EP0549727A1 - Rapamycin carbonsäureester - Google Patents
Rapamycin carbonsäureesterInfo
- Publication number
- EP0549727A1 EP0549727A1 EP19910919248 EP91919248A EP0549727A1 EP 0549727 A1 EP0549727 A1 EP 0549727A1 EP 19910919248 EP19910919248 EP 19910919248 EP 91919248 A EP91919248 A EP 91919248A EP 0549727 A1 EP0549727 A1 EP 0549727A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- alkyl
- rapamycin
- compound
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to novel esters of rapamycin and a method for using them in the treatment of transplantation rejection, host vs. graft disease, autoimmune diseases, diseases of inflammation, and fungal infections.
- Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus. which was found to have antifungal activity, particularly against Candida albicans. both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S.N. Seghal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Patent 3,929,992; and U.S. Patent 3,993,749].
- Rapamycin alone (U.S. Patent 4,885,171) or in combination with picibanil (U.S. Patent 4,401,653) has been shown to have antitumor activity.
- R. Mattel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies.
- rapamycin has been shown to be effective in inhibiting transplant rejection (U.S. Patent Application Ser. No. 362,544 filed June 6, 1989).
- Cyclosporin A and FK-506, other macrocyclic molecules also have been shown to be effective as immunosuppressive agents, therefore useful in preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); and R. Y. Calne et al., Lancet 1183 (1978)].
- Mono- and diacylated derivatives of rapamycin (esterified at the 28 and 43 positions) have been shown to be useful as antifungal agents (U.S.
- Patent 4,316,885 and used to make water soluble prodrugs of rapamycin (U.S. Patent 4,650,803). Recently, the numbering convention for rapamycin has been changed; therefore according to Chemical Abstracts nomenclature, the esters described above would be at the 31- and 42- positions. DESCRIPTION OF THE INVENTION
- This invention provides derivatives of rapamycin which are useful as immunosuppressive, anti-inflammatory, and antifungal agents having the structure
- R 1 , R 2 > and R 3 are each, independently, hydrogen, or R 4 ;
- R 4 is -[C(CH 2 ) ni CH(CH 2 ) n N] p C0 2 R 7 , -C- (CH 2 ) t X(CH 2 ) u CO 2 R 11 , or
- R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
- R 6 and R 9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms;
- R 7 , R 8 , and R 10 are each, independently, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri- substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid;
- R 1 ! and R 12 are each, independently, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid;
- R 13 and R 14 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; Y is CH or N; m is 0 - 4; n is 0 - 4; p is 1 - 2 q is 0 - 4 r is 0 - 4; t is O - 4; u is 0 - 4;
- R5 R 6 subunits when p 2; or a pharmaceutically acceptable salt thereof, with the proviso that R 1 , R 2 * and R 3 are not all hydrogen, further provided that R 1 , R 2 - and R 3 are not all
- R 5 R 6 both 0 when X is O or S.
- R 4 is — [C(CH 2 ) m CH(CH 2 )-.N] p CO 2 R 7
- Preferred compounds also include those
- the pharmaceutically acceptable salts may be formed from inorganic cations such as sodium, potassium, and the like; mono-, di-, and trialkyl amines of 1-6 carbon atoms, per alkyl group and mono-, di-, and trihydroxyalkyl amines of 1-6 carbon atoms per alkyl group; and organic acids such as acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, and the like.
- Preferred basic salts are formed from sodium cations and tris(hydroxymethyl)methyl-.mine.
- the compounds of this invention can be prepared by acylating rapamycin with an acylating agent having the general structures
- the compounds of this invention also can be prepared using an anhydride or a mixed anhydride of the above described carboxylic acid as the acylating species.
- the acylating species can be an acid halide, where Z can be Cl, Br, or I.
- the acylating groups used to prepare the compounds of this invention are commercially available or can be prepared by methods that are disclosed in the literature.
- acyl derivatives having two or three different R 4 groups sequential acylation may be performed using appropriate acylating agents as defined above, if necessary isolating the desired product by appropriate purification techniques.
- the 42-position is acylated first and such a monoacylated product may be isolated prior to the second acylation and so forth.
- Appropriate protecting groups may be used to block any position where acylation is not required.
- Immunosuppressive activity was evaluated in an in vitro standard pharmacological test procedure to measure lymphocyte proliferation (LAF) and in two in vivo standard pharmacological test procedures.
