ANTI-INFLAMMATORY AND ANTIDIABETIC AGENTS

Abstract

The present invention relates to compounds,

##STR00001##

intermediates used in the preparation of such compounds, processes for the preparation of such compounds of the formula V and formula VI and such intermediates, pharmaceutical compositions composing such compounds of the formula V and such compounds of the formula VI, and the uses of such compounds of the formula V and such compounds of the formula VI as anti-inflammatory, antiobesity and cardioprotective agents.

Claims

1. A composition of matter comprising compounds of the formula: ##STR00004## and compounds of the formula ##STR00005## wherein X is R.sup.1, R.sup.2, or R.sup.3, wherein R.sup.1 is ##STR00006## and R.sup.2 is ##STR00007## and R.sup.3 is ##STR00008## and Y.sup.+ is a mono-protonated cation of a monobasic amine or a mono-protonated cation of a dibasic amine and Y.sup.++ is di-protonated cation of a dibasic amine, wherein the mono-protonated cation of a monobasic amine includes a monobasic naturally occurring amino acids including glycine, alanine, valine, serine, phenyl alanine, an alkyl amines including methyl amine, ethyl amine and isopropyl amine, or a hydroxyalkyl amine including mono, di-, tri-ethanol amine or cyclic amines such as glucosamine and morpholine, and wherein the dibasic amine includes lysine, arginine and piperazine.

2. A pharmaceutical composition comprising a compound of the formula: ##STR00009## wherein Y.sup.+ is H, and X is R.sup.1, R.sup.2, or R.sup.3, and wherein R.sup.1 is ##STR00010## and R.sup.2 is ##STR00011## and R.sup.3 is ##STR00012## and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition according to claim 1 wherein said compound is present In an anti-inflammatory effective amount.

5. A kit comprising a) a unit dosage comprising the compound of claim 1; b) instructions on how to use the kit; and c) at least one container for holding the unit dosage forms.

6. A method of treating an inflammatory disease or condition in a mammal, including a human, comprising administering to the mammal in need of such treatment a compound according to claim 1.

7. A method of treating inflammation in a mammal, including a human, comprising administering to the mammal in need of such treatment an anti-inflammatory effective amount of a compound according to claim 1.

8. A method of treating pre-diabetes in a mammal, including a human, comprising administering to the mammal in need of such treatment a pre-antidiabetic effective amount of a compound according to claim 1.

9. A method of treating obesity in a mammal, including a human, comprising administering to the mammal in need of such treatment an anti-obesity effective amount of a compound according to claim 1.

10. A method of treating or preventing the development or progression of atherosclerotic cardiovascular disease in a mammal, including a human, comprising administering to the mammal an effective amount of the compound according to claim 1.

11. A method for the manufacture of the composition of claim 1 comprising fusing the amine with salicylsalicylic acid, trisalicylic acid or tetrasalicylic acid in a reaction inert solvent at a temperature between about 0 degrees C. and about 60 degrees C.

12. A method for the manufacture of the composition of claim 1 comprising reacting the amine with salicylsalicylic acid, trisalicylic acid or tetrasalicylic acid at a temperature between about 50 degrees C. and about 200 degrees C.

13. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition according to claim 2 wherein said compound is present in an anti-inflammatory effective amount.

15. A kit comprising a) a unit dosage comprising the compound of claim 2; b) instructions on how to use the kit; and c) at least one container for holding the unit dosage forms.

18. A method of treating an inflammatory disease or condition in a mammal, including a human, comprising administering to the mammal in need of such treatment a compound according to claim 2.

17. A method of treating inflammation in a mammal, including a human, comprising administering to the mammal in need of such treatment an anti-inflammatory effective amount of a compound according to claim 2.

18. A method of treating pre-diabetes in a mammal, including a human, comprising administering to the mammal in need of said treatment a pre-antidiabetic effective amount of a compound according to claim 2.

19. A method of treating obesity in a mammal, including a human, comprising administering to the mammal in need of such treatment an anti-obesity effective amount of a compound according to claim 2.

