US3903071A - Mycophenolic acid derivatives - Google Patents

Mycophenolic acid derivatives Download PDF

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Publication number
US3903071A
US3903071A US362700A US36270073A US3903071A US 3903071 A US3903071 A US 3903071A US 362700 A US362700 A US 362700A US 36270073 A US36270073 A US 36270073A US 3903071 A US3903071 A US 3903071A
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Prior art keywords
methyl
methoxy
oxo
compound
phthalanyl
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Expired - Lifetime
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US362700A
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English (en)
Inventor
Richard E Holmes
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Eli Lilly and Co
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Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to US362700A priority Critical patent/US3903071A/en
Priority to ZA00742417A priority patent/ZA742417B/xx
Priority to IE806/74A priority patent/IE39218B1/xx
Priority to CA197,708A priority patent/CA1027558A/en
Priority to AU68027/74A priority patent/AU479485B2/en
Priority to PH15753A priority patent/PH10898A/en
Priority to IL44670A priority patent/IL44670A/en
Priority to GB1858374A priority patent/GB1465008A/en
Priority to CH613674A priority patent/CH603681A5/xx
Priority to NL7406542A priority patent/NL7406542A/xx
Priority to DE2424119A priority patent/DE2424119A1/de
Priority to FR7417688A priority patent/FR2230361B1/fr
Priority to PL1974171297A priority patent/PL89967B1/pl
Priority to SU7402026935A priority patent/SU578006A3/ru
Priority to ES426543A priority patent/ES426543A1/es
Priority to BE1005977A priority patent/BE815330A/xx
Priority to HUEI550A priority patent/HU169191B/hu
Priority to AT421274A priority patent/AT337892B/de
Priority to DD178682A priority patent/DD113544A5/xx
Priority to RO7478897A priority patent/RO68642A/ro
Priority to AR253880A priority patent/AR201234A1/es
Priority to CS743663A priority patent/CS187435B2/cs
Priority to BG026761A priority patent/BG25994A3/xx
Priority to JP49058339A priority patent/JPS5019747A/ja
Application granted granted Critical
Publication of US3903071A publication Critical patent/US3903071A/en
Priority to SE7908625A priority patent/SE7908625L/xx
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms

Definitions

  • 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
  • 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.
  • the cells of the epidermis grow and multiply up to seven times faster than do normal epidermis cells.
  • 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.
  • 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
  • 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)].
  • R represents OH, loweralkoxy of 1 to 5 carbon atoms, or amido
  • 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.
  • 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.
  • the Koenigs-Knorr synthetic method H. Krauch and W. Kunz, Organic Name Reactions, John Wiley and Sons, New York,' N.Y., 1964, p. 314
  • 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 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.
  • the reaction is carried out in the presence of a polar aprotic solvent such as, for example, dimethylformamide.
  • 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.
  • 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.
  • a solvent such as xylene or toluene, cooling for several hours.
  • Xylene is especially suitable because it forms a conveniently-removed azeotrope with dimethylformamide.
  • 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.
  • 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 can be further. reacted to obtain the-corresponding, specified alkali-metal and alkaline-earth-metal salts.
  • the above-mentioned acid is reacted slowly with a stoichiometric amount of a suitable base, generally without heating, to obtain the corresponding salt.
  • 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.
  • 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.
  • 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.
  • Table II illustrates the usefulness of various Formula I compounds wherein R is B-D-glucopyranosyl against a variety of tumor systems.
  • Table III further illustrates the antitumor activity of two Formula I compounds wherein R is ,B-D- glucopyranosyl against two leukemia systems.
  • the compounds of Formula I wherein R represents (a) thorugh (g) may be administered either orally or parenterally.
  • 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.
  • the compounds of Formula I wherein R represents (a) through (g) are useful in the treatment of psoriasis.
  • a specified Formulal compound can be administered to a human suffering from psoriasis orally, parenterally or topically.
  • an amount of specified Formula I compound effective for treating psoriasis is applied directly .to the psoriatic lesion.
  • 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:
  • Formula I compound 200 mg starch 400 mg specified Formula I compound 200 mg starch
  • the compounds of the present invention 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:
  • 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.
  • 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.
  • the compounds of Formula I wherein R represents (a) through (g) are useful in the treatment of hyperuricemia.
  • a specified Formula I compound is administered either orally or parenterally to a human with an elevated serum uric acid level.
  • 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.
  • the sodium and potassium salts are especially useful.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • EXAMPLE 2 Ethyl 6-[4-( ,B-D-glucopyranosyl )-6-methoxy-7-methyl-3- oxo-5-phthalanyl]-4-methyl-4-hexenoate
  • 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.
  • 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.
  • EXAMPLE 6 Ethyl 6- 4-( ,B-D-galactopyranosyl )-6-methoxy-7-methyl-3- oxo-5-phthalanyl ]-4-methyl-4-hexenoate
  • 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.

