ASCORBIC ACID DERIVATIVES

Abstract: Compounds represented by the following general for­ mula (I), a process for their preparation, and a therapeutic agent for cataract containing the compound of the general formula (I) as a major component, wherein R¹, R², R³, and R⁴ may be the same or different and each represents a hydrogen atom or a pivaloyl group, provided that R¹, R², R³ and R⁴ do not represent hydrogen atoms at the same time.

Description: SPECIFICATION ASCORBIC ACID DERIVATIVES TECHNICAL FIELD OF THE INVENTION This invention relates to ascorbic acid derivatives of the formula (I), EMI1.1 wherein R1 R2 R3 and R4 each is hydrogen or pivaloyl, R' but R , R2, R and R4 are not hydrogen at the same time, and salts thereof. BACKGROUND OF THE INVENTION Ascorbic acid-is contained in lens and aqueous humor in higher concentration than in other tissues (the usual level in lens; 20 to 30 mg%). The lenticular ascorbic acid as well as glutathion is considered to contribute to oxidation-reduction system in lens and functionally to maintain the lens transparency. The decrement of ascorbic acid in cataractous lens have been observed by many investigators. From the above fact, ascorbic acid instilled to the eyes or given orally is thought to be useful to prevent the cataracts formation. But the solubility of ascorbic acid in lipoid is very small, so its practical use for therapeutics is limited. Although number of esters of ascorbic acid, for example acetylascorbic acid, benzoylascorbic acid, palmitoylascorbic acid, etc. are know, the utility of these compounds for medical drug is limited because of their low solubility in lipoid and low membrane permeability. DESCRIPTION OF THE INVENTION Ascorbic acid is useful for cataracts, but the solubility in lipoid is very small, so its practical use for therapeutics is difficalt. We succeeded to improve the stability, solubility in lipoid, membrane permeability, etc. of ascorbic acid by the conversion to pivalate, and thus we found that the compounds of this invention are useful as therapeutic agents for cataracts. EMI2.1 wherein R1 R2 R3 and R4 each is hydrogen or pivaloyl, but R1, R2, R3 and R4 are not hydrogen at the same time. Compounds of the formula (I) of this invention can be prepared, for example, by the following methods, A), B) and C), A) the reaction of L-ascorbic acid with active derivatives of pivalic acid, for example pivaloyl chloride; B) the reaction of L-ascorbic acid protected by the suitable groups, for example isopropylidene group, with active derivatives of pivalic acid; and C) the rearrangement of 2,6-O,O'-dipivaloyl-L-ascorbic acid to 3,6-dipivaloyl-L-ascorbic acid. Solubility test, acute toxicity test and examples of formulation are shown below. Solubility Test As a lipophilic scale, the partition coefficient in wateroctanol system was measured. Expermental method To 3-4 mg of the compound of this invention or the controle compound (L-ascorbic acid), 10 ml of water and octanol are added respectively and well shaked. The resulting mixture is centrifuged and the contents of the compound of this invention and control compound in water or octanol layer were measured by high performance liquid chromatography. Result The result shows that all of the compounds of this invention are more lipophlic than L-ascorbic acid of the control compound. Peak Hight Octanol Layer Water Layer Compound of Example 1 143.4 0.2 Compound of Example 2 54.8 69.8 GAscorbic acid 4.2 191.0 Acute Toxicity Test Acute toxicity of 3, 6 -O,O'-dipivaloyl-L-ascorbic acid of this invention is shown below. Amimal : ddY-SPF strain male mouse (weight: 25 to 30 g) method of administration : The compound is administered orally as 0.5; tragacanth suspention. Acute toxicity : LD50 > 5000 mg/kg The compounds of this invention can be administered either orally or parenterally. The dosage forms are tablet, capsule, eye drops, etc. The dosage is adusted depending on symptoms or dosage forms, and in oral case usual daily dosage is 1 to 5000 mg, preferably 10 to 1000 mg, in one or few divided doses. In case of eye drops, 2 to 3 drops are instilled to the eyes daily several times. The followings show the examples of the formulation. (l'6ral drug tablet 3,6-O,O'-Dipivaloyl-L-ascorbic acid 100 mg ethyl cellulose 50 mg crystalline cellulose 80 mg carboxymethyl cellulose 7 mg magnesium stearate 3 mg Total 240 mg (2) Eye drops The content of 3,6-O,0'-dipivaloyl-L-ascorbic acid is 5 mg in 5 ml of the aqueous solution of 3,6-0,0' dipivaloyl-L-ascorbic acid. BEST MODE OF MAKING THE INVENTION Example 1 2,6-O,O'-Dipivaloyl-L-ascorbic acid 5.0 g of 5,6-0-isopropylidene-L-ascorbic acid is added to 200 ml of acetone, and 4.7 ml of pyridine is added to make it solution. 13.9 g of pivaloyl chloride is added dropwise to the solution with stirring. After the addition, the solution is stirred for one hour at room temperature, and then 20 ml of methanol is added and further stirred for ten minutes. The reaction mixture is concentrated in vacuo, and to the resulting oily residue water is added to produce crystals. Crystals are collected by filtration to give 5.4 g (68Z) of the titled compound. mp 119.5-1210C ( chloroform - n-hexane ) [&alpha;]24 + 29.0 (c=l.0, methanol ) IR (KBr, cml, the same shall be applied hereinafter unless specified) 3425, 1775, 1760, 1748, 1682, 1162, 1100, 1020 NMR (CDCl3, 6) 1.28(18H, s, -OCOC(CH3)3 x 2), 3.14(1H, s, C3-OH), 3.41(1H, d, J=6.0Hz, C5-OH), 3.83(3H, s, C5-H and C6-H2), 5.18(1H, d, J=1.5Hz, C4-H) Elemental Analysis for C16H2408 Calculated : C, 55.81; H, 7.02 Found : C, 55.77; H, 7.06 Example 2 3,6-O,O'-Dipivaloyl-L-ascorbic acid 3.5 g of L-ascorbic acid is added to 30 ml of N,N-dimethylformamide, and 4.8 ml of pyridine is added to make it solution. 4.8 g of pivaloyl chloride is added dropwise to the solution with stirring. After the addition the solution is stirred for 3 hours at room temperature. The reaction mixture is concentrated in vacuo and to the resulting oily residue water is added and stirred. The mixture is allowed to stand, and then water layer is removed by decantation. The residue is purified by silica gel column chromatography to give 1.2 g (18%) of the titled compound. mp 149.5-152 OC (chloroform - n-hexane) 24 [cr]D + 43.8 o (c=1.0, methanol) IR 3465, 1764, 1740, 1735, 1707, 1640, 1289, 1146, 1128 NMR (CDC13, 6 ) l.21(9H, s, -OCOC(CH3)3 ), 1.30(9H, s, -OCOC(CH3)3 ), 4.27(3H, s, C5-H and C6-H2), 4.83(1H, s, C4-H), 5.31-7.08(2B, br,-OH x 2) Example 3 3-O-Pivaloyl-Gascorbic acid 10 g of 5,6-O-isopropylidene-L-ascorbic acid is added to 400 ml of acetone, and 11.2 ml of pyridine is added to make it solution. 5.7 g of pivaloyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is allowed to stand for 18 hours at room temperature, 300 ml of methanol is added, and further allowed to stand for 30 minutes at room temperature. The reaction mixture is concentrated in vacuo and resulting oily residue is purified by silica gel column chromatography to give 2.3 g (17%) of 3-0-pivaloyl-5,6-0-isopropylidene-L-ascorbic acid. mp 168-170 OC (chloroform - n-hexane) 22 [&alpha;] + 44.2 e (c=l.0, methanol) IR 3425, 1771, 1750, 1660, 1372, 1129 NMR (CDC13, 6 ) 1.34(9H, s, -OCOC(CH3)3 ), 1.40(6H, S, -CH3 x 2), 3.89-4.54(3B, m, C5-H and C6-H2), 4.67-4.87(1H, m, C4-H), 9.20-10.20(1H, br, -OH) Elemental Analysis for C14H2007 Calculated : C, 55.99; H, 6.71 Found : C, 55.92; H, 6.51 1.5 g of the resulting compound (3-O-pivaloyl-5,6-O-iso- propylidene-L-ascorbic acid) is dissolved in 20 ml of 50% aqueous acetic acid and stirred for 25 minutes at 75-850C. After cooling, the solution is neutralized with 14.7 g of sodium hydrogen carbonate and concentrated in vacuo. Acetone is added to the resulting residue and filtered. The filtrate is concentrated in vacuo and purified by silica gel column chromatography to give 840 mg(65%) of the titled compound. IR 3400, 1735, 1590, 1398, 1280, 1146 NMR (CD3OD, 6 ) 1.29(9H, s, -OCOC(CH3)3 ), 3.68(2H, d, J=5.511z, C6-H2), 3.53-4.13(1H, m, C5-H), 4. 45(1H,- d, J=3.0Hz, C4-H) Example 4 3,6-O,O'-Dipivaloyl-L-ascorbic acid 45 g of 2,6-O,O'-dipivaloyl-L-ascorbic acid. is dissolved in 400 ml of dioxane and 53 ml of pyridine is added. The reaction mixture is stirred for 1.5 hours at room temperature and concentrated in vacuo. To the resulting residue dilute hydrochloric acid and ethyl acetate are added, and organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium salfate. The solvent is removed off in vacua to give 31.8 g(71%) of the titled compound The physical constant of the crystals is the same of the compound obtained in Example 2. UTILITY IN AN INDUSTRIAL FIELD This invention offers novel compounds which are useful for therapeutic agent.

