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WO1992005179A1 - Carboxylic acid esters of rapamycin - Google Patents

Carboxylic acid esters of rapamycin Download PDF

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Publication number
WO1992005179A1
WO1992005179A1 PCT/US1991/006824 US9106824W WO9205179A1 WO 1992005179 A1 WO1992005179 A1 WO 1992005179A1 US 9106824 W US9106824 W US 9106824W WO 9205179 A1 WO9205179 A1 WO 9205179A1
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Prior art keywords
carbon atoms
alkyl
rapamycin
compound
hydrogen
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PCT/US1991/006824
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French (fr)
Inventor
Craig Eugene Caufield
Amedeo Arturo Failli
Robert John Steffan
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American Home Products Corporation
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Publication date
Priority claimed from US07/657,294 external-priority patent/US5130307A/en
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to KR1019930700829A priority Critical patent/KR930702357A/en
Priority to AU86599/91A priority patent/AU653175B2/en
Publication of WO1992005179A1 publication Critical patent/WO1992005179A1/en
Priority to FI931203A priority patent/FI931203A7/en

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    • 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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Abstract

A compound of structure (I), wherein R?1, R2, and R3¿ are each, independently, hydrogen, or R4; R4 is (a), (b), or (c); R5 is hydrogen, alkyl, aralkyl, -(CH¿2?)qCO2R?8¿, -(CH¿2?)rNR?9CO¿2R10, carbamylalkyl, aminoalkyl, hydroxyalkyl, guanylalkyl, mercaptoalkyl, alkylthioalkyl, indolylmethyl, hydroxypehnylmethyl, imidazoylmethyl or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl, alkoxy, hydroxy, cyano, halo, nitro, carbalkoxy, trifluoromethyl, amino, or a carboxylic acid; R?6 and R9¿ are each, independently, hydrogen, alkyl, or aralkyl; R?7, R8, and R10¿ are each, independently, alkyl, aralkyl, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted; R?11 and R12¿ are each, independently, alkyl, aralkyl, or phenyl which is optionally mono-, di-, or tri-substituted; X is (d), O, or S; R?13? and R?14¿ are each, independently, hydrogen or alkyl; 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 R5, R6, m, and n are independent in each of (e) subunits when p=2; or a pharmaceutically acceptable salt thereof, with the proviso that R?1, R2, and R3¿ are not all hydrogen, further provided that R?1, R2 and R3¿ are not all (a), and still further provided that t and u are not both 0 when X is O or S, which by virtue of its immuno-suppressive activity is useful in treating transplantation rejection, host vs. graft disease, autoimmune diseases, and diseases of inflammation, and by virtue of its antifungal activity is useful in treating fungal infections.

