MYCOPHENOLIC ACID BISMUTH SALT
OFIELD OF THE INVENTION The instant invention relates to a novel compound, namely, Tris {6-
(l,3-dm)dro-4-h}droxy-6-methoxy-7-memyl-3-oxo-5-isoben2θfuranyl)-4- methyl-, (4E)- 4-Hexenoic acid} bismuth salt.
BACKGROUND OF THE INVENTION 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)- 4- methyl-, (4E)- 4-Hexenoic acid also known as mycophenolic acid (MPA) a mold metabolite first isolated in 1896 (B. Gosio, RU I ne Sanaa PuUka A rtn, 7, 825 (1896)). MPA is a compound with several useful biological activities. It is an antiviral and antitumor agent [K.
Ando et al., J. Antibiot. (Tokyo) 21, 649-652 (1968) and R H Williams et al.,
J. Antibiot. (Tokyo) 21, 463-464 (1968)]. Mycophenolic acid is also an antifungal and an antibacterial agent [ . Gilliver, Ann. Bot. (London) 10, 271-282 (1946) and E. Abraham, Biochem. J. 39, 398-408 (1945)].
Mycophenolic acid has also been reported to be useful in the treatment of psoriasis [I. S. Johnson, Chem. Abstr. 77:92853 (1972)]. Mycophenolic acid is produced by many species of Penicillium, e.g., P. brevi-compactum, P. stoloniferum, P. scabrum, P. nagemi, P. szaferi, P. patus-mei, P. griscobrunneum, and P. viridicatum [P. W. Gutterbuck et al.,
Biochem. J. 26, 1442-1458 (1932)]. In fact, mycophenolic acid was initially isolated from a culture of Penicillium [B. Gosio, Riv. Igiene Sanita Pub. Ann.
7, 825-869 (1896)]. The structure of mycophenolic acid was determined chiefly by Raistrick et al. . H Birkinshaw, H Raistrick, and D. J. Ross, Biochem. J. 50,
630-634 (1952)].
Jones et. al. (Journal of Medkmal Chemistry, 1971, Vol. 14, Na 4) discussed preparation and antitumor Properties of Analogs and derivatives of mycophenolic acid. US 5,380,879 also discloses derivatives of mycophenolic acid (lower alkyl esters; and other substitutions) which are therapeutic agent (no data) useful in treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agent. US 3,705,946 discloses method of treating hyperuricemia using alkali metal salts of mycophenolic acid, specifically sodium and potassium salts. US 3,758,455 discloses mycophenolic acid glucuronide and the process for the preparation thereof. ' US 3,825,571 discloses alkyl, alkenyl derivatives of mycophenolic acid which are useful as anticancer and antitumor agent and process for the preparation thereof . . US 3,853,919 discloses arnine derivatives of mycophenolic acid which are useful as anticancer and antitumor agent and process for the preparation thereof. US 3,903,071 discloses saccharide derivatives of mycophenolic acid which are useful in the treatment of psoriasis. US 4,727,069, US 4,861,776 and US 4748173 disclose heterocyclic aniinoalkyl esters of mycophenolic acid and derivatives thereof which are useful as immunosuppressive agent, antiinflammatory agent, antitumor agent, antiviral agent and antisporiatic agent. ' US 4,753,935 discloses morpholinoethyl esters of mycophenolic acid or pharmaceutically acceptable salts thereof which are useful as immunosuppressive agent, antiinflammatory agent, antitumor agent, antiviral agent and antisporiatic agent.
Many patents including US 5,380,879, US 5,441,953, US 5,455,045, US
5,493,030, US 5,633,279 discloses derivatives of mycophenolic acid with variable substitutions. US 6,025,391 discloses enteric coated pharmaceutical formulations with mycophenolate salts, specif icaEy monosodium. The instant invention is related to a novel compound, namely, Tris {6-
(1 ,3- dihydro-4-hydroxy- 6-methoxy- 7- methyl- 3- oxo- 5-isobenzofuranyl)-4- methyl-, (4E)- 4-Hexenoic acid} bismuth salt which can be used as immunosuppressive agent, anti flammatory agent, antitumor agent, antiviral agent or antisporiatic, in view of the prior art.. SUMMARY OF THE INVENTION Accordingly the present invention relates to a compound, Tris {6-(l,3- dihydro- 4- hydroxy- 6- methoxy- 7- methyl- 3- oxo- 5- is obenzof uranyl)- 4- methyl-, (4E)- 4-Hexenoic acid} bismuth salt (FORMULA I).
FORMULA I The present invention also relates to a pharmaceutical composition, useful as immunosuppressive agent, antiinflammatory agent, antitumor agent, antiviral agent and antisporiatic agent, comprising an effective amount of Tris { 6- (1 ,3-dihydro- 4- hydroxy- 6- methoxy- 7- methyl- 3- oxo- 5- is obenzof uranyl)- 4- methyl-, (4E)- 4-Hexenoic acid} bismuth salt and a pharmaceutically acceptable carrier. Further, the present invention is also a method of treating mammals, including humans, by administering to such mammal a dosage form of the
pharmaceutical composition described above. DESCRIPTION OF FIGURES
FIGURE I. 13C NMR of the compound of formula I. FIGURE II. Η NMR of the compound of formula I. DETAILED DESCRIPTION OF THE INVENTION The most preferred embodiment of the present invention is Tris {6-
(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4- ethyl-, (4E)- 4-Hexenoic acid} bismuth salt (FORMULA I).
