PT98990A - Process for the preparation of carboxylic acid esters of rapamicin - Google Patents

Process for the preparation of carboxylic acid esters of rapamicin Download PDF

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Publication number
PT98990A
PT98990A PT9899091A PT9899091A PT98990A PT 98990 A PT98990 A PT 98990A PT 9899091 A PT9899091 A PT 9899091A PT 9899091 A PT9899091 A PT 9899091A PT 98990 A PT98990 A PT 98990A
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carbon atoms
ch
alkyl
rapamycin
pharmaceutically acceptable
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PT9899091A
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Portuguese (pt)
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Craig Eugene Caufield
Amedeo Arturo Failli
Robert John Steffan
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American Home Prod
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Priority to US58987890A priority
Priority to US07/657,294 priority patent/US5130307A/en
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Publication of PT98990A publication Critical patent/PT98990A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic 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
    • C07D498/18Bridged systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Description

BACKGROUND OF THE INVENTION:

This invention relates to novel esters of rapamycin and a method for their use in the treatment of transplant rejection, host versus graft disease, autoimmune diseases, inflammatory diseases, and fungal infections. Rapamycin is a macrocyclic triene antibiotic produced by Streptomoves hroscrousus. which has been found to have antifungal activity, particularly against Candida albicans. both in vitro and in vivo [. Vezina et al., J. Antibiot. 28, 721 (1975); S.N. Seghal et al., J. Antibiot. 28, 727 (1975); Aaker et al., J. Antibiot. 31, 539 (1978); U.S. Patent No. 3,929,992; and U.S. Patent No. 3,993,749]. Rapamycin alone (U.S. Patent No. 4,885,171) or in combination with picibanil (U.S. Patent No. 4,401,653) has been shown to have antitumor activity. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] indicated 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.

The immunosuppressive effects of rapamycin were reported in FASEB 3, 3411 (1989), with the disclosed rapamycin being effective in inhibiting transplant rejection (U.S. Patent Application Serial No. 362,544 filed June 6, 1989). Cyclosporin A and FK-506, other macrocyclic molecules, have also been shown to be effective as immunosuppressive agents, thus being useful in preventing transplant rejection [FASEB 4 3.3411 (1989); FASEB 3, 5256 (1989); and R.Y. Calne et al., Lancet 1183 (1978)].

Mono- and diacylated derivatives of rapamycin (esterified at positions 28 and 43) have been found to be useful as antifungal agents (U.S. Patent No. 4,316,885) and were used to produce water soluble prodamates of rapamycin (U.S. Patent No. 4,650,803). Recently, the conventional numbering for rapamycin has been altered; thus according to the Chemical Abstracts nomenclature, the esters described above would be at positions 31 and 42. DESCRIPTION OF THE INVENTION:

This invention provides derivatives of rapamycin which are useful as immunosuppressive, anti-inflammatory, and anti-fungal agents having the structure

in which or 1? 3. R 2, R 3 and R 4 are each independently hydrogen,

(CH 2) m CH (CH 2) n N] p CO 2 R 7, or wherein R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkyl; R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 8 q In 7-10 carbon atoms, - (CH 2) g CC> 2R, - (CH 2) r NR CO 2 R, carbamyl alkyl of 2-3 atoms of carbon, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl , hydroxyphenylmethyl, imidazolylmethyl 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; 6 9. . . R and R are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 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 2 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from 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; X is R13 X is -C-, O, O; R14 or R13 and R14 are each independently hydrogen hydrogen 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 0-4; u is 0-4; Wherein R, R, m and n are independent at each of the subunits ο

II

[C (CH 2) m CH (CH 2) n N] R 5 R 6 when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R 1, R 2 and R 3 are not all hydrogen, yet with the proviso of 1.23. that R, R and R are not all 0

(CH2) m CH (CH2) n N] pC02 R7 R5 R5 and further with another proviso that thy are not both 0 when X is 0 or S. 4 "

Of the compounds in which R and ο

II - [C (CH 2) m CH (CH 2) n N] p CO 2 R 7

R 5 = R 6 = 1; M = n = 0; and R 5 Preferred member compounds are those wherein m = 0, n = 0, and 5, 8, n = 0, eps = 2, n = 0, and R e - (CH) m = 0, Q 1 Λ " 3 " and R is hydrogen, preferred also include those members wherein R 4 is 0 - (CH 2) t X (CH 2) u CO 2 R 11.

Pharmaceutically acceptable salts may be formed from inorganic cations such as sodium, potassium, etc .; 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, etc. Preferred basic salts are formed from sodium and tris (hydroxymethyl) methylamine cations.

The compounds of this invention may be prepared by acylation of rapamycin with an acylating agent having general structures

Wherein X is OH in the presence of (C 1 -C 4) alkyl, or a pharmaceutically acceptable salt thereof, a coupling reagent, such as dicyclohexylcarbodiimide. The compounds of this invention may also be prepared using a mixed carboxylic acid anhydride described above as the acylating species. Alternatively, the acylating species may be an acid halide where X may 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 which are presented in the literature. Immunosuppressive activity was evaluated in an in vitro standardized pharmacological test procedure to measure lymphocyte proliferation (LAF) and in two in vivo standardized 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 tight skin graft. The process of comitogen-induced thymocyte proliferation (LAF) was used as an in vitro measurement of the effects 11

immunosuppressants of representative compounds. Briefly, thymus cells from normal BALB / c mice are cultured for 72 hours with PHA and IL-1 and subjected to 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; the radioactivity is determined. Inhibition of lymphocyte proliferation is evaluated in percent change in counts per minute relative to controls not treated with the drug. The results are expressed by the following relationship, or as the percent inhibition of lymphocyte proliferation of 1 μΜ. ". 3. 3. . thymus cells control H - treated thymus cells H -rapamycin 3 3

Thymus control cells H - treated cells ciomposite H test

A mixed lymphocyte reaction (MLR) occurs when lymphoid cells from genetically distinct animals are combined in tissue culture. Each stimulates the other so as to develop to blastula which results in an increase in DNA synthesis that can be quantified by the incorporation of tritiated thymidine. Since stimulation of an MLR is a disparity function in Major Histocompatibility antigens, a popliteal lymph node (PLN) test in vivo correlates closely with host versus graft disease. Briefly, spleen cells irradiated from BALB / c donors are injected into the right hind paw pad of recipient C3H mice. The drug is administered daily, per day from Day 0 to Day 4. On Day 3 and Day 4, tritiated thymidine is administered i.p., b.i. .. On Day 5, the polypeptide lymph nodes are removed and dissolved, and the radioactivity is measured. The corresponding left PLN serves as control for the PLN of the injected hindpaw. Percent suppression is calculated using non-drug treated animals as allogeneic control. Rapamycin at a dose of 6 mg / kg, p.o. gave 86% suppression, while cyclosporin A at the same dose gave 43% suppression. The results are expressed by the following relation:

Mouse C3H control cells ^ H-PLN - mouse C3H treated rapamycin cells% -PLN mouse C3H control cells ^ H-PLN- Treated mouse - compound cells ^ H-PLN The second in vivo test procedure is to determine the survival time of the tightening skin graft from male DBA / 2 donors transplanted into male BALB / c containers. The method is adapted from Billingham R.E. and Medawar P.B., J. Exp. Biol. 28: 385-402, (1951). Briefly, a graft skin graft from the donor is grafted onto the back of the recipient as a homograft, and a self-grafting is used in the same region as control. The containers are treated either with various concentrations of cyclosporin A as test control or with the test compound, intraperitoneally. Untreated containers serve as control of rejection. The graft is monitored daily and observations are recorded until the graft becomes dry and forms a darkened crust. This is considered as the day of rejection. The mean graft survival time (number of days ± S.D.) of the drug treatment group is compared with that of the control group. The table below summarizes the results of representative compounds of this invention in these standardized test procedures. TABLE 1 LAF PLN Graft Skin Composite (rate) (rate) (days + SD) Example 1 1.8 0.61 12.0 ± 1.6 Example 2 0.33 0.62 11.5 + 0.6 Example 3 0.20 ± 9.0 ± 0.9 Example 4 4.9 0.18 12.3 ± 0.5 Example 5 0.006 + 8.8 ± 0.9 Example 6 5.4 0.33 11.5 ± 3.5 Example 7 3% a ΙμΜ ** + 7.7 + 1.5 Example 8 0.03 0.41 + Example 9 0.96 1.34 10.3 ± 0.8 Example 10 2.0 0.96 ++ 12.7 ± 1.2 Example 11 0.004 + 10.5 ± 1.3 Example 12 19.8 -2.87 12.0 ± 2.0 Example 13 22% a ΙμΜ + 7.0 ± 0.6 Example 14 0.37 + 8.2 ± 1.2 Example 15 0.9 0.69 10.7 ± 1.2 14 14

TABLE 1 (Continued) LAF PLN Compound Skin Graft (taxai (taxai (days + SD1) Example 16 3.27 1/04 ## 12.7 + 0.9 Example 17 0.56 1.68 ### 10.2 ± 1.7 Example 18 0.02 1.11 ## 8.0 ± 1.7 Example 19 0.01 0.48 8.0 ± 0.9 Example 20 0.97 0.70 9.3 ± 1.6 Example 21 0.22 -1.93 12.0 ± 1.7 Example 22 0.22 0.41 10.2 ± 1.2 Example 23 0.18 0.39 10.8 ± 0.8 Example 24 0, 00 0.09 7.8 ± 1.7 Rapamycin 1/0 1.0 12.0 ± 1.7 * Calculation of the rates was described supra. ** Result expressed as percent inhibition of lymphocyte proliferation at ΙμΜ Not evaluated ++ Results obtained using cremofore / ethanol as a delivery vehicle Rates of 0.33 and 1.07 were also obtained using carboxymethylcellulose as a vehicle for administration. and 1.08 were also obtained using carboxymethyl cellulose as a vehicle for administration. A rate of 0.42 was also obtained for this compound.

