Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3903071 A
Publication typeGrant
Publication dateSep 2, 1975
Filing dateMay 22, 1973
Priority dateMay 22, 1973
Also published asCA1027558A, CA1027558A1, DE2424119A1
Publication numberUS 3903071 A, US 3903071A, US-A-3903071, US3903071 A, US3903071A
InventorsRichard E Holmes
Original AssigneeLilly Co Eli
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Mycophenolic acid derivatives
US 3903071 A
Abstract
Mycophenolic acid aldose derivatives which are useful in affecting the growth of transplanted tumor cells in mice and rats, and in the treatment of psoriasis and gout, and intermediates useful in the preparation thereof.
Images(7)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent Holmes Sept. 2, 1975 MYCOPHENOLIC ACID DERIVATIVES [75] Inventor: Richard E. Holmes, Indianapolis, Pnmary Exammer l ohnme B town Ind Attorney, Agent, or Fzrm-Nancy J. Harrison;

4 Kathleen R. S. Page; Everet F. Smith [73] Assignee: Eli Lilly and Company, Indianapolis,

Ind.

[2l] Appl No.: 362,700

Mycophenolic acid aldose derivatives which are useful in affecting the growth of transplanted tumor cells in 260/210 mice and rats, and in the treatment of psoriasis and n gout, and intermediates useful in the preparation [58] Field of Search 260/210 R, 210 AB thereofi [56] References Cited UNITED STATES PATENTS 9/1973 Arita 250/210 R 8 Claims, No Drawings MYCOPI-IENOLIC ACID DERIVATIVES BACKGROUND OF THE INVENTION Psoriasis is a common chronic skin disease of undetermined cause. Characteristic features of psoriasis are persistent patches of redness covered with scales. The disease is in part determined by a genetically dominant trait. While it is absent at birth, it can begin at any age from childhood to extreme old age. Psoriasis does not, however, appear to be a communicable disease; there are no known causative factors for it in the environment.

In the involved patches, the cells of the epidermis grow and multiply up to seven times faster than do normal epidermis cells.

No known therapeutic method assures a cure. Agents currently used in the treatment of psoriasis include ultraviolet light, coal tar, ammoniated mercury, anthralin, and topical corticosteroids. Methotrexate has been used to treat psoriasis by systemic administration, but such treatment method is accompanied by severe side effects. Antimetabolite drugs such as aminopterin, thioguanine, and azaribine have also been used in treating this disease.

Although psoriasis seldom affects the general health of the patient, the disease can be debilitating. Psychlogical effects, secondary infections, itching and arthritic manifestations are among the troublesome symptoms encountered. There is, therefore, a continuing need for improved agents in the treatment of this disease.

Another frequently debilitating disease is gout. Gout is caused by uric acid crystal deposits in tissues, particularly in the cartilage of joints, bone and kidney. These uric acid crystal deposits are a result of an increase in circulating uric acid, a condition known as hyperuricemia. The therapeutic agents currently used in the treatment of hyperuricemia are generally accompanied by undesirable side effects, such as gastrointestinal spasm, bone-marrow depression, and skin reactions. Improved agents which reduce serum uric acid levels without causing undesirable side effects are, therefore, in demand.

Mycophenolic acid, from which the compounds of the present invention are prepared, is a well-known natural product. First isolated in 1896, mycophenolic acid is known to exhibit antifungal, antibacterial, antiviral, and antitumor properties [see US. Pat. No

3,705,894; French Pat. No. 2,010,136; South African Pat. No. 6,903,147 (Derwent No, 28275R)]. Mycophenolic acid is also useful in the treatment of psoriasis and hyperuricemia [see US. Pat. No. 3,705,946; Netherlands Pat. No. 7,116,238 (Derwent No. 37140T)]. Mycophenolic acid glucuronide, the natural metabolite of mycophenolic acid, has also been reported to have antitumor activity [see French Pat. No. 2,100,65 3 (Derwent No. 41305T); J. Antibiotics 23 (8) 408413 (1970)].

SUMMARY OF THE INVENTION The present invention is directed to novel mycophenolic acid derivatives having the following formula:

O CH" wherein R represents OH, loweralkoxy of 1 to 5 carbon atoms, or amido; and

The compounds of Formula I wherein R represents (a) through (g) are useful in affecting the growth of transplanted tumor cells in mice and rats, and in the treatment of psoriasis and gout. The compounds of Formula I wherein R represents a peracylated (a) through (g) moiety as defined are useful intermediates.

