , 9,9-tetramethyldecanedioic acid per dosage unit.