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US362700A 1973-05-22 1973-05-22 Mycophenolic acid derivatives Expired - Lifetime US3903071A (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
US362700A US3903071A (en) 1973-05-22 1973-05-22 Mycophenolic acid derivatives
ZA00742417A ZA742417B (en) 1973-05-22 1974-04-06 Mycophenolic acid derivatives
IE806/74A IE39218B1 (en) 1973-05-22 1974-04-17 Mycophenolic acid derivatives
CA197,708A CA1027558A (en) 1973-05-22 1974-04-17 Mycophenolic acid derivatives
AU68027/74A AU479485B2 (en) 1973-05-22 1974-04-18 Mycophenolic acid derivatives
PH15753A PH10898A (en) 1973-05-22 1974-04-19 Mycophenolic acid derivatives
IL44670A IL44670A (en) 1973-05-22 1974-04-19 History of mycophenolic acid
GB1858374A GB1465008A (en) 1973-05-22 1974-04-29 Mycophenolic acid deriv atives
CH613674A CH603681A5 (enrdf_load_stackoverflow) 1973-05-22 1974-05-06
NL7406542A NL7406542A (enrdf_load_stackoverflow) 1973-05-22 1974-05-15
DE2424119A DE2424119A1 (de) 1973-05-22 1974-05-17 Mycophenolsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
SU7402026935A SU578006A3 (ru) 1973-05-22 1974-05-21 Способ получени производных микофенольной кислоты
FR7417688A FR2230361B1 (enrdf_load_stackoverflow) 1973-05-22 1974-05-21
ES426543A ES426543A1 (es) 1973-05-22 1974-05-21 Un procedimiento para la preparacion de nuevos derivados deacido micofenolico.
BE1005977A BE815330A (fr) 1973-05-22 1974-05-21 Derives de l'acide mycophenolique
HUEI550A HU169191B (enrdf_load_stackoverflow) 1973-05-22 1974-05-21
AT421274A AT337892B (de) 1973-05-22 1974-05-21 Verfahren zur herstellung von neuen mycophenolsaurederivaten
PL1974171297A PL89967B1 (enrdf_load_stackoverflow) 1973-05-22 1974-05-21
RO7478897A RO68642A (ro) 1973-05-22 1974-05-22 Procedeu pentru prepararea unor derivati de acid micofenolic
DD178682A DD113544A5 (enrdf_load_stackoverflow) 1973-05-22 1974-05-22
AR253880A AR201234A1 (es) 1973-05-22 1974-05-22 Procedimiento para preparar aldosas derivados del acido micofenolico
CS743663A CS187435B2 (en) 1973-05-22 1974-05-22 Process for preparing derivatives of mycophenolic acid
BG026761A BG25994A3 (bg) 1973-05-22 1974-05-22 Метод за получаване на производни на микофенолната киселина
JP49058339A JPS5019747A (enrdf_load_stackoverflow) 1973-05-22 1974-05-22
SE7908625A SE7908625L (sv) 1973-05-22 1979-10-17 Acetylglykosylmykofenolsyraforeningar for framstellning av glykosylmykofenolsyraforeningar