DETAILED DESCRIPTION OF THE INVENTION The scope of compounds in accordance with the present invention is as defined hereinabove. In the moieties defined herein as loweralkoxy, the alkyl portion can be a straightor branched-chain alkyl group. In the intermediate compounds, peracylation refers to complete acylation of hydroxyl groups in the respective R moiety. I

In the case of salts, an alkali-metal or alkaline-earth metal may be chosen to form a salt with special advantages, such as ready solubility, ease of crystallization and the like; but in any event, the salt formed must be pharmaceutically acceptable. Representative and suitable salts include the sodium, potassium, lithium, magnesium and calcium salts.

The compounds of the present invention are not readily prepared by conventional methods for the formation of glycosides. For example, the Koenigs-Knorr synthetic method (H. Krauch and W. Kunz, Organic Name Reactions, John Wiley and Sons, New York,' N.Y., 1964, p. 314) was used to prepare the naturallyoccurring B-D-glucuronide metabolite [K. Ando, S. Suzuki, and M. Arita, J. Antibiotics 23 (8), 408-413 1970)]. The Koenigs-Knorr method waw not found to be useful, however, in the preparation of the novel compounds of the present invention.

The compounds of the present invention are prepared by reacting a per-O-acylglycosyl halide with a mycophenolic acid ester in the presence of a nonnucleophilic base.

The mycophenolic acid ester derivatives useful in the preparation of the present compounds are known in the art [see, for example, J. Med. Chem. 14, 305 (1971 )1.

The appropriate per-,O-acylglycosyl halides used to prepare the compounds of. the present invention are also known in the art. For a review of the chemistry of these compounds, see Advan. Carlwlrvcl. Chem. l0,

207256 (1955). The per-O-acetylglycosyl halides are most frequently used. However, other acylglycosyl halides, for example, the other per(C. ,C,- alkanoyl)glycosyl halides and the perO- benzoylglycosyl halides, are also useful. Of the various useful halides, the bromides and chlorides are most commonly employed, since iodides decompose easily and fluorides are less reactive.

Non-nucleophilic bases, such as hinderedamines or quinoline, which do not interact with the per-O- acylglycosyl halide but which do take up the liberated hydrogen halide, are suitable for use in the reaction.

Good results are typically achieved with this reaction when the number of moles of per-O-acylglycosyl halide is either equivalent to or up to about three times the number of moles of mycophenolic ester used.

Conveniently, the reaction is carried out in the presence of a polar aprotic solvent such as, for example, dimethylformamide. The reactants are heated to temperatures in therange of about 50 to about;lOOC. and preferably in the range of about 75 to about 80C. Under these conditions, the reaction is usually complete in about 25 to about 48 hours.

' In a typical workup, the amine hydrohalide formed during the course of the above-described reaction is separated by precipitation in a solvent such as xylene or toluene, cooling for several hours. Xylene is especially suitable because it forms a conveniently-removed azeotrope with dimethylformamide.

The filtrate from the above-described precipitation is evaporated under vacuum, and the residue is dissolved in a solvent such as, for example, diethyl ether. If necessary, undissolved solids are again separated, and the ether filtrate is evaporated under vacuum to give coinpounds of Formula I wherein R is a peracylated (a) through (g) moiety. In general, these compounds are useful as intermediates without further purification at this point.

The acyl groups of the R moiety are cleaved by treatment with base. A saturated solution of ammonia in alcohol is generally useful for deacylating the sugar moiety without affecting the ester function of the mycophenolic acid moiety.

The reaction mixture resulting from the deacylation step is treated further to remove excess per-O- acylglycosyl halide. In a preferred manner, thesolvent is removed, and the residue is dissolved in water. This solution is extracted .with an organic solvent, such as chloroform. The unreacted per-O-acylglyco syl halide is separated in the aqueous phase to give inthe organic phase a compound of Formula I wherein R is alkoxy. The compound is separated and characterized by wellknown procedures. From this alkoxy derivative, other corresponding Formula 1 alkoxy derivatives are conveniently prepared by routine ester-exchange techniques.

The compounds of Formula I wherein R is OH are prepared by standard procedures for hydrolysis and cleavage of esters [see J. Amer. Chem. Soc. 55, 4079 1933)] from the corresponding esters obtained as described hereinabove.