Claims: What we claim is 1. Ascorbic acid derivative of the formula (I), EMI10.1 wherein R1 R2 R3 and R4 each is hydrogen or pivaloyl, but R , R , R3 and R4 are not hydrogen at the same time, and salts thereof. 2. 2,6-O,O'-Dipivaloyl-L-ascorbic acid as in claim 1. 3. 3,6-O,O'-Dipivaloyl-L-ascorbic acid as in claim 1. 4. 3-O-Pivaloyl-L-ascorbic acid as in claim 1. 5. A process for preparing a compound of the formula (I), EMI10.2 wherein R1, R2 R3 and R4 each is hydrogen or pivaloyl, R but R1, R2, R3 and R4 are not hydrogen at the same time, and salts thereof, which comprises following A), B), and C), A) a process for preparing the compound of the formula (I) by the reaction of L-ascorbic acid with active derivatives of pivalic acid, for example pivaloyl chloride; B) a process for preparing the compound of the formula (I) by the reaction of L-ascorbic acid protected by the suitable groups, for example isopropylidene group, with active derivatives of pivalic acid; and C) a process for preparing the compound of the formula (I) by the rearrangement of 2,G-O,O'-dipivalol-L-ascorbic acid. 6. Therapeutic agent for cataracts comprising a compound as in claim 1.

Inventors: ISO, TADASHI, IWAO, JUN-ICHI, OYA, MASAYUKI
Applicants: SANTEN PHARMACEUTICAL CO., LTD.
Application year: 1982
Main classification: C07D307
IPC codes: A61K31, A61P27, C07D307