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US (1) US3903071A (enrdf_load_stackoverflow)
JP (1) JPS5019747A (enrdf_load_stackoverflow)
AR (1) AR201234A1 (enrdf_load_stackoverflow)
AT (1) AT337892B (enrdf_load_stackoverflow)
BE (1) BE815330A (enrdf_load_stackoverflow)
BG (1) BG25994A3 (enrdf_load_stackoverflow)
CA (1) CA1027558A (enrdf_load_stackoverflow)
CH (1) CH603681A5 (enrdf_load_stackoverflow)
CS (1) CS187435B2 (enrdf_load_stackoverflow)
DD (1) DD113544A5 (enrdf_load_stackoverflow)
DE (1) DE2424119A1 (enrdf_load_stackoverflow)
ES (1) ES426543A1 (enrdf_load_stackoverflow)
FR (1) FR2230361B1 (enrdf_load_stackoverflow)
GB (1) GB1465008A (enrdf_load_stackoverflow)
HU (1) HU169191B (enrdf_load_stackoverflow)
IE (1) IE39218B1 (enrdf_load_stackoverflow)
IL (1) IL44670A (enrdf_load_stackoverflow)
NL (1) NL7406542A (enrdf_load_stackoverflow)
PH (1) PH10898A (enrdf_load_stackoverflow)
PL (1) PL89967B1 (enrdf_load_stackoverflow)
RO (1) RO68642A (enrdf_load_stackoverflow)
SE (1) SE7908625L (enrdf_load_stackoverflow)
SU (1) SU578006A3 (enrdf_load_stackoverflow)
ZA (1) ZA742417B (enrdf_load_stackoverflow)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4103006A (en) * 1976-05-20 1978-07-25 Wisconsin Alumni Research Foundation Glycosides of 2,6-bis(hydroxy-phenyl)-3,7-dioxabicyclo [3,3,0] octane
US4686234A (en) * 1985-11-27 1987-08-11 Syntex (U.S.A) Inc. Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis
US4725622A (en) * 1986-01-23 1988-02-16 Syntex (U.S.A.) Inc. Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4868153A (en) * 1987-01-30 1989-09-19 Syntex (U.S.A.) Inc. Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US5098899A (en) * 1989-03-06 1992-03-24 Trustees Of Boston University Method for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites
US5177072A (en) * 1987-01-30 1993-01-05 Syntex (U.S.A.) Inc. Treatment of autoimmune inflammatory, and psoriatic diseases with heterocyclic aminoalkyl esters of mycophenolic acid and derivatives
US5455045A (en) * 1993-05-13 1995-10-03 Syntex (U.S.A.) Inc. High dose formulations
US6025391A (en) * 1996-04-12 2000-02-15 Novartis Ag Enteric-coated pharmaceutical compositions of mycophenolate
US6471980B2 (en) 2000-12-22 2002-10-29 Avantec Vascular Corporation Intravascular delivery of mycophenolic acid
US20030139801A1 (en) * 2000-12-22 2003-07-24 Avantec Vascular Corporation Delivery of therapeutic capable agents
US6641611B2 (en) 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
US20050107869A1 (en) * 2000-12-22 2005-05-19 Avantec Vascular Corporation Apparatus and methods for controlled substance delivery from implanted prostheses
US20050125054A1 (en) * 2000-12-22 2005-06-09 Avantec Vascular Corporation Devices delivering therapeutic agents and methods regarding the same
US20050203612A1 (en) * 2000-12-22 2005-09-15 Avantec Vascular Corporation Devices delivering therapeutic agents and methods regarding the same
US20060106453A1 (en) * 2000-12-22 2006-05-18 Avantec Vascular Corporation Delivery of therapeutic capable agents
US20060212109A1 (en) * 2001-02-13 2006-09-21 Avantec Vascular Corporation Delivery of therapeutic capable agents

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5414176Y2 (enrdf_load_stackoverflow) * 1971-05-31 1979-06-13
JPH0736475Y2 (ja) * 1987-05-14 1995-08-16 阪神エレクトリック株式会社 インバ−タ装置

Citations (1)

* Cited by examiner, † Cited by third party
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US3758455A (en) * 1970-05-14 1973-09-11 Chugai Pharmaceutical Co Ltd Reof mycophenolic acid glucuronide and the process for the preparation the