The compounds of Formula I wherein R is OH can be further. reacted to obtain the-corresponding, specified alkali-metal and alkaline-earth-metal salts. In such further reaction the above-mentioned acid is reacted slowly with a stoichiometric amount of a suitable base, generally without heating, to obtain the corresponding salt. These reactions are of a type well known in the art, and the particular steps employed to prepare such salts are carried out in accordance with these well-known procedures.

The compounds of Formula I wherein R is NH are prepared by reacting the corresponding compound wherein R is alkoxy, especially those wherein R is methoxy, with ammonia in methanol for about three days or more. The product is recovered by standard procedures.

Those compounds. of Formula I wherein R is B-D- glucopyranosyl or tetraacetyl-B-D-glucopyranosyl are preferred compounds. The starting tetra-O-acetyI-a-D- glucosyl halide used in the preparation of these compounds is more readily available and, in addition, is less expensivehThus the, resulting Formula I glucopyranosides are superior,-having the advantages of greater availability and lowered cost.

The novel compounds of Formula I wherein R represents (a) through (g) are useful in affecting the growth of transplanted tumor cells in mice and rats.

Standardized procedures were used to test various of the Formula'l compounds. These procedures are described by I. S Johnson et al. in Cancer Res. 20, 1016 1960). More recently, M. LI. Sweeney et al. evaluated the antitumor activity of mycophenolic acid by these methods [see Cancer Res. 32, 1795 (1972)].

METHOD Solid tumor fragments are implanted subcutaneously by trocar in the axillary region of mice and rats. Animals receive daily intraperitoneal doses of test compounds for seven to ten days after implantation. Control groups of tumor-bearing mice or rats receive daily doses of vehicle only. Therapy against the rapidly growing tumors begins 24 hours after implantation. Treatment of X5563 plasma cell myeloma is delayed for 3 to 5 days after implantation. The inhibition of tumor growth is determined by comparing the average tumor Host" MLS Mecca lymphosarcoma AKR Ca-755 Adenocarcinoma 755 C57.Bl./6 GLS Gardner lymphosarcoma C 3H I.l2l() LlZlO lymphocytic leukemia DBA/Z Walker 256 Walker carcinosarcoma 256 I SD" rat X5563 X5563 plasma cell myeloma C3H 5-9] 8-9] melanoma DBA/l "Mouse strain designations conform to the listing of The Committee on Standardired Genetic Nomenclature for Mice (Staats. J. Standardized Nomenclature for Inbred Strains of Mice: Fourth Listing- Cancer Res. 2K: 391-420 I968) Sprague-Dawley Table I illustrates the usefulness of the compounds defined above as antitun'ior agents against Mecca lymphosarcoma.

TABLE I Antitumor Activity Against Mecca Lymphosarcoma Formula I Compound Dose" Av. Tumor Inhibi- (mg/kg Diameter tion of R' R no. days) T/C (mm) Tumor Growth B-D-gluco- OC H 100 X 7 Ill/23.5 48 pyranosyl ,B-D-gluco- 0C H 100 x 7 0/ I61 100" pyranosyl B-D-gluco- OC H 150 X 9 9.6/26.4 64 pyranosyl BDgluco- 00 11,, 150 x 7 ()/l6.l 100 pyranosyl B-D-gluco- OCH I45 X 9 84/264 68 pyranosyl fi-Dgluco- OCH,, 150 X 8 l4.2/24.4 42 pyranosyl B-D-galacto- OC- H,-, 100 X 7 167/235 29 pyranosyl "Doses were given once daily for the specified number of days.

Table II illustrates the usefulness of various Formula I compounds wherein R is B-D-glucopyranosyl against a variety of tumor systems.

"Doses were given once daily for the specified number of days.

Table III further illustrates the antitumor activity of two Formula I compounds wherein R is ,B-D- glucopyranosyl against two leukemia systems.

TABLE III Comparison of Antileukemic Activities Dose (mg/kg Av. Life Prolongation R System days) T/C of Life OCH, C1498 150x10 l9.l/l4.5 32 OC. .H, 1.1210 150 X l8.()/l5.4 16

When used as antitumor agents, in mice and rats the compounds of Formula I wherein R represents (a) thorugh (g) may be administered either orally or parenterally. Although the dosage administered will vary according to factors such as the tumor system involved, the compound being used, the severity of the disease and the like, the above-specified Formula I compounds are typically effective as antitumor agents when given in the range of about 40 mg/kg to about 300 mg/kg.