The results of these standard pharmacological test procedures demonstrate immunosuppressive activity both in vitro and in vivo for the compounds of this invention. Rates 15 4

relative in the LAF and PLN test procedures indicate suppression of T cell proliferation. As transplanted tightening skin grafts are rapidly discarded within 6-7 days without the use of an immunosuppressive agent, the increased survival time of the graft skin when treated with the compounds of this invention further demonstrates their utility as immunosuppressive agents. While it appears that the compound shown in Examples 12 and 21 can cause proliferation of T cells in the PLN test procedure, it is believed that a negative rate in this test procedure coupled with an increased survival time observed in the skin graft test procedure indicates a proliferation of " mvA " A > T cells, which are

(See, I. Roitt et al., Immunology, C.V. Moseby Co. 1989, p 12.8-12.11). The antifungal activity of the compounds of this invention was measured against 5 strains of Candida albicans using a plate test method for inhibition measurement. The following represents the typical process used. The compound to be tested was placed on 1/4 plate discs " dried with sterilization, and allowed to dry. Agar plates were seeded with fungi and allowed to solidify. The impregnated discs were placed on the seeded agar surface and incubated for the time required for a given culture. Results are expressed as MIC (μg / ml) to inhibit growth. The results of this test procedure revealed that the compounds of this invention possess antifungal activity; however, it was surprising that the compounds of this invention are less active than the like compound, rapamycin.

. *

Table 2

Strain of Candida albicans

Compound ATCC 10231 ATCC 38246 ATCC 38247 ATCC 38248 3669 Example 1> 0.4> 0.4> 0.4> 0.4 0.4 Example 2 0.1 0.2 0.2 0.2 0 , 1 Example 3 0.4 &gt; 0.4 &gt; 0.4 &gt; 0.4 0.4 Example 4 0.1 0.4 0.1 0.1 0.2 Example 5 &gt; 0.4 &gt; > 0.4> 0.4> 0.4> 0.4 Example 6 0.1 &gt; 0.4 0.2 0.4 &gt; 0.4 Example 7 + &gt; > 0.4> 0.4> 0.4> 0.4> 0, Example 9 0.4> 0.4 0.4> 0.4 <0, Example 10 0.2 > 0.4 0.2 0.4 0, Example 11> 0.4> 0.4> 0.4> 0.4> 0, Example 12 0.2> 0.4 , 1 0.2 0, Example 13> 0.4> 0.4> 0/4> 0.4> 0, Example 14> 0.4> 0.4> 0.4 &gt; 0.4 &gt; 0, Example 15 &gt; 0.4 &gt; 0.4 &lt; 0.4 &gt; 0, Example 16 &lt; 0.2 &gt; , 4 0.2 &gt; 0.4-0.0, Example 18 0.4 &gt; 0.4 &gt; 0.4 &gt; 0.4 &gt; 0, Example 19 0.4 &gt; 0.4 , 4 &gt; 0.4 &gt; 0.17

Table 2 (Continued)

Strain of Candida albicans Comoosto ATCC 10231 ATCC 38246 ATCC 38247 ATCC 38248 3669 Example 20 0.1 0.4 0.1 0.1 0.2 Example 21 0.4 &gt; 0.4 &gt; 0.4 &gt;; 0.4 Example 22 0.2 &gt; 0.4 0.2 0.4 &gt; 0.4 Example 23 0.1 &gt; 0.4 0.2 0.4 &gt; 0.4 Example 24 &gt; 0.4 &gt; 0.4 &gt; 0.4 &gt; 0.4 &gt; 0.4 Rapamycin 0.003 0.025 0.003 0.006 0.025 expressed non-titrated MIC &gt;

Based on the results of these pharmacological test procedures, the compounds are useful in the treatment of rejection of transplants such as heart, kidney, liver, bone marrow, and skin transplants; of autoimmune diseases such as, lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and inflammatory diseases such as psoriasis, dermatitis, eczema, seborrhoea, inflammatory bowel disease; and fungal infections.

The compounds may be administered neat or with a pharmaceutical carrier to a mammal in need of such treatment. The pharmaceutical carrier may be solid or liquid.

A solid carrier may 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; may also

be an encapsulating material. In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in appropriate proportions and pressed into the desired size and shape. 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, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ions.

Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both pharmaceutically acceptable oils and fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers and osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as mentioned above, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example, coconut oil and fractionated arachis oil). For parenteral administration, the carrier may 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 19 for pressurized compositions may be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. The compound may also be administered orally in a liquid or solid composition form.

Preferably, the pharmaceutical composition is in unit dosage form, for example in the form of tablets or capsules. In that form, the composition is subdivided into a unit dose containing appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example, prepackaged powders, vials, ampoules, pre filled syringes or sachets containing liquids. The unit dosage form may be, for example, itself a capsule or tablet, or may be the appropriate number of any such compositions in packaged form. The dose to be used for treatment should be determined subjectively by the attending physician.

In addition, the compounds of this invention may be used as a solution, cream, or lotion by formulation with pharmaceutically acceptable carriers containing 0.1-5 percent, preferably 2%, active compound that can be administered to a surface affected by fungi.

The following examples illustrate the preparation of representative compounds of this invention. EXAMPLE 1 Ester-42-Rapamycin with N-β- (1,1-dimethylethoxylcarbonyl) -cyclicquinoline

Under anhydrous conditions, a solution of rapamycin (3 g, 3.28 mmol) and N - [(1,1-dimethylethoxy) carbonyl] glycylglycine (3.04 g, 13.1 mmol) in anhydrous dichloromethane (40 mL) (1.35 g, 6.56 mmol) followed by 4-dimethylaminopyridine (0.8 g, 6.56 mmol). After stirring at room temperature for 48 hours, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were absorbed directly onto Merck silica gel 60 by addition of the gel and evaporation to dryness. Light chromatography of the preabsorbed material (using gradient elution with 2: 1 to 1: 0 v / v ethyl acetate-toluene) afforded 1.05 g (28.3%) of the title compound isolated as a solvate three quarts of toluene together with the diester 31.42 of Example 2. HPLC analysis revealed that the monoester is an 8.3: 1 mixture of two confections. 1H NMR (CDCl3, 400 MHz): δ 1.46 (m, 9H, COOBut), 1.654 (s, 3H), CH3C = C), 1.751 (s, 3H, CH3C = C), 3.14 (s, 3H), 3.33 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.18 (d, 1H, CHOH), 4.75 (m, 1H, CHO), 4.79 (s, 1H, OH); MS Elev. Sep. (FAB ion neg.) Calc. for c60H39N3O17: 1127.6504, metered mass 1127.6474.

Anal. Calc. for C60 H30 N3 O177 * 0.75 P CHCl3: C, 65.45 H, 8.33; N, 3.51 Found: C, 65.23; H, 8.32; N, 3.86

The following representative compounds may be prepared from rapamycin and the appropriate amino acid 21

terminally N-substituted using the method used to prepare the title compound in Example 1. with N - [(fluorenylmethoxy) carbonyl] alanylserine with N - [(fluorenylmethoxy) carbonyl] -glycyl-

Ester-42-Rapamycin in Ester-42-Rapamycin cine Ester-42-Rapamycin Ester-4 2-Rapamycin gynein Ester-42-Rapamycin Ester-42-Rapamycin N-ethylalanine Ester-4 3-Rapamycin nylphenylalanine Ester-42-Rapamycin glycine with N - [(ethoxy) carbonyl] arginylmethionine with N - [(4'-chlorophenoxy) carbonyl] -histidyl- with N - [(phenoxy) carbonyl] -tryptophanyl ketine with N - [(phenylmethoxy) carbonyl] -N N-methylglycine with N - [(phenylmethoxy) carbonyl] -N-methyl-B-ala with N - [(1,1-dimethylethoxy) carbonyl] -cysteinyl-

Example 2

The title compound (1.85 g, 42%) was separated from the monoester-42 as described in Example 1 and isolated with a solvate of three (1) -dimethylsilyloxycarbonyl- (m, 18H, COOBut), 1.6612 (S, 3H, CH3 C = C), 1.38 (s, 3H) (S, 3H, OCH3), 3.34 (s, 3H, = CH3), 3.35 (s, 3H, OCH3), 3.78 , 52 (s, 1H, OH), 4.79 (m, 1H, 42-CHO), MS (Sep) (FAB ion neg.): Calc'd for CgHH7NN °O 13 21 1341.7458, measured mass: 1341.7463 .)

Anal. Calc. for C 6 H 10 7 N 5 O 2 • 0.75 P CH 3: C, 63.17: H, 8.06: N, 4.96 Found: C, 62.83; H, 8.09; N, 5.00

The following representative compounds may be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 2.