20. A method of treating or preventing the development or progression of atherosclerotic cardiovascular disease in a mammal, including a human, comprising administering to the mammal an effective amount of the compound according to claim 2.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0023] The compounds of the present invention, i.e., the salts of salicylsalicylic acid, tri-salicylic acid and tetra-salicylic acid with monobasic amines and dibasic amines can be prepared as set forth below.

[0024] One equivalent of a monobasic amine, may be dissolved in an appropriate reaction inert solvent. The solvent may be a polar solvent such as water. As used herein, the expression “reaction inert solvent” refers to a solvent or a mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. Preferred solvents include methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, ethyl methyl ketone, diethyl ketone and methyl isobutyl ketone. Particularly preferred solvents for this reaction are acetonitrile, acetone and methyl isobutyl ketone. To this solution may be added a solution of one equivalent of salicylic acid, also known as salsalate and (2-(2-hydroxybenzoyl)oxybenzoic acid), trisailcylic acid or tetrasalicylic acid in a reaction inert solvent. (Salsalate is commercially available.) The reaction mixture can be stirred at about ambient temperature to about the reflux temperature of the solvent being used for about two hours to about six hours, preferably at ambient temperature for about two hours. The compounds of this invention can be isolated from the reaction mixture by methods well known to those skilled in the art, including according to the method of U.S. Pat. No. 3,957,853.

[0025] Trisalicylic acid is described by Don Carlos Monserrat Vidal et al (E8308897 A1, “Procedimiento Para Obtencion De Polimeros Del Acido 2-Hydroxibenzoico”) and tetrasalicylic acid is described by O. Shulga and J. Dunn (U. 2004, 410, 15-21). Furthermore, trisalicylic acid and tetrasalicylic acid can be prepared by adapting procedures described by Galzigna, L. et all. in Farmaco, 1993, 48(1), 95-103 with the title “Synthesis and some properties of two salsalate derivatives,” Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995). [0026] Oral Administration

[0027] The compounds of the invention may be administered orally. Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particulates, liquids, or powders; lozenges (including liquid-filled), chews; multi- and nano-particulates; gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays, and liquid formulations. [0028] Dosage

[0029] For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 1 g to 1.2 g depending, of course, on the mode of administration. In one embodiment, the total daily dose is in the range 1 g to 10 g and in another embodiment, the total daily dose is in the range 4 g to 8 g. The total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

[0030] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet capsule, pill, powder, sustained release formulations, solution, or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0031] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings and binders. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

[0032] A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0033] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0034] Compounds of the formula II, III, IV, V, and VI can be tested for anti-diabetes activity as follows. Male Wistar rats 8-10 weeks of age 210-230 g. of body weight (bw) are used. The rats are housed at temperature of 18-21° C. on a 12 hour light-dark cycle. Rats are fed on a stock laboratory diet (59% carbohydrates, 17% protein, 3% fat, 21% minerals, water, and cellulose) and are allowed water ad libitum. Diabetes mellitus is induced in Wistar male rats by two intravenous injections of alloxan (40 mg/kg bw) in the tail vein. The rats are used in experiments 6 days after the first alloxan injection. Fasting glucose, insulin, total cholesterol, and triglycerides levels of these animals are recorded. Then rats are treated with metformin hydrochloride (100-300 mg/kg bw) for the next 5 days. On the sixth day, Fasting glucose, insulin, total cholesterol, and triglycerides levels of these animals are recorded.

[0035] Compounds of the formula II, III, IV, V and VI can also be tested for anti-diabetes activity as follows. Spontaneously diabetic Bio-Bred (BB/W) rats from the colony maintained at the University of Massachusetts Medical Center, Worcester, were used in this study. BB/W rats were chosen for the current study because the BB/W rats have been considered a useful model of autoimmune human insulin-dependent diabetes DM). Like human IDDM, spontaneous diabetes appears during adolescence, with an abrupt clinical onset characterized by weight loss, hyperglycemia, hypoinsulinemia, and ketonuria. As in the case of human diabetics, pathological changes in retina, myocardium, liver, kidney, bone metabolism and peripheral nerves have all been well documented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992). The BB/W rats were 3 to 4 months old and weighed about 300 to 350 g. The BB/W rats received daily insulin, which was discontinued 24 h prior to performing the isolated heart perfusion studies, leading to a hyperglycemic stale. The rats were acutely diabetic, receiving 2.02±0.04 units of insulin daily, and had been diabetic for at least 12±3 days. The mean blood glucose levels in these diabetic rats were 386±24 mg/dL. The age-matched non-diabetic controls had mean blood glucose levels of 92±12 mg/dL.