It is known that mycophenolic acid is converted in vivo to its less toxic glucuronide derivative. In the novel compounds of this invention, a carbohydrate moiety blocks the phenolic group of mycophenolic acid and thereby blocks such glucuronide. formation. Initial studies of bile and urine from animals receiving a typical Formula I compound, methyl 6-[4-(B-D- glucopyranosyl )-6-methoxy-7 -methyl-3 -oxo-5- phthalanyl]-4-methyl-4-hexenoate, did not reveal a detectable amount of either mycophenolic acid or mycophenolic acid glucuronide. This would indicate that the carbohydrate moiety may not undergo hydrolysis in the liver. Understanding the unique mechanism by which the compounds of the present invention exhibit antitumor activity in mice and rats will serve to clarify the mechanism of action of mycophenolic acid.

In another aspect, the compounds of Formula I wherein R represents (a) through (g) are useful in the treatment of psoriasis. When used in carrying out this embodiment, a specified Formulal compound can be administered to a human suffering from psoriasis orally, parenterally or topically. When administered topically, an amount of specified Formula I compound effective for treating psoriasis is applied directly .to the psoriatic lesion. For oral use, a specified Formula I compound is administered orally in tablets or capsules or in a liquid solution or suspension. A preferred mode for oral administration is via gelatin capsules. A typical formulation in capsules is as follows: 9.4 kg of specified Formula I compound is thoroughly mixed with 4.7 kg of starch, and the mixture is loaded into empty telescoping gelatin capsules. Each capsule contains the following ingredients:

400 mg specified Formula I compound 200 mg starch For topical use it is preferable to formulate the compounds of the present invention, for example, as ointments or solutions. 4

A typical ointment useful in applying a specified Formula I compound to a psoriatic lesion contains the following ingredients per gram of ointment:

Specified Formula I compound mg Polyethylene glycol 300 (N.F.) 600 mg Polyethylene glycol 4000 (U.S.). 350 mg Specified Formula I compound 50 mg Polyethylene glycol 300 (N.F.)

For topical administration, a specified compound of Formula I, formulated as indicated above, is applied to a psoriatic lesion at a rate varying from 3 mcg per square cm of skin surface per day up to 300 mcg per square cm of skin surface per day until the psoriatic process is checked. The typical formulation can be applied daily for 14 days using a continuous occlusive dressing. The concentration of specified Formula I compound in the formulation can vary from about 0.05 percent to about 5 percent; with these concentrations a dose of 0.01 ml of, for example, ointment per square cm of skin surface readily supplies the necessary amount of specified Formula I compound. The daily topical dose of specified Formula I compound for a 70- kg person should not exceed about 1.5 g.

For oral administration, a daily dosage of from about 1 to about 10 g of specified Formula I compound given in divided doses, for example, 3 to 4 times per day, can be employed, using any of the commonly accepted oral dosage forms.

In yet another aspect the compounds of Formula I wherein R represents (a) through (g) are useful in the treatment of hyperuricemia. To achieve a uric acidlowering effect, from about 200 to about 5000 mg/kg/day of a specified Formula I compound is administered either orally or parenterally to a human with an elevated serum uric acid level. Although any specified Formula] compound may be employed for oral administration, the alkali-metal salts of the Formula I compounds wherein R is OH are customarily employed for parenteral administration. Of the alkali-metal salts, the sodium and potassium salts are especially useful.

When preparing specified Formula I compounds for parenteral administration, it is convenient toformulate the agent into ampoules. For example, an ampoule can be prepared containing 220 mg of sodium 6-[4-( B-D- glucopyranosyl )-6-methoxy-7-methyl-3-0xo-5- phthalanyll-4-methyl-4-hexenoate, 5 mg of phenol and 2 ml of water. Similarly, ampoules containing 620 mg of sodium 6-[4-( B-D-glucopyranosyl)-6-methoxy-7- methyl-3-oxo-5-phthalanyl]-4-methyl-4-hexenoate, 0.4 ml of ethanol, 0.042 mg of benzyl alcohol, 10 mg of phenol, 14 mg of monobasic potassium phosphate, 10 mg of sodium citrate and 4 ml of water can be used. The pH of this solution is adjusted, if necessary, to about pH 7 by addition of acid or base, as required prior to placing in ampoules.