- the first in vivo procedure was a popliteal lymph node (PLN) test procedure which measured the effect of compounds of this invention on a mixed lymphocyte reaction and the second in vivo procedure evaluated the survival time of a pinch skin graft.
- the comitogen-induced thymocyte proliferation procedure (LAF) was used as an in vitro measure of the immunosuppressive effects of representative compounds. Briefly, cells from the thymus of normal B ALB/c mice are cultured for 72 hours with PHA and IL-1 and pulsed with tritiated thymidine during the last six hours.
- Cells are cultured with and without various concentrations of rapamycin, cyclosporin A, or test compound. Cells are harvested and incorporated; radioactivity is determined. Inhibition of lymphoproliferation is assessed in percent change in counts per minute from non-drug treated controls. The results are expressed by the following ratio, or as the percent inhibition of lymphoproliferation of 1 ⁇ M. 3 H-control thvmus cells - H 3 -rapamvcin-treated thvmus cells
- a mixed lymphocyte reaction occurs when lymphoid cells from genetically distinct animals are combined in tissue culture. Each stimulates the other to undergo blast transformation which results in increased DNA synthesis that can be quantified by the incorporation of tritiated thymidine. Since stimulating a MLR is a function of disparity at Major Histocompatibility antigens, an in vivo popliteal lymph node (PLN) test procedure closely correlates to host vs. graft disease. Briefly, irradiated spleen cells from B ALB/c donors are injected into the right hind foot pad of recipient C3H mice. The drug is given daily, p.o. from Day 0 to Day 4.
- tritiated thymidine is given i.p., b.i.d.
- the hind popliteal lymph nodes are removed and dissolved, and radioactivity counted.
- the corresponding left PLN serves as the control for the PLN from the injected hind foot.
- Percent suppression is calculated using the non-drug treated animals as allogenic control. Rapamycin at a dose of 6 mg kg, p.o. gave 86% suppression, whereas cyclosporin A at the same dose gave 43% suppression.
- Results are expressed by the following ratio: 3 H-PLN cells control C3H mouse - 3 H-PLN cells rapamvcin-treated C3H mouse 3 H-PLN cells control C3H mouse - 3 H-PLN cells test compound-treated C3H mouse
- the second in vivo test procedure is designed to determine the survival time of pinch skin graft from male DBA/2 donors transplanted to male BALB/c recipients.
- the method is adapted from Billingham R.E. and Medawar P.B., J. Exp. Biol. 28:385- 402, (1951). Briefly, a pinch skin graft from the donor is grafted on the dorsum of the recipient as a homograft, and an autograft is used as control in the same region.
- the recipients are treated with either varying concentrations of cyclosporin A as test control or the test compound, intraperitoneally. Untreated recipients serve as rejection control.
- the graft is monitored daily and observations are recorded until the graft becomes dry and forms a blackened scab. This is considered as the rejection day.
- the mean graft survival time (number of days ⁇ S.D.) of the drug treatment group is compared with the control group.
- Antifungal activity of the compounds of this invention was measured against 5 strains of Candida albicans using a plate test procedure for measurement of inhibition. The following represents the typical procedure used. Compound to be tested was placed on sterile dried 1/4" plate disks, and allowed to dry. Agar plates were seeded with fungi and allowed to solidify. The impregnated disks were placed on the seeded Agar surface and incubated for the time required for the particular culture. Results are expressed in MIC ( ⁇ g/ml) to inhibit growth. The results of this test procedure showed that the compounds of this invention have antifungal activity; however, it was surprising that the compounds of this invention were less active than the parent compound, rapamycin.
- the compounds are useful in the treatment of transplantation rejection such as, heart, kidney, liver, bone marrow, and skin transplants; autoimmune diseases such as, lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and diseases of inflammation such as, psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease; and fungal infections.
- transplantation rejection such as, heart, kidney, liver, bone marrow, and skin transplants
- autoimmune diseases such as, lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis
- diseases of inflammation such as, psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease
- fungal infections e.g., osis, dermatitis, eczema, seborrhea,
- a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
- the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compound can also be administered orally either in liquid or solid composition form.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the dosage to be used in the treatment must be subjectively determined by the attending physician.
- the compounds of this invention may be employed as a solution, cream, or lotion by formulation with pharmaceutically acceptable vehicles containing 0.1- 5 percent, preferably 2%, of active compound which may be administered to a fungally affected area.
- the following representative compounds can be prepared from rapamycin and the appropriately terminally-N-substituted amino diacid monoester by employing the method used to prepare the title compound in Example 5.