Dyster-31.42-Rapamycin Nilserine Diester-31.42-Rapamycin Cylglycine Diester-31.42-Rapamycin Diester-31.42-Rapamycin Dilarginine Diester-31.42-Rapamycin Cine Diester-31.42-Rapamycin Glycyl-N- ethyl-alanine Diester-31.42-Rapamycin-B-alanylphenylalanine Diester-31.42-Rapamycin theinylglycine with N - [(fluorenylmethoxy) carbonyl] -ala- with N - [(fluorenylmethoxy) carbonyl] -glycine N - [(ethoxy) carbonyl] -atginylmethionine with N - [(4'-chlorophenoxy) carbonyl] -histidine with N - [(phenoxy) carbonyl] -tryptophanyl with N - [(phenylmethoxy) carbonyl] -N-methyl - with N - [(phenylmethoxy) carbonyl)] - N-methyl- with N - [(1,1-dimethylethoxy) carbonyl]

Example 3

Diester-31.42-Rapamycin with Ν-Γ (1,1-dimethylethoxy) carbonyl-N-methylglycine

Under anhydrous conditions, an ice cold solution of rapamycin (2 g, 2.18 mmol) and Na-Boc sarcosine (1.65 g, 8.75 mmol) in 20 mL of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide (1 , 8 g, 8.7 mmol) followed by 4-dimethylamino pyridine (1 g, 8.7 mmol). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were evaporated to dryness to give an amorphous amber solid (3 g). The crude product was purified by flash chromatography (on Merck silica 60, elution with hexane-ethyl acetate 1: 1, v / v) to provide the title compound (0.75 g, 27.4%) along with monoester- 42 of Example 4. HPLC analysis showed the diester to be a 19.8: 1 mixture. The multiplicity of the NMR peaks suggested the presence of amide rotamers. 1 H NMR (CDCl 3, 400 MHz): δ 1.411, 1.438, 1.448 and 1.474 (m, 18 H, COOBut), 2.91 (m, 6H, NCH 3), 3.14 (s, 3H, CH 3) 34 (s, 3H, CH3), 3.37 (s, 3H, CH3), 4.73 (broad, 1H, 42-CHO), 4.82 (2s, 1H, OH); MS Elev. Sep. (FAB ion neg.): Calc. for C67H1Q5N3019 1255.7342, measured mass 1255.7289.

Anal. Calc. for nc; Found: C, 64.04; H, 8.42; N, 3.34 67 105 3 19

Found: C, 64.14; H, 8.74; N, 3.63

The following representative compounds can be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 3. Diester-31.42-Rapamycin with Diester-31, 42-Rapamycin with alanine Diester-31.42-Rapamycin with nil] -isoleucine Diester-31.42-Rapamycin with tamin Diester-31.42-Rapamycin with Diester-31.42-Rapamycin with nobutyric Diester-31.42-Rapamycin with N-[(ethoxy) carbonyl] tyrosine N - [(fluorenylmethoxy) carbonyl] -phenyl · N - [(3 ', 4', 7 ' 5'-trihydroxyphenoxy) carbon · N - [(1,1-dimethylethoxy) carbonyl] -glu · N - [(phenoxy) carbonyl] -N-methylalanine N - [(propyloxy) carbonyl] -4- [(phenylmethoxy) carbonyl] -7 N - [(fluorenylmethoxy) carbonyl] serine N - [(1,1-dimethylethoxy) carbonyl] -N-

Under anhydrous conditions, a solution of rapamycin (0.95% CL *

g, 1.02 mmol) and N-Boc sarcosine (0.21 g, 1.1 mmol) in anhydrous dichloromethane (20 mL) was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmol) was added 4-dimethylamino pyridine (0.21 g, 1 mmol). After stirring for 4 hours at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give an amorphous amber solid. Chromatography of the crude product (on silica merck 60, elution with 1: 1 v / v hexane-ethyl acetate to remove the diester of Example 3, followed by 75: 25: 1 chloroform-ethyl acetate-methanol / v) afforded the partially purified title compound (0.38 g, 35%). The pure product was obtained by preparative HPLC (Waters Prp 500, silica gel, 75: 25: 1 v / v chloroform-ethyl acetate-methanol, flow rate 250 mL / min). HPLC analysis revealed that the ester is a 6.6: 1 mixture of two conformers. The multiplicity of NMR peaks suggests the presence of amide rotamers. 1 H NMR (CDCl 3, 400 MHz): δ 1.42-1.46 (ds, 9H, COOBut), 2.91 (ds, 3H, NCH3), 1.644 (s, 3H, CH3 C = C), 1.738 , 3.32 (s, 3H, CH 3), 3.35 (s, 3H, CH 3), 4.18 (d, 1H, CHOH), 4.71 (broad, 1H, 42-CHO), 4.78 (broad s, 1H, OH); MS Elev. sep. (FAB ion neg.): Calc. for C59H92N2O6 1084.6446, measured mass 1084.6503.

Anal. Calc. for C 59 H 21 N 2 O 16: C, 62.59; H, 8.54; N, 2.58 Found: C, 65.25; H, 8.52; N, 2.42

The following representative compounds can be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 4. N-ethoxy-carbonyl] tyrosine Ester-42-Rapamycin with N - [(fluorenylmethoxy) carbonyl] -phenylalanine Ester-42-Rapamycin with N - [(3 ', 4', 5'-trihydroxyphenoxy) carbonyl] -isoleucine Ester-42-Rapamycin with N - [(1,1-dimethylethoxy) carbonyl) -glutamine Ester-42-Rapamycin with N - [(phenoxy) carbonyl] -N-methylalanine Ester-42-Rapamycin with N - [(propyloxy) carbonyl] -4- -aminobutyric acid Ester-42-Rapamycin with N - [(phenylmethoxy) carbonyl] -7-aminoheptanoic acid

Diester-31.42-Rapamycin with N - [(fluorenylmethoxy) carbonyl] serine 26

Example 5

Diester-31.42-Rapamycin with 5- (1-dimethylethoxy) -2- (1-dimethylethoxy) carbonyl) aminol-5-oxopentanoic acid

Under anhydrous conditions, an ice cold solution of rapamycin (4 g, 4.37 mmol) and L-glutamic acid N-Boc-T-tert-butyl ester (4.9 g, 16.1 mmol) in 40 ml of dichloromethane was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmol) followed by 4-dimethylaminopyridine (1 g, 8.7 mmol). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to provide 11 g of an amorphous solid of amber. The crude product was purified by flash chromatography (on silica Merck 60, gradient elution with hexane-ethyl acetate from 2: 1 to 1: 1, v / v) to provide 4.52 g (69.6%) of of the title compound together with the monoester-42 of Example 6. HPLC analysis revealed that the diester consisted of a 6.6: 1 mixture of two conformers. ¹H NMR (CDCl,, 400 MHz): δ 1.42 (m, 36 H, COOBut), 1.646 (s, 3H, CHCC CC), 1.701 (s, 3H, CHCC CC), 3.13 (s, 3H, Cl2 O), 3.34 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.735 (m, 2H, OH + 42-CH-O); MS Sep.

He v. (FAB ion neg.): Calc. for C79 H25 N3 O23 1483/8715 / metered mass 1483.8714.

Anal. Calc. for C79 H125 N3 C &gt; 23: C, 63.90; H, 8.49; N, 2.83 Found: C, 63.63; H, 8.41; N, 2.44

The following representative compounds can be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 5. 27

Diester-31.42-Rapamycin with 6- (phenylmethoxy) -2 - [[fluorenylmethoxy) carbonyl] amino] -6-oxohexanoic acid

Diester-31.42-Rapamycin with 6- (4-methylphenoxy) -3 - [[(phenylmethoxy) carbonyl] amino-6-oxohexanoic acid

Diester-31/42-Rapamycin with 6- (ethoxy) -4 - [[(phenoxy) carbonyl] amino] -6-oxohexanoic acid

Diester-31.42-rapamycin with 6- (methoxy) -5 - [[(ethoxy) carbonyl] amino] -6-oxohexanoic acid

Diester-31.42-Rapamycin 4- (phenoxy) -2- [N - [(1,1-dimethylethoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid

Diester-31.42-Rapamycin with 4- (phenylmethoxy) -3- [N - [(methoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid

Example 6 Ester-42-rapamycin with 5- (1,1-dimethylethoxyl-2 - [(1,1-dimethylethoxy) carbonyl] amino] -5-oxopentanoic acid The title compound (1.14 g, 20.6% was separated from the diester-31.42 as described in Example 5 and isolated as the one-fourth hydrate / monoethyl acetate solvate. HPLC analysis revealed that the monoester is an 11.5: 1 mixture of two mono- (s, 3H, CH3 C = C), 3.13 (s, 3H, CH3 C = C), 1.737 (s, 3H, CH3 C = C) 3H), 3.32 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.17 (d, 1H, CHOH), 4.71 (m, 1H, , 4,785 (s, 1H, OH), MS Elev. Sep. (FAB ion neg.): Calc'd for N-Cl 1198.7127, metered mass 1198.7077.