For oral administration, it is preferable to administer the compounds in telescoping gelatin capsules. For example, capsules can be prepared, each containing 260 mg of 6-[4-(B-D-glucopyranosyl)-6-methoxy-7-methyl- 3-oxo-5-phthalanyl]-4-methyl-4-hexenoic acid and up to 700 mg of talc, silica gel, starch, or microcrystalline cellulose singly or in combination, up to mg of magnesium stearate and up to 50 mg of stearic acid.

The preparation of compounds of the present invention is further illustrated by the following specific examples:

EXAMPLE 1 Ethyl 6-[4-( 2,3 ,4,6-tetra-O-acetyl-B-D-glucopyranosyl )-6- methoxy-7-methyl-3-oxo-5-phthalanyl -4-methyl-4- hexanoate 2,3,4,6-Tetra-O-acetyl-a,D-glucopyranosyl bromide (10.2 g) was added to a solution of the ethyl ester of mycophenolic acid 17.4 g) and N- ethyldiisopropylamine (10 g) in dimethylformamide (80 ml); the mixture was stirred and heated at 8590C. in an oil bath. After 2 hours, more 2,3,4,6- tetra-O-acetyl-a,D-glucopyranosyl bromide (10.2 g) was added; this mixture was stirred and heated for five hours. At this time a third portion of 2,3,4,6-tetra-O- acetyl-a,D-glucopyranosyl bromide (10 g) and more N-ethyldiisopropylamine (5 g) were added; this mixture was stirred and heated for 18 hours. At this point a fourth portion of 2,3,4,6-tetra-O-acetyl-a,D- glucopyranosyl bromide 10 g) was added; this mixture was stirred and heated for another 4 hours. The reaction mixture thus obtained was poured into 1 liter of xylene, and the resulting solution was chilled in a refrigerator for 1 hour. A precipitate formed and was separated by filtration, washing with xylene. The combined filtrates were evaporated under vacuum, and the residue thus obtained was taken into diethyl ether (about 800 ml). The undissolved solids were removed by filtration, and the diethyl ether filtrate was evaporated under vacuum to give ethyl 6-[4(2,3,4,6-tetra-O- acetyl-B-D-glucopyranosyl)-6-methoxy-7-methyl-3 oxo-5-phthalanyl]-4-methyl-4-hexenoate: nmr indicated the presence of four acetyl peaks at 6 2.1-2.2

EXAMPLE 2 Ethyl 6-[4-( ,B-D-glucopyranosyl )-6-methoxy-7-methyl-3- oxo-5-phthalanyl]-4-methyl-4-hexenoate Ethyl 6-[4-( 2,3 ,4,6-tetra-O-acetyl-B-D- glucopyranosyl )-6-methoXy-7-methyl-3-oxo-5- phthalanyl]-4-methyl-4-hexenoate obtained as described in Example 1 was dissolved in 150 ml of ethanol, and this solution was added to a chilled (ca. 30C.) solution of ethanol (250 ml)-ammonia (added to give a total volume of about 500 ml). The resulting solution was allowed to.return to room temperature and then was stirred for 24 hours. The solvents were evaporated under vacuum. The residue was dissolved in water (250 ml), and this solution was extracted twice with chloroform (300-ml portions). The chloroform extract was dried (Na SO and evaporated in vacuo. The residue was recrystallized twice from ethanol to give 13.6 g of ethyl 6-[4-(B-D-glucopyranosyl)-6- methoxy-7-methyl-3-oxo-5-phthalanyl]-4-methyl-4- hexenoate, m.p. 5659C.

Analysis.

Calculated for C- H O (percent): C, 58.81; H, 6.71; O, 34.47. Found (percent): C, 58.77; H, 6.59; O,

EXAMPLE 3 Methyl 6- 4-( B-D-glucopyranosyl )6-methoxy-7'methyl-3- oxo-5-phthalanyl -4-methyl-4-hexenoate Ethyl 6- 4-( B-D-glucopyranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanyl l-4-methyI-4-hexenoate (8 g) was added to a solution of N-ethyldiisopropylamine (5 g) in methanol (200 ml). The resulting solution was heated under reflux under nitrogen for 48 hours. The solvent was then removed in vacuo. The residue thus obtained was recrystallized from methanol-benzene to give 4.8 g of methyl 6-[4-(B-D-glucopyranosyl)-6- methoxy-7-methyl-3 -oxo-5-phthalanyl -4-methyl-4- hexenoate, m.p. 73C.