[0036] Animal models to determine the effects of compounds of the invention on diabetes and complications of diabetes have been reviewed by Tirabassi et al., ILAR Journal 2004, 45, 292-302. Antidiabetic activity may also be tested according to protocols described in the following patents: U.S. Pat. Nos. 4,340,605; 4,342,771; 4,367,234; 4,617,312; 4,687,777 and 4,703,052. Additional references relevant to this application include the following: French Patent 2798551 and United States Published Patent Application No. 20030220301.

[0037] Efficacy in treating prediabetes can be determined according to protocols described by Armato et al in Endocrinology Practice, 2011, Nov 8: 1-21 (Epub ahead of print).

[0038] Efficacy in ameliorating atherosclerotic cardiovascular disease can be determined according to Shoelson et al (US 2011/0021468 A1, Jan. 27, 2011).

[0039] One mole of monobasic amine is dissolved in 3 L of acetone contained in a concentration reactor. To this solution, one mole of salicylsalicylic acid dissolved in 1 L of acetone is added and the reaction is stirred for about one to two hours. Excess acetone is cautiously evaporated under vacuum at or below room temperature. The resulting solid is collected and dried to obtain the monobasic amine mono-salt of salicylsalicylic acid.

[0040] One mole of dibasic amine is dissolved in 31 of acetone contained in a concentration reactor. To this solution, one mole of salicylsalicylic acid dissolved in 1 L of acetone is added and the reaction is stirred for about one to two hours. Excess acetone is cautiously evaporated under vacuum at or below room temperature. The resulting solid is collected and dried to obtain the dibasic amine mono-salt of salicylsalicylic acid.

[0041] One mole of dibasic amine is dissolved in 3 L of acetone contained in a concentration reactor. To this solution, two moles of salicylsalicylic acid dissolved in 1 L of acetone is added and the reaction is stirred for about one to two hours. Excess acetone is cautiously evaporated under vacuum at or below room temperature. The resulting solid is collected and dried to obtain the dibasic amine di-salt of salicylsalicylic acid. [0042] Rat Paw Edema Anti-Inflammatory Assay

[0043] Adult male Wistar rats (100-200 g) are used throughout this study. Fifteen rats, five per cage, are housed in a room maintained at a constant temperature of 24-26° C. with 12-h light/dark cycle and had free access to food and water. Before experimentation, animals have 1 week to adapt to the conditions of the facility. Prior to the start of the experiment, body weights are measured individually to determine proper treatment dose, and animals are randomly divided into three different groups of five rats. Initial paw sizes (basal volume) are measured by a volume displacement method using a digital plethysmometer (Ugo Basile, Comerio VA, Italy).

[0044] Paw edemas are induced by subcutaneous injection of 100 μl of 1% lambda carrageenan solution (Sigma) (w/v solution in saline, 0.9% NaCl) in the plantar aponeurosis of the right hind paw. Carrageenan is a sulfated polysaccharide that promotes acute inflammation by activating proinflammatory cells. One hour after carrageenan injection, PEO and test compounds, for example, trisalate are orally gavaged. An equal volume of the vehicle (4% apricot kernel balm) is given to the control group. Edemas are measured 3, 5, 24, and 48 h after PEO and test compound treatments. Time-dependent paw edema size reduction reflected the anti-inflammatory effect of the specific treatment. The increase in volume and the percent change caused by the irritant are estimated after subtracting the basal volume of the paw before injection. A lower numerical value (in percent) would indicate stronger anti-inflammatory activity.