OO light Δ XO

Anal. Calc. for -CH 3 COOEt · 0.25 H 2 O: 65 102 2 18 3 2 C, 64.13; H, 8.60; N, 2.17 Found: C, 64.18; H, 8.52 N, 2.01

The following representative compounds can be prepared from rapamycin and the appropriate N-terminally-substituted amino acid using the method used to prepare the title compound in Example 6. ß-Rapamycin with 6- (phenylmethoxy) -2- - [[fluorenylmethoxy-carbonyl] amino] -6-oxohexanoic acid Ester-42-Rapamycin with 6- (4'-methylphenoxy) -3 - [[(phenylmethoxy) carbonyl] amino] -6-oxohexanoic acid Ester Rapamycin with 6- (ethoxy) -4 - [[(phenoxy) carbonyl] amino] -6-oxohexanoic acid Ester-42-Rapamycin with 6- (methoxy) -5 - [[(ethoxy) carbonyl] ] amino] -6-oxohexanoic acid Ester-42-Rapamycin with 4- (phenoxy) -2- [N - [(1,1-dimethylethoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid Ester- 42-Rapamycin with 4- (phenylmethoxy) -3- [N - [(methoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid

Example 7

Diester-31.42-Rapamycin with 2 - [(1, 1-dimethylethoxy) carbonylamino] -4-oxo-4- (phenylmethoxy) butanoic acid

Under anhydrous conditions, 295 mg (1.21 mmol) of 2,4,6-trichlorobenzoyl chloride were added to a solution of 391 mg (1.21 mmol) of Nra_Boc_Lastrastic acid β-benzyl ester and 170 μΐι (1, 21 mmol) of Et 3 N in 1 mL of THF at room temperature. After stirring for 30 minutes, 500 mg (0.55 mmol) of rapamycin and 295 mg (2.42 mmol) of dimethylaminopyridine were added and the reaction was allowed to stir overnight. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The pure product (200 mg, 25%) was obtained by preparative HPLC (5 cm column, 40% ethyl acetate-hexane). The product was isolated as the heptahydrate. 1 H NMR (CDCl 3, 400 MHz): 7.37 (s, 10 H, Ar), 6.223, 5.136 (S, 4 H, CH 2 Ph), 4.698 (m, 1 H, CH- CO 2), 4.587 (m, 2 Η , 3.353 (s, 3 H, CH 3), 3.377 (s, 3 H, CH 3), 3.301 (s, 3 H, CH 3), 2.775 (m, 4 H, CH 2 CO 2); IR (KBr) 3420 (OH), 2935 (CH), 2920 (CH), 1730 (C = O), 1650, 1500, 1455, 1370, 1170 cm -1; MS (FAB ion neg.) 1523 (M +), 1433, 297, 248, 205, 148, 44, 25 (100).

Anal. Calc. for C83 H117 N3 O23 • 7H2 O: C, 60.40: H, 7.09; N, 2.54

Found: C, 60.54; H, 7.28; N, 2.56 30 30

Example 8

Diester-31.42-Rapamycin with 3 - [(1,1-dimethylethoxylcarbamoyl) -4-oxo-4- (phenylmethoxy) butanoic acid

Under anhydrous conditions, 532 mg (2.18 mmol) of 2,4,6-trichlorobenzoyl chloride in 1 ml of THF was added to a solution of 704 mg (2.18 mmol) of N α- Boc-L-aspartic acid and 303 μl (2.18 mmol) of Et3 N in 5 mL of THF at room temperature. After stirring for 20 minutes, the reaction mixture was filtered over agglomerated glass, and the precipitate was washed with THF. The filtrate was concentrated in vacuo to give a thick oil. The oil was dissolved in 5 ml of benzene and 1.00 g (1.09 mmol) of rapamycin and 532 mg (4.36 mmol) of dimethylaminopyridine in 1 ml of benzene were added dropwise. The reaction was stirred for 2 hours, poured into ethyl acetate, and washed consecutively with 0.5N HCl and brine. The solution was dried over sodium sulfate, decanted, concentrated in vacuo to give a foamy solid which was purified by flash chromatography on a 60 mm x 100 mm silica (20-40% ethyl acetate / hexane as eluent) to give 532 mg (33%) of the title compound which was isolated as the hydrate. 1 H NMR (CDCl3, 400 MHz): Î'7.362 (S, 10 H, Ar), 5.193 (s, 4 H, CH 2 Ph), 4.596 (m, 1 H, CH- (CH 3) 3,36 (s, 3 H, CH 3), 3.306 (s, 3 H, CH 3), 3.145 (s, 3 H, CH 3), IR (KBr) 3410 TOH), 2950 (CH) , 1735 (C = C), 1710 (C = O), 1640, 1490, 1445, 1350, 1150 cm-1; MS (FAB ion neg.) 1524 (M_1), 1434, 297, 248, 232, 214, 205, 167, 148, 42 (100), 26.

Anal. Calc. Calc'd for CHHH77N23O2323N₂O23H₂O: H₂O: C, 65.38; H, 7.73; N, 2.76 Found: C, 64.85; H, 7.67; N, 2.56

The title compound (374 mg, 23%) was prepared by the method described in Example 1. The title compound (374 mg, 23%) was prepared by the method described in Example and separated from the compound described in the previous Example by flash chromatography (20-40% ethyl acetate / hexane as eluent) and isolated as the sesquihydrate. 1 H NMR (CDCl 3, 400MHz): 7.356 (s, 5 H, MH), 5.185 (s, 2 H, CH 2 Ph), 4.635 (m, 1 H, CH 2), 4.582 (m, 1 Η NH ), 3.330 (s, 6 H, δH30), 3.135 (s, 3H, CH2); IR (KBr) 3410 (OH), 2950 (CH), 2920 &quot; (CH), 1735 (C = O), 1710 (C = O), 1640, 1490, 1445, 1350, 1150 cm -1; MS (FAB ion neg.) 1218 (M +), 1127, 590, 168, 42, 25, 17 (100).

Anal. Calc. for C ""HQNNOO · 1.5Η0: C, 63.64; H, 8.21; N, 2.22.

Found: C, 63.64; H, 7.51; N, 2.13

Exemolo 10 Ester-42-Rapamycin with 5- (1,1-dimethyloxyl-4 - [(1,1-dimethyloxy) carbonyl] amino] -5-oxopentanoic acid

Under anhydrous conditions, an ice cold solution of rapamycin (4 g, 4.37 mmol) and L-glutamic acid Na-Boc-α-tert-butyl ester (4.9 g, 16.1 mmol) in 40 mL of anhydrous dichloromethane was treated with dicyclohexyl carbodiimide (1.8 g, 8.7 mmol) followed by 4-dimethylamino pyridine (1 g, 8.7 mmol). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give 9 g of an amber amorphous solid. The crude product was purified by flash chromatography (on silica Merck 60, elution gradient with hexane-ethyl acetate from 2: 1 to 3: 2, v / v) to provide 1.35 g (25.7%) of the title compound of the title together with the diester-31.42 of Example 11. HPLC analysis revealed that the monoester-ter is a 7.5: 1 mixture of two conformers. NMR (CDCl3, 400 MHz): δ 1.43 (s, 9H, COOBut) and 1.46 (s, 9H, COOBut), 1.65 (ε, 3H, CH3 C = C), 1.75 (S, 3H, CH3), 3.34 (s, 3H, CH3), 3.38 (s, 3H, CH3), 4.18 (d, 1H, CH3) -OH), 4.65 (m, 1H, 42-CHO), 4.80 (s, 1H, OH); MS Elev. Sep. (FAB ion neg.): Calc. for C65H102N2O18: 1198 &gt; 7126 / mass measured 1198.7135.

Anal. Calc. for C65H102N2O8: c / 65/09 / * H / 8/57 / 'N / 2/34 Found: C, 65.04; H, 8.33; N, 2.64

Exemolo 11

Diester-31.42-Rapamycin with 5-fluoro-1-dimethylethoxy-4- (1-dimethylethoxy) carbonylamino] -5-oxopentanoic acid The title compound (0.83 g, 12.8%) was prepared along with monoester-42 as described in Example 10. HPLC analysis revealed that the diester is a 7.7: 1 mixture of two conformers. Δ (CDCl 3, 400MHz): δ 1.43 (s, 18Η, COOBut), 1.46 (s, 18H, COOBut), 1.659 (s, 3H, CH3C = C), 1.759 (s, 3H, = C), 3.14 (s, 3H, CH3), 3.34 (s, 3H, CH2 O), 3.38 (s, 3H, CH2 O), 4.66 (m, 1H, 42 CHO), 4.72 (s, 1H, OH); MS Elev. Sep. (FAB ion neg.): Calc. for C7 H25 N3 O3: 1483/8704 / metered mass 1483.8636.