Analysis.

Calculated for C H;, O (percent): C, 58.05; H, 6.50; O, 35.45. Found (percent): C, 58.05; H, 6.42; O,

EXAMPLE 4 6-[4-([3-D-glucopyranosyl)-6-methoxy-7-methyl-3- oxo-S-phthalanyl]-4-methyl-4-hexenoic acid N-Ethyldiisopropylamine (8 ml) and water (10 ml) were added to a solution of ethyl 6-[4-(B-D-glucopyranosyl)-6-methoxy-7methyl-3-oxo-5-phthalanyl]-4- methyl-4-hexenoate (3 g) in methanol (60 ml). The resulting solution was heated under reflux for 132 hours. Additional N-ethyldiisopropylamine (2 ml) was added, and refluxing was continued for 48 hours. The solvents were evaporated'in vacuo, and the residue thus obtained was dissolved in water (50 ml). This aqueous solution was adjusted to about pH 7.6 with dilute sodium hydroxide and then was extracted three times with chloroform (25-ml portions). The resulting aqueous solution was adjusted to about pH 4.5 with dilute hydrochloric acid and then was extracted twice with diethyl ether (25-ml portions) and 12 times with chloroform (25-ml portions). The 12 chloroform extracts were combined, dried (Na2SO4) and evaporated in vacuo. The residue thus obtained was crystallized from ethyl acetate-benzene to give 550 mg of 6-[4-(,8-D-glucopyranosyl)-6-methoxy-7-methyl-3- oxo-5-phthalanyl]-4-methyl-4-hexenoic acid, m.p. l7918lC.

Analysis.

Calculated for C H O (percent): C, 57.25; H, 6.26; O, 36.47. Found (percent): C, 57.09; H, 6.44; O, 36.44.

EXAMPLE 5 Ethyl 6- 4-( 2,3 ,4,6-tetra-O-acetyl-,B-D-galactopyranosyl )-6- methoxy-7-methyl-3-oxo-5-phthalanyl]-4-methyl-4- hexenoate 2,3,4.6-Tetra-O-acetyl-a,D-galactopyranosyl bromide (6.7 g) was added slowly to a solution of the ethyl ester of mycophenolic acid (6 g) and N- ethyldiisopropylamine (4 g) in dimethylformamide ml); the mixture was stirred and heated at 7580C. in an oil bath for 48 hours. The reaction mixture then was added to 200 ml of xylene, and the resulting solution was refrigerated for 3 hours. A precipitate formed and was separated by filtration. The filtrate was evaporated in vacuo to give ethyl 6-[4-(2,3,4,6-tetra-O-acetyl-B-D- galactopyranosyl )-6-methoxy-7-methyl-3-oxo-5- phthalanyl1-4-methyl hexenoate.

EXAMPLE 6 Ethyl 6- 4-( ,B-D-galactopyranosyl )-6-methoxy-7-methyl-3- oxo-5-phthalanyl ]-4-methyl-4-hexenoate Ethyl 6-[4-(2,3,4,6-tetra-O-acetyl-B-D- galactopyranosyl )-6-methoxy-7-methyl-3-oxo-5- phthalanyl1-4-methyl hexenoate, obtained as described in Example 5, was dissolved in a chilled (about -30C.) solution of ethanol (200 ml) ammonia (dissolved to give a total volume of about 400 ml). The resulting solution was allowed to return to room temperature and then was stirred for 18 hours. The solvents were removed under vacuum. Water 100 ml) and chloroform 100 ml) were added to the residue thus obtained. The chloroform layer was separated. The aqueous layer was extracted further with chloroform (three 75-ml portions). The combined chloroform extracts were dried (Na SOQ and evaporated in vacuo. Water (250 ml) and diethyl ether ml) were added to this residue. The aqueous layer was separated, was washed twice more with diethyl ether (150-ml portions), and was evaporated under vacuum. The resulting residue was crystallized from ethanol to give 1.6 g of ethyl 6-[4-( B- D-galactopyranosyl)-6-methoxy-7-methyl-3-oxo-5- phthalanyl]-4-methyl-4-hexenoate, m.p. 6468C.

Analysis.

