DAS GOUTAM (IN)
ATIGNAL SHANKARA RAO ARVIND (IN)
MAZUMDAR-SHAW KIRAN (IN)
GANESH SAMBASIVAM (IN)
DAS GOUTAM (IN)
ATIGNAL SHANKARA RAO ARVIND (IN)
MAZUMDAR-SHAW KIRAN (IN)
| GB1157100A | 1969-07-02 |
| 1. | Bis {6(1, 3dihydro4hydroxy6methoxy7methyl3oXo5 isobenzofuranyl)4methyl, (4E) 4hexenoic acid} zinc salt (FORMULA I). |
| 2. | FORMULA I. |
| 3. | A process for the preparation of a compound of claim 1, comprising of reacting zinc salt with mycophenolic acid, a salt or a derivative thereof. |
| 4. | The process of claim 23, wherein the zinc salt is zinc chloride or zinc acetate. |
| 5. | A pharmaceutical composition for use as immunosuppressive agent, antiinflammatory agent, antitumor agent, antiviral agent and antisporiatic agent comprising effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. |
| 6. | A method of treatment comprising use of compound of claim 1. |
BACKGROUND OF THE INVENTION 6- (1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-<BR> isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid also known as MPA a mold metabolite first isolated in 1896 (B. Gosio, Riu Igiene Sanita Publica Ann., 7,825 (1896)). It 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. <BR> <BR> <P>Williams et al., J. Antibiot. (Tokyo) 21,463-464 (1968) ]. It is also an antifungal and an antibacterial agent [K. Gilliver, Ann. Bot.
(London) 10, 271-282 (1946) and E. Abraham, Biochem. J. 39, 398-408 (1945) ]. It has also been reported to be useful in the treatment of psoriasis [I. S. Johnson, Chem. Abstr. 77: 92853 (1972)].
MPA 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. <BR> <BR> <P>Clutterbucketal., Biochem. J. 26, 1442-1458 (1932) ]. In fact, MPA was initially isolated from a culture of Penicillium [B. Gosio, Riv.
Igiene Sanita Pub. Ann. 7, 825-869 (1896) ].
The structure of MPA was determined chiefly by Raistrick et al. [J. H. Birkinshaw, H. Raistrick, and D. J. Ross, Biochem. J. 50, 630-634 (1952)].
Jones et. al. (Journal of Medicinal Chemistry, 1971, tlol. 14, No. 4) discussed preparation and antitumor Properties of Analogs and derivatives of MPA.
US 5,380, 879 also discloses derivatives of MPA (lower-alkyl esters; and other substitutions) which are therapeutic agent (no data) useful in treatment of disease states indicated for MPA 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 MPA-glucuronide and the process for the preparation thereof.
US 3, 825, 571 discloses alkyl, alkenyl derivatives of MPA which are useful as anticancer and antitumor agent and process for the preparation thereof.
US 3,853, 919 disclose amine derivatives of MPA, which are useful as anticancer and antitumor agent and process for the preparation thereof.
US 3, 903, 071 disclose saccharide derivatives of MPA, which are useful in the treatment of psoriasis.
US 4, 727, 069, US 4, 861, 776 and US 4748173 disclose heterocyclic aminoalkyl esters of MPA and derivatives thereof,
which are useful as immunosuppressive agent, anti-inflammatory agent, antitumor agent, antiviral agent and anti-psoriatic agent.
US 4,753, 935 disclose morpholinoethyl esters of MPA or pharmaceutically acceptable salts thereof which are useful as immunosuppressive agent, anti-inflammatory 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 MPA with variable substitutions.
US 6,025, 391 disclose enteric coated pharmaceutical formulations with mycophenolate salts, specifically monosodium.
The instant invention is related to a novel compound, namely, Bis {6- (l, 3-dihydro-4-hydroxy-6-methoxy-7-methy !-3-oxo- 5-isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid} zinc salt which can be used as immunosuppressive agent, anti-inflammatory agent, antitumor agent, antiviral agent or antipsoriatic, in view of the prior art.
SUMMARY OF THE INVENTION Accordingly the present invention relates to a compound, Bis <BR> <BR> 6- (1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-<BR> isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid} zinc salt (FORMULA I).
FORMULA I The present invention also relates to a pharmaceutical composition, useful as immunosuppressive agent, anti- inflammatory agent, antitumor agent, antiviral agent and antisporiatic agent, comprising an effective amount of Bis {6-(l, 3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl )-<BR> 4-methyl-, (4E) -4-Hexenoic acid} zinc 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 1. 13C NMR of the compound of formula I.
FIGURE II. tH NMR of the compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION The most preferred embodiment of the present invention is Bis {6- (l, 3-dihydro-4-hydroxy-6-methoxy-7-methy !-3-oxo-5- isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid} zinc salt (FORMULA I).
FORMULA I
The compound according to present invention is used as immunosuppressive agent, anti-inflammatory agent, antitumor agent, antiviral agent. or anti-psoriatic agent.
The other embodiment of the invention is the process for preparation of Bis 6- (1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxo-5-isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid} zinc salt.
The pharmaceutical acceptable salt of the invention is generally derived from the acid, the lactone or a salt or a derivative <BR> of 6- (1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-<BR> isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid.
The pharmaceutical acceptable salt of the invention can be derived by a process comprising dissolving the acid or a salt of 6- (1, 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, treating the solution with a zinc compound and isolating the compound of formula I.
The pharmaceutical acceptable salt of the invention can also be derived by a process comprising dissolving a derivative of 6- (1, 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, optionally, adjusting pH of the mixture; vaporizing of the solvents ; optionally treating with a suitable solvent ; optionally adjusting the pH; treating the solution with a zinc compound and isolating the compound of formula I.
The pharmaceutical acceptable salt of the invention can be derived by a process comprising, adding a salt of 6- (1, 3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-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 with a zinc compound and isolating the compound of formula I.
The third embodiment of present invention is the pharmaceutical composition prepared from the compound of the formula I.
Likewise, the present invention relates to a method of treatment for disease states indicated for MPA 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 O. 1 to 8 mg/kg of body weight per day. The dosages may be 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 parental use may be varied or adjusted from 5 to 500 mg, preferably from 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 To a solution of 6- (l, 3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid sodium salt (2.5 g, 0.0073 mol) in water (25 ml), a solution of zinc chloride (0.99 g, 0.0073 mol) in water (25 ml) was added and stirred for 1 hour. The product was filtered and dried.
Example 2 To a solution of 6- (1, 3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, (4E) -4-Hexenoic acid sodium salt (5 g, 0. 0146 mol) in water (50 ml), a solution of zinc acetate. 2H20 (3. 2 g, 0.0146 mol) in water (50 ml) was added and stirred for 30 minutes. The product was filtered and dried.
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