Anal. Calc. for C79 H125 N3 O3: 63/90 / H, 8.49, N, 2.83 Found: C, 63.68; H, 8.60; N, 3.20

Example 12 Ester-42-Ranamycin with Na, N 6 -bisf fl, 1-dimethylethoxy) carbonin-L-lysine

Under anhydrous conditions, a solution of rapamycin (3 g, 3.28 mmol) and Na, N-bis-Boc-L-lysine (4.5 g, 13 mmole) in 40 ml of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide , 35 g, 6.56 mmole) followed by 4-dimethylaminopyridine (0.8 g, 6.56 mmole). After stirring overnight at room temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give an amorphous amber solid. Light product chromatography (on silica Merck 60, elution with 1: 1 v / v hexanes-ethyl acetate) gave the partially purified title compound. The pure product (0.8 g, 19.6%) was obtained by preparative HPLC (Waters prep 500, silica gel, 3: 2 v / v hexane-ethyl acetate, flow rate 250 ml / min). HPLC analysis revealed that the monoester is a 9: 1 mixture of two conformers. 34

(S, 3H, CH 3 C = C), 1.752 (s, 3H, CH 3 C = C), 1.65 (s, 9H, COOBut), 1.652 (s, 3H, CH 3 C = (S, 3H, CH3), 3.33 (s, 3H, OE3 O), 3.37 (s, 3H, CH3), 4.18 (d, 1H, 72 (m, 1H, 42-CHO), 4.79 (s, 1H, OH), MS Elev. Sep. (FAB ion neg.): Calc'd for C 67 H 17 N 3 O 8: 1241.7549, metered mass 1241.7604 C, 64.76, H, 8.68, N, 3.38

Anal. Calc. for C HH _ NN₂O.. ". * 67,107 18;

Found; C, 64.58; H, 9.01; N, 3.10

Example 13

Diester-31.42-Rapamycin with Na.N-bis-bis (1,1-dimethylethoxy) carbonyl-L-lysine

Under a nitrogen atmosphere, a solution of Na, Ne bis-Boc-L-lysine (1.038 g, 3 mmol) and triethylamine (0.42 mL, 3 mmol) in 10 mL of anhydrous THF was treated in a portion with 2,4,6-trichlorobenzoyl chloride (0.73 g, 3 mmol). After stirring at room temperature for 20 minutes, the precipitated solid was collected and the filtrate was concentrated in vacuo. The resulting mixed anhydride was dissolved in 5 ml of benzene and added to a stirred solution of rapamycin (1 g, 1.09 mmol) containing 4-dimethylamino pyridine (0.59 g, 4.8 mmol) in 10 ml of benzene. After stirring at room temperature overnight, the precipitated solid was collected and the filtrate evaporated to dryness (yellow foam). The crude product was purified by flash chromatography (on silica Merck 60, eluting with 1: 1 hexane-ethyl acetate) to provide the title compound (1.15 g, 67%). HPLC analysis shows that the diester is a 9: 1 mixture of two conformers. 1 H NMR (CDCl 3, 400 MHz): δ 1.426 (m, 9H, COOBut), 1.438 (s, 9H, COOBut), 1.443 (S, 9H, COOBut), 1.446 (S, 9H, s, 3H, CH3), 3.36 (s, 3H, CH3), 3.378 (s, 3H, CH3), 4.68-4.76 (m, 2H, OH and 42.-CHO); MS elev. sep. (FAB ion neg.): Calc. for C83 H13 N5 O3 1569/9526, measured mass 1569.9537.

Anal. Calc. Calc'd for C 19 H 38 N 5 O 2: C, 63.46: H, 8.66: N, 4.46 Found: C, 63.06; H, 8.84; N, 4.09

Example 14

To a solution of 5.0 g (5.47 mmol) of rapamycin, 3.41 g (16.41 mmol) of monobenzyl succinate, and 3.15 g (16.41 mmol) mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 20 ml of dry dichloromethane was added 200 mg of 4-dimethylaminopyridine. The solution was stirred at room temperature for 3 days. The reaction mixture was poured into 2N HCl and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light yellow foam. Light chromatography on a 60 mm x 150 mm silica gel column eluting with 20% ethyl acetate / hexane to 75% ethyl acetate / hexane gave three fractions. Fraction # 1, after concentration, gave 330 mg (4.1%) of pure tris (monobenzylsuccinate) -14,31,42-ra-kamycin. 36

1 H NMR (CDCl 3, 400 MHz): δ 7.353 (bs, 15 H, arom), 5.168 (d, J = 2.0 Hz, 1 H, CH2 CH2), 5.148 (m, 6H, (m, 1 H, CH2 CO2 CH3), 3.335 (s, 3H, CH2), 3.337 (s, 3H, CH2), 3.327 (s, 3H, CH3) (s, 3H, CH3 C = C), 1.655 (s, 3H, CH3 C = C); IR (KBr) 3450 (OH), 2950 (CH), 11745 (C = O), 1650, 1460, 1385, 1360, 1160, 1105, 995 cm -1.

Anal. Calc. for C84 H109NO2 Â · 3 H2 O / 66.27 / * H / 7/56; N, 0.92

Found: C, 65.96; H, 7.24; N, 1.00

The following representative compounds can be prepared from rapamycin and the appropriate ester-acid medium using the method used to prepare the title compound in Example 14.

Tris (monomethylsuccinate) -14,31,42-Rapamycin

Tris (monophenyl-3 ', 3'-dimethylglutarate) -14,31,42-Rapamycin

Tris (mono t-butyl-3'-methylglutarate) -14,31,42-Rapamycin

Tris (monobenzylthiodiglycolate) -14,31,42-Rapamycin

Tris (monohexyldiglycolate) -14,31,42-Rapamycin

Tris (monopropylphthalate) -14,31,42-Rapamycin

Tris (monoethyl-2 ', 6'-pyridinedicarboxylate) -14-31-42-Rapamycin Example 15

Fraction # 2, obtained from the procedure used in Example 14, gave 1.25 g (17.7%) of bis (monobenzylsuccin-to) -31,42-diisopropylethylamine rapamycin after concentration. 37

1 H NMR (CDCl 3, 400 MHz) δ 7.351 (bs, 10 H, arom 5.18 (d, J = 2.0 Hz, 1 H, CH 2 O), 5.125 (m, 4H, CH 2 Ph), 4.680 , 3.356 (s, 3 H, CH 2 O-), 3.329 (s, 3 H, CH 2 OH), 3.146 (S, 3 H, CHH-), 2.639 (m, IR (KBr) 3450 (OH), 2940 (CH), 1740 (C = CH3), 1.40 (s, 3H) (M-), 1202, 1103, 1012, 590, 511, 475, 297, 207, 167 (M-), 1650, 1455, 1380, 1355, 1160, 1105, 995 cm &quot; , 148, 99 (100); MS Elev. Sep. (FAB ion neg.) Calc. Calc'd for C73 H19 NN2 O 1293.68108, found 1293.6811.

Calc'd. Calc'd for C73 H20 NO5 · H2 O C, 66.82, H, 7.70, N, 1.07

Found: C, 67.17; H, 7.67; N, 1.23

The following representative compounds can be prepared from rapamycin and the appropriate ester-acid medium using the method used to prepare the title compound in Example 15.

Bis (monomethylsuccinate) -31.42-Rapamycin

Bis (monophenyl-3 ', 3'-dimethylglutarate) -31,42-Rapamycin

Bis (mono t-butyl-3'-methylglutarate) -31.42-Rapamycin

Bis (monobenzylthiodiglycolate) -31.42-Rapamycin

Bis (monohexyldiglycolate) -31.42-Rapamycin

Bis (monopropylphthalate) 31.42-Rapamycin

Bis (monoethyl-2 ', 6'-pyridinedicarboxylate) -31,42-Rapamycin

1 H NMR (CDCl 3, 400 MHz)? 7.355 (bs, 5 H, arom), 5.141 (m, 2 H, CH2 CH2), 4.680 (b1, 1 H, CO2 CH2 CH3 Me), 3.364 (s, (M, 4H, CH2CH2 CH2 CH2 CH2 CH2), 1.751 (S, 3 H, CH3 C = C), 3.15 (s, 3 H, CH3 O-), 3.31 (s, 3H, CH3) 1.655 (S, 3 H, CH C = C); IR (KBr) 3450 (OH), 2940 (CH), ~ 1740 (C = O), 1645, 1455, -11380, 1165, 1105, 990 cm; MS / FAB ion neg.) 1103 (M-), 1045, 1012, 624, 590, 167, 99 (100); MS Elev. Sep. (FAB ion neg.) Calc. for c62H89NO66 1103/6181, found 1103,6048.

Anal. Calc. for C62 H89 N06 · 20 C, 66.36, H, 8.02, N, 1.24 Found: C 66.02, H 7.69, N, 1.26

The following representative compounds can be prepared from rapamycin and the appropriate ester-acid medium using the method used to prepare the title compound in Example 16. (Monomethylsuccinate) -42-Rapamycin (Monophenyl-3 ', 3'- dimethylglutarate) -42-Rapamycin (Mono-t-butyl-3'-methylglutarate) -42-Rapamycin (Monobenzylthiodiglycolate) -42-Rapamycin (Monohexyldiglicolato) -42-Rapamycin (Monopropylphthalate) -42-Rapamycin (Monoethyl- -pyridinecarboxylate) -42-Rapamycin

Example 17

Bishemiglutarate-31.42-Rapamycin To a solution of 2.0 g (2.2 mmol) of rapamycin in 10 ml of dry dichloromethane was added 1.24 g (10.9 mmol) of glutaric anhydride followed by 881 ul 861 mg, 10.9 mmol) of pyridine. To this was added 200 mg of 4-dimethylaminopyridine 39

and the reaction mixture was allowed to reflux for 8 hours. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on a C18 column and eluted starting with 60% acetonitrile / water. 586 mg (24%) of bishemiglutarate-31-42-rapamycin were collected after concentration. ¹H NMR (CDCl,, 400 MHz) δ 5.388 (m, 1 H, -CH₂CHCHOMe). (M, 1 H, -CH 2 -C H 3 O), 3.364 (s, 3 H, CH 3 -), 3.362 (s, 3 H, CH 3 -), (M, 4 H, -OCH 2 CH 2 CH 2 CH 2 CH 2), 1.770 (s, 3 H, CH 3 C = C), 1.653 (s, 3 H, CH 3 C = C); 13 C NMR (CDCl3, MHz) 211.45 (C = O), 206.84 (C = O), 200.44 (C = O), 177.83 (C = O), 177.04 (C = O) ), 172.43 (C = O), 171.20 (C = O), 165.27 (C = O), 159.08 (C = O); IR (KBr) 3430 (OH), 2940 (CH), 2880 (CH), 1745 (C = O), 1685, 1625, 1580, 1450, 1385, 1330, 1200, 1140, 1100, 990 cm -1; MS (FAB ion neg.) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ion neg.) Calc. for C 61 H 9 O 9 N (M-H) 1140.6107, Found 1140.6106.