Calculated for C H O (percent): C, 58.81; H,

6.71; O, 34.47. Found (percent): C, 58.55; H, 6.91; O,

34.75. EXAMPLE 7 Methyl 6- 4-( B-D-galactopyranosyl )-6-methoxy-7- methyl-3-oxo-5 phthalanyl]-4-methyl-4-hexenoate Ethyl 6- 4-( B-D-galactopyranosyl )-6-methoxy-7- methyl-3-oxo-S-phthalanyl ]-4-methyl-4-hexenoate (610 mg) was added to a solution of methanol (20 ml) and N-ethyldiisopropylamine 1 ml). The resulting solution was heated under reflux for 48 hours. The solvent was evaporated in vacuo. and the residue thus obtained was crystallized from ethanol to give 362 mg of methyl 6- 4-( B-D-galactopyranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanylj-4-methyl-4-hexenoate, m.p. l4ll42C.

Analysis.

Calculated for C H O (percent): C, 58.05; H, 6.50; O, 34.45. Found (percent): C, 57.77; H, 6.58; O, 35.15.

EXAMPLES 8 to 21 Other representative compounds of the present invention, prepared using the methods described and exemplified hereinabove, include:

n-Pentyl 6-[ 4-( ,B-D-ribofuranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanyl ]-4-methyl-4-hexenoate Sodium 6- 4-( ,B-D-allopyranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanyl ]-4-methyl-4-hexenoate 6- 4-( B-D-Gulopyranosyl )-6-methoxy-7-methyl-3- oxo-5-phthalanyl1-4-methyl-4-hexenoic acid Isopropyl 6-[4-( B-D-xylopyranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanyl ]-4-methyl-4-hexenoate 6- 4-( ,B-D-Glucopyranosyl -6-methoxy-7-methyl-3- oxo-S-phthalanyl]-4-methyl-4-hexenamide Lithium 6 4-( B-D-ribopyranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanyl]-4-methyl-4-hexenoate Calcium 6-[4-(13-D-glucopyranosyl )-6-methoxy-7- methyl-3-oxo-5-phthalanyl]-4-methyl-4-hexenoate Potassium 6- 4-( B-D-galactopyranosyl )-6-methoxy- 7-methyl-3-oxo-5-phthalanyl]-4-methyl-4-hexenoate Magnesium 6- 4-( ,B-D-glucopyranosyl )-6-methoxy- 7-methyl-3-oxo-S-phthalanyl]-4-methyl-4-hexenoate n- Pentyl 6- 4-( 2 ,3 ,5 -tri-O-benzoyl-B-D- ribofuranosyl )-6-methoxy-7-methyl-3-oxo-5 phthalanyl]-4-methyl-4-hexenoate Ethyl 6- 4-( 2 ,3 ,4,6-tetra-O-propionyl-B- D- allopyranosyl )-6-methoxy-7-methyl-3-oxo-5 phthalanyl -4-methyl-4-hexenoate Methyl 6-[4-( 2,3,4-tri-O-benz0yl-B-D- xylopyranosyl )-6-methoxy-7-methyl-3-oxo-5 phthalanyl]-4-methyl-4-hexenoate Isopropyl 6-[ 4-( 2,3 ,4-tri-O-benzoyl-B-D- ribopyranosyl )-6-methoxy-7-methyl-3-oxo-5- phthalanyl1-4-methyl-4-hexenoate Ethyl 6- 4-( 2,3 ,4,6-tetra-O-acetyl-B-D- gulopyranosyl )-6-methoxy-7-methyl-3 -o xo-S phthalanyl]-4-methyl-4-hexenoate.

I claim: 1. A compound of the formula:

f. ,B-D-ribopyranosyl, or g. ,B-D-xylopyranosyl; or, when R is loweralkoxy .as defined, R can additionally represent any of the (a) through (g) moieties peracylatcd with C- ,C ,-alkanoyl or benzoyl; and the pharmaceutieally acceptable, alkali-metal or alkaline-earth-metal salts derived from those compounds wherein R is on.

2. A compound of claim 1 wherein R represents (a) through ,(g).

3. A compound of claim 2 wherein R is ,B-D- glucopyranosyl.

4., The compound of claim 3 which is ethyl 6-[4-(13- D-glucopyranosyl )-6-methoxy-7-methyl-3-oxo-5- phthalanyl ]-4-methyl-4-hexenoate.

5. The compound of claim 3 which is methyl 6-[4-(B- D-glueopyranosyl )-6-methoxy-7-methyl-3-oxo-5 phthalanyl ]-4-methyl-4-hexenoate.