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3758455A (en) * 1970-05-14 1973-09-11 Chugai Pharmaceutical Co Ltd Reof mycophenolic acid glucuronide and the process for the preparation the

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4103006A (en) * 1976-05-20 1978-07-25 Wisconsin Alumni Research Foundation Glycosides of 2,6-bis(hydroxy-phenyl)-3,7-dioxabicyclo [3,3,0] octane
US4686234A (en) * 1985-11-27 1987-08-11 Syntex (U.S.A) Inc. Mycophenolic acid derivatives in the treatment of inflammatory diseases, in particular rheumatoid arthritis
US4725622A (en) * 1986-01-23 1988-02-16 Syntex (U.S.A.) Inc. Mycophenolic acid derivatives in the treatment of rheumatoid arthritis
US4868153A (en) * 1987-01-30 1989-09-19 Syntex (U.S.A.) Inc. Treatment of allograft rejection with mycophenolic acid, its morpholinoethylester and derivatives thereof
US4948793A (en) * 1987-01-30 1990-08-14 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
US4952579A (en) * 1987-01-30 1990-08-28 Syntex (U.S.A.) Inc. Method of treating diseases by administering morpholino-ethylester of mycophenolic acid or derivatives thereof
US4992467A (en) * 1987-01-30 1991-02-12 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with mycophenolic acid, and derivatives and formulations thereof
US5177072A (en) * 1987-01-30 1993-01-05 Syntex (U.S.A.) Inc. Treatment of autoimmune inflammatory, and psoriatic diseases with heterocyclic aminoalkyl esters of mycophenolic acid and derivatives
US5098899A (en) * 1989-03-06 1992-03-24 Trustees Of Boston University Method for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites
US5455045A (en) * 1993-05-13 1995-10-03 Syntex (U.S.A.) Inc. High dose formulations
US5472707A (en) * 1993-05-13 1995-12-05 Syntex (U.S.A.) Inc. High dose ranolazine formulations
US6172107B1 (en) 1996-04-12 2001-01-09 Novartis Ag Entric-coated pharmaceutical compositions
US6025391A (en) * 1996-04-12 2000-02-15 Novartis Ag Enteric-coated pharmaceutical compositions of mycophenolate
US6306900B1 (en) 1996-04-12 2001-10-23 Novartis Ag Enteric coated pharmaceutical compositions
US20050107869A1 (en) * 2000-12-22 2005-05-19 Avantec Vascular Corporation Apparatus and methods for controlled substance delivery from implanted prostheses
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BE815330A (fr) 1974-11-21
BG25994A3 (bg) 1979-01-12
CA1027558A (en) 1978-03-07
CH603681A5 (enrdf_load_stackoverflow) 1978-08-31
CS187435B2 (en) 1979-01-31
SE7908625L (sv) 1979-10-17
ZA742417B (en) 1975-11-26
IE39218B1 (en) 1978-08-30
PL89967B1 (enrdf_load_stackoverflow) 1976-12-31
AU6802774A (en) 1975-10-23
NL7406542A (enrdf_load_stackoverflow) 1974-11-26
AR201234A1 (es) 1975-02-21
DD113544A5 (enrdf_load_stackoverflow) 1975-06-12
GB1465008A (en) 1977-02-16
JPS5019747A (enrdf_load_stackoverflow) 1975-03-01
ES426543A1 (es) 1976-07-01
IE39218L (en) 1974-11-22
FR2230361B1 (enrdf_load_stackoverflow) 1977-01-28
RO68642A (ro) 1980-06-15
SU578006A3 (ru) 1977-10-25
FR2230361A1 (enrdf_load_stackoverflow) 1974-12-20
DE2424119A1 (de) 1974-12-12
ATA421274A (de) 1976-11-15
PH10898A (en) 1977-09-30
AT337892B (de) 1977-07-25
IL44670A0 (en) 1974-06-30
HU169191B (enrdf_load_stackoverflow) 1976-10-28
IL44670A (en) 1977-08-31

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