FORMULAI
The compound according to present invention is used as immunosuppressive agent, antiinflammatory agent, antitumor agent, antiviral agent or antisporiatic agent. The other embodiment of the invention is the process for preparation of Tris {6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4- methyl-, (4E)- 4-Hexenoic acid} bismuth salt. The pharmaceutically acceptable salt of the invention is generally derived from the free acid, the lactone or a salt or a derivative of 6-(l-3- dmydro-4-hydroxy-6-memoxy-7-mem^ (4E)- 4-Hexenoic acid. The pharmaceutically acceptable salt of the invention can be derived by a process comprising dissolving a salt of 6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, (4E)- 4-Hexenoic
acid; in aqueous or aqueous alcohol solvent or other suitable solvents, extracting the free acid or lactone into water immiscible solvent, isolating the acid or lactone or mixture thereof by vaporizing the solvent; treating the residue with an alcohol, optionally containing base; optionally adjusting the pH; treating the solution with a bismuth compound and isolating the compound of formula I.
FORMULA I The pharmaceutically acceptable salt of the invention can also be derived by a process comprising dissolving a derivative of 6-(l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxo- 5- isoberizofuranyl)-4- methyl-, (4E)- 4- Hexenoic acid; in aqueous or aqueous alcohol solvent or other suitable solvents, optionally, adjusting pH of the mixture; vaporizing of the solvents; optionally treating with a water immiscible solvent; optionally adjusting the pH treating the solution with a bismuth compound and isolating the compound of formula I.
FORMULA I The pharmaceutically acceptable salt of the invention can be derived by a process comprising, adding a salt of 6-(l,3-dihydro-4-hydroxy-6-
methoxy-7-methyl-3-oxo-5-isobenzofuranyι)-4- methyl-, (4E)- 4-Hexenoic acid; to aqueous or aqueous alcohol solvent or other suitable solvents, optionally adjusting pH of the mixture; treating the solution wit a bismuth compound and isolating the compound of formula I.
FORMULA I The third embodiment of present invention is the pharmaceutical composition prepared from the compound of the formula I.
FORMULA I Likewise, the present invention relates to a method of treatment for disease states indicated for mycophenolic acid and/ or mycophenolate mofetil and other immunosuppressant agent. The compound of present invention utilized in the pharmaceutical method of this invention is administered to the patient at dosage levels of from 2 to 500 mg per day which for a normal human adult of approximately 70 kg is a dosage of from 0.1 to 8 mg/kg of body weight per day. The dosages maybe preferably from 0.2 to 1.5 mg/kg per day. The dosage is preferably administered as a unit dosage form. The unit dosage form for oral or parenteral use may be varied or adjusted from 5 to 500 mg, preferably f om 20 to 100 mg according to the particular application
and the potency of the active ingredient. The compositions can, if desired, also contain other active therapeutic agent. Determination of optimum dosages for a particular situation is within the skill of the art. The compound, of the formula I is in general equivalent for the activity of the utility as described herein. The following examples illustrate particular methods for preparing compounds in accordance with this invention. These examples are thus not to be read as limiting the scope of the invention. EXAMPLES Example 1: A suspension of 6- (l,3-dihydro-4- hydroxy-6- methoxy- 7- methyl-3- oxo- 5- isobenzofuranyl)-4- methyl-, (4E)- 4-Hexenoic acid sodium (5 g, 0.0146 mol) in water (20 mL) was heated to 40-45° C and a solution of bismuth nitrate pentahydrate (2.0 g, 0.004 mol) in water (250 mL) was added under stirring. The reaction mixture was further stirred at 40-45° C for 1 hour and cooled to room temperature. The precipitated product was filtered and dried. Yiled: 4.0 g. Example 2: To a suspension of 6- (1 ,3- dihydro- 4- hydroxy- 6- methoxy- 7- methyl- 3- oxo- 5- isobenzofuranyl)-4- methyl-, (4E)- 4-Hexenoic acid ammonium (10 g, 0.03 mol) in water (200 mL), aqueous HQ (1.5 N) was added till pH of the mixture was 3.5-4.0 and the mixture was extracted with ethyl acetate (2 x 250 mL). The combined extract was washed with brine and water and concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and a solution of sodium hydroxide (1.25 g, 0.035 mol) in water (100 mL) was added under stirring. The reaction mixture was extracted with methyl tert-butyl ether (75 mL) and pH of aqueous layer was adjusted to 7.5- 8.0 by adding aqueous HQ (1.0 N). After heating the aqueous layer to 35-40° a solution of bismuth nitrate pentahydrate (2.5 g, 0.006 mol) in water (250
mL) was added under stirring. The reaction mixture was further stirred at 35- 40° C for 1 hour and cooled to room temperature. The precipitated product was filtered and dried. Yiled: 7.0 g. Example 3: 6- (1 ,3- dihydro- 4- hydroxy- 6- methoxy- 7- methyl- 3- oxo- 5- isobenzof uranyl)- 4- methyl-, (4E)- 4-Hexenoic acid (10 g, 0.0312 mol) was added to a solution of sodium hydroxide (1.4 g, 0.035 mol) in water (100 mL) and stirred for 30 minutes. The reaction mixture was extracted with methyl tert-butyl ether (25 mL) and pH of aqueous layer was adjusted to 7.5- 8.0 by adding aqueous HQ (1.0 IN). After heating the aqueous layer to about 40° Q a solution of bismuth nitrate pentahydrate (2.5 g, 0.006 mol) in water (250 mL) was added under stirring. The reaction mixture was further stirred at 35-40° Cfor 1 hour and cooled to room temperature. The precipitated product was filtered and dried. Yiled: 8.0 g.