6. The compound of claim 3 which is 6-[4-(B-D- glucopyranosyl )-6-methoxy-7-methyl-3 -oxo-5 phthalanyl]-4-methyl-4-hexer1oic acid.

7. A compound of claim 2 wherein R is B-D- galactopyranosyl.

8. A compound of claim 1 wherein R is loweralkoxy and R is any of the (a) through (g) moieties peracy-

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3758455 *May 4, 1971Sep 11, 1973Chugai Pharmaceutical Co LtdReof mycophenolic acid glucuronide and the process for the preparation the
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4103006 *May 20, 1976Jul 25, 1978Wisconsin Alumni Research FoundationGlycosides of 2,6-bis(hydroxy-phenyl)-3,7-dioxabicyclo [3,3,0] octane
US4686234 *Nov 27, 1985Aug 11, 1987Syntex (U.S.A) Inc.Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis
US4725622 *Jan 23, 1986Feb 16, 1988Syntex (U.S.A.) Inc.Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4868153 *Aug 17, 1988Sep 19, 1989Syntex (U.S.A.) Inc.Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US4948793 *Jun 29, 1989Aug 14, 1990Syntex (U.S.A.) Inc.Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
US4952579 *Nov 14, 1988Aug 28, 1990Syntex (U.S.A.) Inc.Method of treating diseases by administering morpholino-ethylester of mycophenolic acid or derivatives thereof
US4992467 *Mar 28, 1990Feb 12, 1991Syntex (U.S.A.) Inc.Treatment of autoimmune diseases with mycophenolic acid, and derivatives and formulations thereof
US5098899 *Dec 14, 1990Mar 24, 1992Trustees Of Boston UniversityMethod for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites
US5177072 *Dec 9, 1991Jan 5, 1993Syntex (U.S.A.) Inc.Treatment of autoimmune inflammatory, and psoriatic diseases with heterocyclic aminoalkyl esters of mycophenolic acid and derivatives
US5455045 *May 13, 1993Oct 3, 1995Syntex (U.S.A.) Inc.High dose formulations
US5472707 *May 9, 1994Dec 5, 1995Syntex (U.S.A.) Inc.High dose ranolazine formulations
US6025391 *Apr 10, 1997Feb 15, 2000Novartis AgEnteric-coated pharmaceutical compositions of mycophenolate
US6172107Dec 22, 1999Jan 9, 2001Novartis AgEntric-coated pharmaceutical compositions
US6306900Oct 23, 2000Oct 23, 2001Novartis AgEnteric coated pharmaceutical compositions
US6471980Feb 13, 2001Oct 29, 2002Avantec Vascular CorporationIntravascular delivery of mycophenolic acid
US6641611Nov 26, 2001Nov 4, 2003Swaminathan JayaramanTherapeutic coating for an intravascular implant
US6858221Sep 11, 2002Feb 22, 2005Avantec Vascular CorporationIntravascular delivery of mycophenolic acid
US7077859Dec 14, 2001Jul 18, 2006Avantec Vascular CorporationApparatus and methods for variably controlled substance delivery from implanted prostheses
US7083642Jul 25, 2002Aug 1, 2006Avantec Vascular CorporationDelivery of therapeutic capable agents
US20030139801 *Jul 25, 2002Jul 24, 2003Avantec Vascular CorporationDelivery of therapeutic capable agents
US20050107869 *Dec 9, 2004May 19, 2005Avantec Vascular CorporationApparatus and methods for controlled substance delivery from implanted prostheses
US20050125054 *Nov 19, 2004Jun 9, 2005Avantec Vascular CorporationDevices delivering therapeutic agents and methods regarding the same
US20050131532 *Dec 10, 2004Jun 16, 2005Avantec Vascular CorporationApparatus and methods for controlled substance delivery from implanted prostheses
US20050203612 *Jun 27, 2003Sep 15, 2005Avantec Vascular CorporationDevices delivering therapeutic agents and methods regarding the same
US20060106453 *Dec 13, 2005May 18, 2006Avantec Vascular CorporationDelivery of therapeutic capable agents
US20060212109 *May 19, 2006Sep 21, 2006Avantec Vascular CorporationDelivery of therapeutic capable agents
Classifications
U.S. Classification536/18.1, 514/863
International ClassificationC07H17/04
Cooperative ClassificationC07H17/04, Y10S514/863
European ClassificationC07H17/04