- Example 11 HPLC analysis showed that the monoester is a 7.5 :1 mixture of two conformers.
- the title compound was prepared (0.83 g, 12.8%) along with the 42- monoester as described in Example 10. HPLC analysis showed that the diester is a 7.7:1 mixture of two conformers.
- Rapamycin-14,31,42-tris (monomethylsuccinate) Rapamycin-14,31,42-tris (monophenyl-3',3'-dimethylglutarate)
- Rapamycin-14,31,42-tris (mono t-butyl-3'-methylglutarate)
- Rapamycin-14,31,42-tris (monobenzylthiodiglycolate)
- Rapamycin-14,31,42-tris (monohexyldiglycolate)
- Rapamycin-14,31,42-tris (monopropylphthalate) Rapamycin-14,31,42-tris (monoethyl-2',6'-pyridinedicarboxylate) Example 15.
- Rapamycin-31 ,42-bis (monomethylsuccinate) Rapamycin-31 ,42-bis (monophenyl-3',3'-dimethylglutarate)
- Rapamycin-31,42-bis (mono t-butyl-3'-methylglutarate)
- Rapamycin-31 ,42-bis (monopropylphthalate) Rapamycin-31,42-bis (monoethyl-2',6'-pyridinedicarboxylate)
- the crude product was purified via reverse phase HPLC on a Cig column eluting starting with 60 % acetonitrile/water. Collected, after, concentration, 586 mg (24 %) of rapamycin-31, 42-bishemiglutarate. J H NMR (CDCI3.
- Rapamycin-31 ,42-bishemi-3'-methylglutarate Rapamycin-31 ,42-bishemi-3',3'-dimethylglutarate Rapamycin-31 ,42-bishemi-3'-oxoglutarate
- ion FAB 1112 (M-l, free acid), 994, 589, 475, 297, 167, 148, 117, 99 (100); High Res. MS (neg. ion FAB) Calcd for C6iH 8 9 ⁇ 9 NNa (M-Na) 1162.5926, Found 1162.5899.
- the crude product was purified via reverse phase HPLC on a Cis column eluting starting with 60 % acetonitrile/water. After concentration, 870 mg ( 26 %) of rapamycin-42-hemi-3'-oxoglutarate and 500 mg (13 %) of rapamycin-31,42-bishemi-3'oxoglutarate were isolated.
- the following representative compounds can be prepared from rapamycin and the appropriate half acid-ester by employing the method used to prepare the title compound in Example 20.
- the crude product was purified via reverse phase HPLC on a C ⁇ 8 column gradient eluting starting with 20 % acetonitrile/water to 60 % acetonitrile/water. Collected, after, concentration, 770 mg (31 %) of rapamycin-31,42-bishemisuccinate.
- the purified bis-31,42 hemisuccinate of rapamycin (770 mg, 686 umol) was dissolved in 10 mL of 95 % ethanol and 166 mg (1.37 mmol) of tris(hydroxymethyl)- methylamine was added. Water (1 mL) was added to completely dissolve the amine. Once dissolved, the yellow solution was concentrated in vacuo to give a foamy yellow solid. The very hygroscopic foam was dried in a drying pistol for 24 h, refluxing over acetone at reduced pressure to give 890 mg (95 %) of the bistromethamine salt. The bistromethane salt was evaluated in the standard pharmacological test procedures.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US58483390A | 1990-09-19 | 1990-09-19 | |
US584833 | 1990-09-19 | ||
US58987890A | 1990-09-28 | 1990-09-28 | |
US589878 | 1990-09-28 | ||
US657294 | 1991-02-19 | ||
US07/657,294 US5130307A (en) | 1990-09-28 | 1991-02-19 | Aminoesters of rapamycin |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0549727A1 true EP0549727A1 (de) | 1993-07-07 |
Family
ID=27416444
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19910919248 Ceased EP0549727A1 (de) | 1990-09-19 | 1991-09-19 | Rapamycin carbonsäureester |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0549727A1 (de) |
JP (1) | JPH06501012A (de) |
AU (1) | AU653175B2 (de) |
FI (1) | FI931203A0 (de) |
HU (1) | HUT65763A (de) |
IE (1) | IE913302A1 (de) |
MX (1) | MX9101139A (de) |
PT (1) | PT98990A (de) |
WO (1) | WO1992005179A1 (de) |
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DE69021833T2 (de) * | 1989-11-09 | 1996-03-21 | Sandoz Ag | Heteroatome enthaltende tricyclische Verbindungen. |
FI921595A (fi) * | 1991-04-17 | 1992-10-18 | American Home Prod | Rapamycinkarbamater |