Anal. Calc. Calc'd for C61 H9 N3 O: C, 63.15; H, 8.02; N, 1.20 Found: C, 63.35; H, 7.88; N, 1.40

The following representative compounds can be prepared from rapamycin and the appropriate anhydride using the method used to prepare the title compound in Example 17.

Bishemi-3'-methylglutarate-31.42-Rapamycin

Bishemi-3 ', 3'-dimethylglutarate-31.42-Rapamycin Bishemi-3'-oxoglutarate-31.42-Rapamycin Bishemi-3'-thioglutarate-31.42-Rapamycin Bishemi-phthalate-31.42-Rapamycin

Bishemi-2 ', 3'-pyridine dicarboxylate-31-42-Rapamycin I

Example 18

Rapamycin-31-42-Rapamycin bisylated bis-31 / 42.hemiglutarate, 8740 mg, 649 μmol), prepared as described in Example 4, was dissolved in 5 ml of 95% ethanol and added 107 mg (1.27 mmol) of sodium bicarbonate. Water (1 ml) was added to completely dissolve the salt. Once dissolved, the pale yellow solution was concentrated in vacuo to give a yellow foamy solid. The foam was dried on a drying gun for 24 hours, refluxed over acetone under reduced pressure to give 520 mg of the bis (disodium salt). Δ NMR (d6 -DMSO, 400 MHz) δ 5.235 (m, 1 H, -CH2 C), 4.488 (m, 1H, MeOHCH2 O-), 3.277 (s, 6 H, 2 Î'H30-), 3.266 , 3.45 (s, 3 H, CH3 C = C), 1.593 (S, 3 H, CH3 C = C), 1.59 (s, 3H); IR (KBr) 3420 (OH), 2920 (CH), -1725 (C = O), 1675, 1620, 1560, 1450, 1400, 1375, 1230, 1195, 1130, 1090, 980 cm -1; MS (FAB negative ion) 1112 (M-1, free acid), 994, 589, 475, 297, 167, 148, 117, 99 (100); MS Elev. Sep. (FAB ion neg.) Calc. Calc'd for C61 H9 O9 NNa (M-Na) 1162.5926, Found 1162.5899.

Anal. Calc. Calc'd for C 61 H 9 O 6 N 2 O 2 · C 20, 60.85, H, 7.56, N, 1.16

Found: C, 60.67; H, 7.36; N, 1.58.

Example 19

Bistrymetamide salt of bishemicrlutarate-31.4 2-Rapamycin

Purified purified amoxyglutarate bis-31.42 (950 mg, 833 μmol), prepared as described in Example 4, was dissolved in 5 ml of 95% ethanol and 197 mg (1.63 mmol) of tris hydroxymethyl) methylamine. Water (1 ml) was added until the amine was completely dissolved. Once dissolved, the yellow solution was concentrated in vacuo to give a yellow foamy solid. The very hygroscopic foam was dried on a drying gun for 24 hours, refluxed over acetone under reduced pressure to give 900 mg (78%) of bromethamine salt. 1 H NMR (d 6 -DMSO, 400 MHz): δ 5.253 (m, 1 H, -CHCl 3), 4.523 (m, 1 H, MeOH CH 2 O-), 3.347 (s, 6 H, (S, 3 H, CH3 C = C), 1.595 (s, 3 H, CH3 C = C ) IR (KBr) 3400 (OH), 2920 (CH), 1730 (C = O), 1620, 1555, 1450, 1400, 1370, 1185, 1060, 980 cm-1; (MH, free acid), 1028, 167, 148, 131 (100), 113: MS Elev. Sep. (FAB ion neg.) Calc'd for C61 H9 N3 O4 N (MH, free acid) 1140.6107, Found 1140 , 6069.

Anal. calc. Calc'd for C69 H11 N3 O2: C, 58.77; H, 7.58; N, 2.98

Found: C, 58.47; H, 7.94; N, 3.58

Example 20

Hemi-3'-oxoqlutarate-42-Rapamycin To a solution of 3.0 g (3.3 mmol) of rapamycin in 20 ml of dry dichloromethane was added 1.90 g (16.4 mmol) of

diglycol anhydride followed by pyridine (1.32 ml, 1.29 g, 16.4 mmol). To this were added 200 mg of 4-dimethylaminopyridine and the reaction mixture was allowed to stir at room temperature for 2 days. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on a Cl 2 column by eluting starting with 60% acetonitrile / water. After concentration, 870 mg (26%) of hemi-3'-oxoglutarate-42-rapamycin and 500 mg (13%) of bishemi-3'-oxoglutarate-S, 42-rapamycin were isolated. 1 H NMR (CDCl3, 400 MHz) Î'4.768 (m, 1 H, CH 2 CH 2 CH 3), 4.250 (m, 4 H, OCHâ,,CHâ,,CHâ,,COâ,,Oâ,,), 3.356 (s, 3 H, CHâ,ƒ-), 3.331 (s, 3 H (KBr): 3420 (M + H) +, 1 H-NMR (DMSO-d 6):? , 2920 (CH), 2875 (CH), 1740 (C = O), 1720 (C = O), 1640, 1625, 1445, 1370, 1320, 1200, 1135, 1095, 980 cm -1 MS (FAB 1028 (Μ-H), 327, 167 (100), 148, 133, 115, Found: 1028.5599 (M + H) +. .

Anal. Calc. for C 55 H 83 O 13 N 3 H 2 0 C, 60.97, H, 8.22, N, 1.29

Found: C, 61.33; H, 7.74; N, 1.69

The following representative compounds can be prepared from rapamycin and the appropriate anhydride using the method used to prepare the title compound in Example 20.

Hemi-3'-methylglutarate-42-Rapamycin Hemi-3 ', 3'-dimethylglutarate-42-Rapamycin

Hemi-3'-thioglutarate-42-Rapamycin Hemi-phthalate-42-Rapamycin

Hemi-2 ', 3'-pyridine dicarboxylate-42-Rapamycin

Example 21

Bishemi-3'-oxoqlutarate-31.42-Rapamycin To a solution of 5.0 g (5.47 mmol) of rapamycin in 20 ml of dry dichloromethane was added diglycolic anhydride (3.17 g, 27.3 mmol) 2.17 ml (2.12 g, 27.3 mmol) of pyridine. To this was added 400 mg of 4-dimethylaminopyridine and the reaction mixture was allowed to stir under reflux for 24 hours. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on a C20 column, eluting with 60% acetonitrile / water. After concentration, 1.75 g (28%) of bishemi-3'-oxoglutarate-31,42-rapamycin was isolated. 1 H NMR (CDCl3, 400 MHz) δ 4.785 (m, 1 H, CH3 CHCHOMe). 4.260 (m, 8H, OCH3), 3.360 (s, 3 H, CH3 -), 3.343 (s, 3H, OCH2), 3.143 (S, 3H, CH3 -), 1.775 (s, 3 H, CH3 C = C), 1.656 (s, 3 H, CH3 C = C); 13 C NMR (CDCl3, 13 MHz) 211.12 (C = O), 7207.73 (C = O), 193.11 (C = O), 171.90 (C = O), 171.59 (C = O), 170.15 (C = O), 169.35 (C = O), 168.83 (C = O), 166.63 (C = O); IR (KBr) 3420 (OH), 2920 (CH), 2850 (CH), 1740 (C = O), 1645, 1625, 1440, 1370, 1190, 11300, 980, cir. MS (FAB ion neg.) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ion neg.) Calc. Calc'd for C5 H8 N2 O2 N (M-H) 1144.5701, Found 1144.5702.

Anal. Calc. Calc'd for C5 H8 N2 O2 N: C, 61.82; H, 7.56; N, 1.22

Found: C, 61.59; H, 7.36; N, 1.84

Example 22

Disodium salt of bishemi-3'-oxyocrutarate-31-42-Rapamycin

Purified bis-31.42 hemi-3'-oxoglutarate (720 mg, 629 μmol), prepared by the procedure used in Example 8, was dissolved in 10 ml of 95% ethanol and 106 mg (1.26 mmol) of bicarbonate sodium and water. Water (1 ml) was added to completely dissolve the salt. Once dissolved, the pale yellow solution was concentrated in vacuo to give a yellow foamy solid. The foam was dried on a drying gun for 48 hours, refluxed over dichloromethane under reduced pressure to give 435 mg (58%) of disodium salt. 45 ¹ NMR (d6 -DMSO, 400 MHz) Î'4.975 (m, 1 H, -CHOgC). 4.593 (m, 1 H, MeOH CH 2 CO-), 4.135 (s, 2H, -CH 2 CH 2 CH 2 CO 2 R 3, 3.617 (s, 2 H, -O 2 CCH 2 CH 2 CO 2 R), 3.299 (s, 6 H, 2 H CH 3) IR (KBr) -3420 (OH), 2920 (CH), 1735 (s, 3 H, CH3 C = C), 1.553 (s, 3 H, CH3 C = (M-Na), 1144 (M), 1166 (M-Na), 1144, 1051 (C = O), 1615, 1445, 1395, 1380, 1220, 1130, 1090, 980 cm- , 1028, 590, 459, 167, 155 (100), 148, 133, 115.