US5262533A (en) * | 1991-05-13 | 1993-11-16 | Merck & Co., Inc. | Amino O-aryl macrolides having immunosuppressive activity |
US5565560A (en) * | 1991-05-13 | 1996-10-15 | Merck & Co., Inc. | O-Aryl,O-alkyl,O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
US5247076A (en) * | 1991-09-09 | 1993-09-21 | Merck & Co., Inc. | Imidazolidyl macrolides having immunosuppressive activity |
US5284877A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkyl and alkenyl macrolides having immunosuppressive activity |
US5284840A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkylidene macrolides having immunosuppressive activity |
ES2258763T3 (es) * | 1992-10-13 | 2006-09-01 | Wyeth | Carbamatos de rapamicina. |
US5262423A (en) * | 1992-10-29 | 1993-11-16 | American Home Products Corporation | Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents |
US5258389A (en) * | 1992-11-09 | 1993-11-02 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives |
US5260300A (en) | 1992-11-19 | 1993-11-09 | American Home Products Corporation | Rapamycin carbonate esters as immuno-suppressant agents |
US5310901A (en) * | 1993-03-05 | 1994-05-10 | Merck & Co., Inc. | O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynlheteroarylrapamycin derivatives |
US5310903A (en) * | 1993-03-05 | 1994-05-10 | Merck & Co., Inc. | Imidazolidyl rapamycin derivatives |
USRE40596E1 (en) * | 1993-04-08 | 2008-12-02 | Novartis Ag | Rapamycin assay |
GB9307491D0 (en) * | 1993-04-08 | 1993-06-02 | Sandoz Ltd | Organic compounds |
JPH08509499A (ja) * | 1993-04-23 | 1996-10-08 | アボツト・ラボラトリーズ | ラパマイシン結合体及び抗体 |
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WO1994025072A1 (en) * | 1993-04-23 | 1994-11-10 | American Home Products Corporation | Rapamycin conjugates and antibodies |
US5504091A (en) * | 1993-04-23 | 1996-04-02 | American Home Products Corporation | Biotin esters of rapamycin |
JP4105761B2 (ja) * | 1993-11-19 | 2008-06-25 | アボット・ラボラトリーズ | ラパミシン(マクロライド)の半合成類似体免疫調節剤 |
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WO1995016691A1 (en) * | 1993-12-17 | 1995-06-22 | Sandoz Ltd. | Rapamycin derivatives useful as immunosuppressants |
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US5362718A (en) * | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
US5693648A (en) * | 1994-09-30 | 1997-12-02 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity |
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US4316885A (en) * | 1980-08-25 | 1982-02-23 | Ayerst, Mckenna And Harrison, Inc. | Acyl derivatives of rapamycin |
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-
1991
- 1991-09-17 PT PT98990A patent/PT98990A/pt not_active Application Discontinuation
- 1991-09-18 MX MX9101139A patent/MX9101139A/es unknown
- 1991-09-19 JP JP3516749A patent/JPH06501012A/ja active Pending
- 1991-09-19 AU AU86599/91A patent/AU653175B2/en not_active Expired - Fee Related
- 1991-09-19 WO PCT/US1991/006824 patent/WO1992005179A1/en not_active Application Discontinuation
- 1991-09-19 EP EP19910919248 patent/EP0549727A1/de not_active Ceased
- 1991-09-19 IE IE330291A patent/IE913302A1/en unknown
- 1991-09-19 HU HU9300776A patent/HUT65763A/hu unknown
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1993
- 1993-03-18 FI FI931203A patent/FI931203A0/fi not_active Application Discontinuation
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HU9300776D0 (en) | 1993-06-28 |
MX9101139A (es) | 1992-05-04 |
HUT65763A (en) | 1994-07-28 |
AU653175B2 (en) | 1994-09-22 |
WO1992005179A1 (en) | 1992-04-02 |
FI931203A (fi) | 1993-03-18 |
IE913302A1 (en) | 1992-02-25 |
PT98990A (pt) | 1992-08-31 |
AU8659991A (en) | 1992-04-15 |
JPH06501012A (ja) | 1994-01-27 |
FI931203A0 (fi) | 1993-03-18 |
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