Anal. Calc. for C 55 H 50 N 2 O 2 • 2 H 2 O: C, 57.79, H, 7.26, N, 1.14

Found: C, 57.94; H, 7.11; N, 1.26

Example 23

Bishemi-3'-oxocyluterato-3,14-Rapamycin salt

Hemi-3'-oxoglutarate bis-31.42 purified rapamycin (1.01 g, 882 μmol) prepared by the procedure of Example 8 was dissolved in 10 ml of 95% ethanol and 213 mg (1.76 mmol ) of tris (hydroxymethyl) -methylamine. Water (1 ml) was added to completely dissolve the amine. Once dissolved, the yellow solution was concentrated in vacuo to give a yellow foamy solid. The very hygroscopic foam was dried on a drying gun for 48 hours, refluxing over dichloromethane under reduced pressure to give 805 mg (66%) of bistromethamine salt. NMR (d6 -DMSO, 400 MHz): δ 4.955 (m, 1 H, -CHCl3), 4.600 (m, 1 H, MeOCHCHC> 2C-), 4.149 (s, 2 Î', -O- , 3.407 (s, 6H, 2CH₂O-), 3.257 (s, 3 H, C O-O-), 1.80 (s, 2 H, -O₂CH₂O 0CH₂CO₂R,) IR (KBr) -3400 (OH), 2920 (CH), 1730 (C = O), 1620, 1550, 1450, 1395 (s, 3 H, CH3 C = C) , 1370, 1200, 1060, 985 cm-1; MS (FAB negative ion) 1144 (MH, free acid), 1028, 167, 148, 133, (100), 115.

Anal. Calc. Calc'd for C 67 H 109 N 2 O 2 · H 2 O: C, 57.22; H, 7.90; N, 2.98

Found: C, 57.26; H, 7.90; N, 3.15

Example 24

Bishemisuccinate-31.42-Rapamycin To a solution of 2.0 g (2.2 mmol) of rapamycin in 10 ml of dry dichloromethane was added 1.19 g (10.9 mmol) of succinic anhydride followed by 881 μl (861 mg , 10.9 mmol) of pyridine. To this were added 200 mg of 4-dimethylaminopyridine and the reaction mixture was refluxed for 24 hours. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on an elution gradient Cl 2 column starting with 20% acetonitrile / water to 60% acetonitrile / water. 770 mg (31%) of bishemisuccinate-31,42-rapamycin were collected after concentration. The purified bis-31.42 Hemisuccinate of purified rapamycin (770 mg, 686 μmol) was dissolved in 10 ml of 95% ethanol and 166 mg (1.37 mmol) of tris (hydroxymethyl) methylamine was added. 47

Water (1 ml) was added to completely dissolve the amine. Once dissolved, the yellow solution was concentrated in vacuo to give a yellow foamy solid. The highly hygroscopic foam was dried on a drying gun for 24 hours, refluxed over acetone under reduced pressure to give 890 mg (95%) of the bromethamine salt. Bistromethane salt was evaluated in the standard pharmacological test procedures. 1 H NMR (CDCl 3): δ (DMSO, 400 MHz), 5.231 (m, 1 H, -CHO), 4.554 (m, 1 H, MeOH, CH 2 O-), 3.446 (s, 6 H, CH 2 O-), 3.249 , 3.31 (m, 8Η, OCH₂CH₂CO₂-), 1.700 7s, 3 H, CH 3 C = C), 1.554 (s, 3 H, CH 3 C = C); 13 C NMR (d6 -DMSO), 211.28 (C = O), -205.23 (C = O), 199.59 (C = O), 174.86 (C = O), 173.62 (C = 0), 171.72 (C = O), 171.50 (C = O), 166.56 (C = O), 166.53 (C = O); IR (KBr) 3420 (OH), 2040 (CH), 1735 (C = O), 1630, 1580, 1460, 1400, 1380, 1170, 1070, 990 cm -1; MS (FAB negative ion) 1112 (M-1, free acid), 994, 859, 475, 297, 167, 148, 117.99 (100).

Calc'd. for C 67 H 10 9 O 25 N 3 • 2 H 2 O • 57.80 H, 8.12 N, 3.01 Found: C, 57.91; H, 8.21; N, 2.37

Claims (1)

  1. A process for the preparation of a compound of structure
    Wherein R 1, R 2 and R 3 are each independently hydrogen, or R 4; R 4 is - [C (CH 2) m CH (CH 2) n N] p CO 2 R 1 2 or R 2 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of (CH 2) q CO 2 R, - (CH 2) r NR CO 2 R, carbamyl alkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms
    carbon, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl, hydroxyphenylmethyl, imidazolylmethyl or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of &gt; 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid; ) R and R are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R 2 and R 3 are each independently alkyl of 1 to 6 carbon atoms, aralkyl of 7-10 carbon atoms or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; The R13 is X is -C-, O, or S;
    R and R are each independently hydrogen or alkyl of 1 to 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 0-4; u is 0-4; Wherein R, R, m and n are independently in each of the subunits [C (CHO) CH (CHn) N] when p = 2; Or a pharmaceutically acceptable salt thereof, with the proviso that R 3, R 4 and R 5 are not all hydrogen, with the proviso that R 1, R 2 and R 3 are not all 0 [ C (CH 2) m CH (CH 2) n N] p CO 2 E 7 / R 5 R when, and still with another proviso that tu are not both X is 0 or S; characterized in that: (a) acylating a rapamycin with an acylating agent, or (b) sequentially acylating a rapamycin with one or more acylating agents, said acylating agents being selected from the acids of the formula: II or Z- [C (CH2) m CH (CH2) n N] COO R7, or ZC (CH2) t X (CH2)
    wherein R2 is OH; or reactive derivatives thereof if desired by protecting any of the rapamycin positions 42, 31 and 14 with an appropriate protecting group and removing said group if required, and further if desired isolating the product as a pharmaceutically acceptable salt. 2. A process according to claim 10 wherein R 4 is [C (CH 2) CH (CH 3) n] A process according to claim 10 characterized in that R 4 is [C (CH 2) CH (CH 3) 2], or a pharmaceutically acceptable salt thereof. N] CO_R7, ΔIl j Δ ΠI p ΔRM = 0, n = 0, and p = 2 or a pharmaceutically acceptable salt thereof. 4. A process according to claim 1 wherein R4 is [C (CH3) CH (CHO) N] COO R7, c '2' m | '2 ηIJp 2 R5 R6 5 8. . 11 = 0, and R is - (CHâ,,) Râ,, or a pharmaceutically acceptable salt thereof. The process according to claim 1 wherein R 4 is [C (CH 2) CH (CH 3) n] CO 2 R 7, and R 5 is - (CH ) NR9 CO-R10 or an acceptable pharmaceutically acceptable salt thereof. 6. A process as claimed in claim 1 wherein R 4 is [C (CH 2) CH (CH 2) n COO], R 1 is hydrogen, or a pharmaceutically acceptable salt thereof. A process according to claim 10 wherein R4 is -C (CH2) t X (CH2) uC02 R11, or a pharmaceutically acceptable salt thereof.
    8. A process according to claim 1 for preparing rapamycin-42-ester with N - [(1,1-dimethylethoxy) carbonyl] -glycylglycine or a pharmaceutically acceptable salt thereof. 9. A process according to claim 1 characterized in that rapamycin-31,42-diester is prepared with N - [(1,1-dimethyl-ethoxy) carbonyl] -glycylglycine or a pharmaceutically acceptable salt thereof. 10. A process according to claim 1 characterized in that rapamycin-31,42-diester is prepared with N - [(1,1-dimethylethoxy) carbonyl] -N-methylglycine or a pharmaceutically acceptable salt thereof. The process according to claim 1 characterized in that rapamycin-42-ester is prepared with N - [(1,1-dimethylethoxy) carbonyl] -N-methylglycine or a pharmaceutically acceptable salt thereof. The process according to claim 1 characterized in that rapamycin-31,42-diester is prepared with 5- (1,1-dimethylethoxy) -2 - [[(1,1-dimethylethoxy) carbonyl] amino] -5-oxo-pentanoic acid or a pharmaceutically acceptable salt thereof. A process according to claim 1 characterized in that rapamycin-42-ester is prepared with 5- (1,1-dimethylethoxy) -2 - [[(1,1-dimethylethoxy) carbonyl] amino] -5- -oxopentanoic acid or a pharmaceutically acceptable salt thereof. A process according to claim 1 characterized in that rapamycin-31,42-diester is prepared with 2 - [[(1,1-dimethylethoxy) carbonyl] amino] -4-oxo-4- (phenylmethoxy) ) or a pharmaceutically acceptable salt thereof. A process according to claim 1 characterized in that rapamycin-31,42-diester is prepared with 3 - [[(1,1-dimethylethoxy) carbonyl] amino] -4-oxo-4- (phenylmethoxy) buta -amide or a pharmaceutically acceptable salt thereof. 16. A process according to claim 1 characterized in that rapamycin-42-ester is prepared with 3 - [[(1,1-dimethylethoxy) carbonyl] amino] -4-oxo-4- (phenylmethoxy) butanoic acid or a its pharmaceutically acceptable salt. 17. A process according to claim 1 characterized in that rapamycin-42-ester is prepared with 5- (1,1-dimethyloxy) -4 - [[(1,1-dimethylethoxy) carbonyl] amino] - 5-oxopentanoic acid or a pharmaceutically acceptable salt thereof. A process according to claim 1 characterized in that rapamycin-31/42-diester is prepared with 5- (1,1-dimethylethoxy) -4 - [[(1,1-dimethylethoxy) carbonyl] amino] -5-oxo-pentanoic acid or a pharmaceutically acceptable salt thereof. 19. A process according to claim 1 for preparing rapamycin-42-ester with Na, Ne-bis [(1,1-dimethylethoxy) carbonyl] -L-lysine or a pharmaceutically acceptable salt thereof. 20. A process according to claim 1 characterized in that rapamycin-31,42-diester is prepared with Na, Ne-bis [(1,1-dimethylethoxy) carbonyl] -L-lysine or a pharmaceutically acceptable salt thereof. 55
    2. A process according to claim 1 for preparing rapamycin-14,31,42-tris (monobenzylsuccinate) or a pharmaceutically acceptable salt thereof. 22. A process according to claim 1 for preparing rapamycin-31,42-bis (monobenzylsuccinate) or a pharmaceutically acceptable salt thereof. 23. A process according to claim 1 for preparing rapamycin-42- (monobenzylsuccinate) or a pharmaceutically acceptable salt thereof. The process according to claim 1 characterized in that rapamycin-31,42-bishemiglutarate or a pharmaceutically acceptable salt thereof is prepared. The process according to claim 1 characterized in that the rapamycin-31,42-hemiglutarate bissodium salt is prepared. 26. A process according to claim 1 characterized in that the preparation of the rapamycin-31,42-bishemiglutarate salt is bromethamine. 27. A process according to claim 1 for preparing rapamycin-42-hemi-3'-oxoglutarate or a pharmaceutically acceptable salt thereof. A process according to claim 1 characterized in that rapamycin-31,42-bishemi-3'-oxoglutarate or a pharmaceutically acceptable salt thereof is prepared. 56
    29. A process according to claim 1 characterized in that the disodium rapamycin-31,42-bishemi-3'-oxoglutamate salt is prepared. 30. A process according to claim 1 characterized in that the preparation of the rapamycin-31,42-bishemi-3'-oxoglutamate mouse salt is bromethamine. 3. A process as claimed in claim 1 for preparing rapamycin-31,42-bis-hemisuccinate or a pharmaceutically acceptable salt thereof. 32. A process according to claim 1 which is characterized in that the rapamycin-31,42-bishemisuccinate salt bistromethane is prepared. 33. A method for treating transplant rejection, host versus graft disease, autoimmune diseases, and inflammatory diseases characterized in that an immunosuppressive amount of a compound of structure 57
    In which R 1, R 2 and R 3 are each independently hydrogen. 4, or R; R 4 is - [C (CH 2) m CH (CH 2) n] p CO 2 R 2 3 6 6 6 7 7 or CO 2 R 8; 1-carbon, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl-, C1-3 alkoxycarbonyl, C1-4 alkoxycarbonyl, C1-4 alkoxycarbonyl, C 1 -C 5 alkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, R 7 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 8-, hydroxyphenylmethyl, imidazolylmethyl or phenyl which is 58
    optionally mono-, di-, or tri-substituted with one 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, carbon atoms, trifluoromethyl, amino, or a carboxylic acid; R 1 and R 2 are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R 2 and R 3 are each independently alkyl of 1 to 6 carbon atoms, aralkyl of 7-10 carbon atoms or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R13 X is
    O, or S; R and R are each independently hydrogen or alkyl of 1 to 6 carbon atoms; Y is CH or N; m is 0-4; n is 0-4; p is 1-2; q is 0-4; R4 is 0-4; t is 0-4; u is 0-4; Wherein R 1, R 2, m and n are independently at each of 2; (C (CHO) CH (CHâ,,) n N] when p is 2 or 2 or a pharmaceutically acceptable salt thereof, with the proviso that Râ μ, Râ, and Râ,, are not all hydrogen, yet with the proviso of which R 1, R 2 and R 3 are not all of which may be the same or different; and also with another condition that thy are not both 0 when X is 0 or S. A method for the treatment of fungal infections characterized in that it comprises the administration of a compound of structure 60
    Wherein R 1, R 2 and R 3 are each independently hydrogen; 4, or R; R 4 is - [C (CH 2) m CH (CH 2) n N] p CO 2 R 12, -C (CH 2) t X (CH 2), or R c is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 2 to 10 carbon atoms, - (CH) COR, - (CH) NR COR, carbamyl- carbonyl, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl- hydroxyphenylmethyl, imidazolylmethyl or phenyl which is
    optionally mono-, di-, or tri-substituted with one 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, carbon atoms, trifluoromethyl, amino, or a carboxylic acid; R 1 and R 2 are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R 2 and R 3 are each independently alkyl of 1 to 6 carbon atoms, aralkyl of 7-10 carbon atoms or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R13 is X is -C-, O, or S; R 1 to Y is m is n is p is q is 14 and R 9 are each independently hydrogen or alkyl of 6 carbon atoms; CH or N; 0-4; 0-4; 1- 2; 0-4; 62
    r is 0-4; t is 0-4; u is 0-4; wherein R 1, R 2, m and n are independently in each of the subunits [C (CH 2) m CH (CH 2) n N] where p = 2; Or a pharmaceutically acceptable salt thereof, with the proviso that R 3, R 4 and R 5 are not all hydrogen, furthermore with the proviso that R 1, R 2 and R 3 are not all 0 [C (CH 2) m CH (CH2) n N] p CO2 R2 R7 and further with another proviso that thy are not both 0 when X is 0 or S. A process for the preparation of a composition for the treatment of transplant rejection, host disease versus graft, autoimmune diseases, and inflammatory diseases characterized by mixing a pharmaceutically acceptable carrier with an immunosuppressive amount of a compound of structure
    Wherein R 1, R 2 and R 3 are each independently hydrogen; 4, or R; Wherein R 1 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of Q 1 Π 2 7-10 carbon atoms, C 1 -C 10 alkyl, - (CH) CO-R, - (CH₂) NR RR,, carbamyl-C Cá-C Cá-CΓ-C 3-alkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl, hydroxyphenylmethyl, imidazolylmethyl or phenyl which is 64
    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, 2-7 carbalkoxy carbon atoms, trifluoromethyl, amino, or a carboxylic acid; R6 and R6 are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R 1 and R 2 are each independently, alkyl of 1 to 6 carbon atoms, aralkyl of 7-10 carbon atoms or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R13 is X, -C-, O, or S; R and R are each independently hydrogen or alkyl of 1 to 6 carbon atoms; Y is CH or N; m is 0-4; n is 0-4; p is 1-2; q is 0-4; 65
    r is 0-4; t is 0-4; u is 0-4; R 5, m and n are independently in each of the subunits [C (CH 2) m CH (CH 2) n N] where p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R 3, R 4 and R 5 are not all hydrogen, furthermore with the proviso that R 1, R 2 and R 3 are not all 0, (CH 2) m CH (CH 2) N ] pC02R7 / R5 and with another proviso that thy are not both 0 when X is 0 or S. A process for the preparation of a composition for the treatment of fungal infections characterized in that a pharmaceutically acceptable carrier is mixed with a quantity immunosuppressant of a compound of structure 66
    Wherein R 1, R 2 and R 3 are each independently hydrogen; 4, or R; 0 0 R
    R6 [C (CH2) m CH (CH2) n H] p CO2 R2 R3 -C
    C02R12; OR 1. R 2 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 3-7 carbon atoms, - (CH 2) n R 5, - (CH 2) NR 6 CO-, R 7, carbamyl-, hydroxyphenylmethyl, imidazolylmethyl or phenyl which is Alkyl of 2-3 carbon atoms, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl-
    optionally mono-, di-, or tri-substituted with one 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, carbon atoms, trifluoromethyl, amino, or a carboxylic acid; 6 9. R 1 and R 2 are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R 2 and R 3 are each independently alkyl of 1 to 6 carbon atoms, aralkyl of 7-10 carbon atoms or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from alkyl of 1 to 6 carbon atoms carbon, alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2 to 7 carbon atoms, trifluoromethyl, amino or carboxylic acid; R13 X is -C-O, or S; R and R are each independently hydrogen or alkyl of 1 to 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 0-4; u is 0-4; wherein R 5, R 6, m and n are independently in each of the subunits [C (CH 2) m CH (CH 2) n N] where p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R 1, R 2 and R 3 are not all hydrogen, with the proviso that R 1, R 2 and R 3 are not all 0, R 7, R 5 R 6, and with another proviso that your are not both 0 when X is 0 or S. Lisbon, September 17, 1991
    J. PEREIRA DA CRUZ Oticial Agent of Industrial Property RUA VtCTOR COROON, 10-A 3? 1200 USBOA
PT9899091A 1990-09-19 1991-09-17 Process for the preparation of carboxylic acid esters of rapamicin PT98990A (en)

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