Description

CARBOXY TC ACTD ESTERS OF RAPAMYCTN
BACKGROUND OF THE INVENTION
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.
The immunosuppressive effects of rapamycin have been disclosed in FASEB 3, 3411 (1989), 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
Figure imgf000004_0001
wherein R1, R2> and R3 are each, independently, hydrogen, or R4;
O
H ?
R4 is -[C(CH2)niCH(CH2)nN]pC02R7 , -C- (CH2)tX(CH2)uCO2R11 , or
I I
R5 R6
Figure imgf000004_0002
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
-(CH2)qCO2R8, -(CH2)rNR9CO2R10, carbamylalkyl 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, 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;
R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R7, R8, and R10 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;
R1 ! and R12 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;
Figure imgf000005_0001
R13 and R14 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;
O wherein R >5 , R , , and n are independent in each of the[C(CH2)mCH(CH2)nN]
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2* and R3 are not all hydrogen, further provided that R1, R2- and R3 are not all
O
II
— [C(CH2)mCH(CH2)nN]pCO2R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S. O
II
Of the compounds when R4 is — [C(CH2)mCH(CH2)-.N]pCO2R7
I I
R5 R6 preferred members are those in which m = 0, n = 0, and p = l; m = 0, n = 0, and p = 2; n = 0, and R5 is -(CH2)qCO2R8; m = 0, n = 0, and R5 is -(CH2)rNR9CO2R10; and m = 0, n = 0, and R5 is hydrogen. Preferred compounds also include those
O
Δ. 'I 11 members in which R4 is -C- (CH2)tX(CH2)uCO2Rn .
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
, Z- VC-(CH2)tX(CH2)uCO2Rn , or
Figure imgf000006_0001
Figure imgf000006_0002
where Z is OH in the presence of a coupling reagent, such as dicyclohexyl- carbodiimide. 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. Alternatively, 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.
Where it is desired to prepare acyl derivatives having two or three different R4 groups then sequential acylation may be performed using appropriate acylating agents as defined above, if necessary isolating the desired product by appropriate purification techniques. In general 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 μM. 3H-control thvmus cells - H3-rapamvcin-treated thvmus cells
3H-control thymus cells - H3-test compound-treated cells
A mixed lymphocyte reaction (MLR) 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. On Day 3 and Day 4, tritiated thymidine is given i.p., b.i.d. On Day 5, 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: 3H-PLN cells control C3H mouse - 3H-PLN cells rapamvcin-treated C3H mouse 3H-PLN cells control C3H mouse - 3H-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.
The following table summarizes the results of representative compounds of this invention in these three standard test procedures.
TABLE 1
Figure imgf000008_0001
TABLE 1 (Continued)
Compound Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Rapamycin
Figure imgf000009_0001
** Result expressed as percent inhibition of lymphoproliferation at 1 μM. + Not evaluated ++ Results obtained using cremophore/ethanol as a vechicle for administration. Ratios of 0.33 and 1.07 were also obtained using carboxymethyl cellulose as a vehicle for administration. ## Results obtained using cremophore/ethanol as a vechicle for administration. Ratios of 0.20 and 1.08 also were obtained using carboxymethyl cellulose as a vehicle for administration. ### A ratio of 0.42 also was 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. Positive ratios in the LAF and PLN test procedures indicate suppression of T cell proliferation. As a transplanted pinch skin grafts are typically rejected within 6-7 days without the use of an immunosuppressive agent, the increased survival time of the skin graft when treated with the compounds of this invention further demonstrates their utility as immunosuppressive agents. While it appears that the compound disclosed by Examples 12 and 21 may cause T cell proliferation in the PLN test procedure, it is believed a negative ratio in this test procedure coupled with an increased survival time observed in the skin graft test procedure indicates a proliferation of TSUppressor cells, which are implicated in suppressing the immune response, (see, I. Roitt et al. Immunology, CV.Moseby Co. 1989, p 12.8-12.11).
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 ( μg/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.
Table 2*
Strain of Candida albicans
Figure imgf000010_0001
Table 2* (Continued) Strain of Candida albicans
Figure imgf000011_0001
* expressed as MIC (μg/ml) + not evaluated
Based on the results of these standard pharmacological test procedures, 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. The compounds may be administered neat or with a pharmaceutical carrier to a mammal in need thereof. The pharmaceutical carrier may be solid or liquid.
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. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, 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). For parenteral administration, 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.
Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, 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. In addition, 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 examples illustrate the preparation of representative compounds of this invention. Example 1
Rapamycin-42-ester with N-fH . l-dimethylethoxy)carbonyl l-glycylglycine
Under anhydrous conditions, a solution of rapamycin (3 g, 3.28 mmole) and
N-[(l,l-dimethylethoxy)carbonyl]-glycylglycine (3.04 g, 13.1 mmole) in 40 mL of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide (1.35 g, 6.56 mmole) followed by 4-dimethylaminopyridine (0.8 g, 6.56 mmole). After stirring at ambient temperature for 48 hours, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were absorbed directly onto silica gel Merck 60 by adding the gel and evaporation to dryness. Flash chromatography of the preabsorbed material (using a gradient elution with ethylacetate-toluene from 2:1 to 1:0 v/v) afforded 1.05 g (28.3 %) of the title compound isolated as a three quarter toluene solvate, along with the 31,42-diester of Example 2. HPLC analysis showed that the monoester is a 8.3: 1 mixture of two conformers. H NMR (CDCI3, 400 MHz): δ 1.46 (m, 9H, COOBu1), 1.654 (s, 3H,
CH3C=C), 1.751 (s, 3H, CH3C=C), 3.14 (s, 3H, CH3O), 3.33 (s, 3H, CH3O), 3.36 (s, 3H, CH3O), 4.18 (d, 1H, CtfOH), 4.75 (m, 1H, 42-CHO ), 4.79 (s, 1H, OH); High Res. MS (neg. ion FAB) Calcd for C60H93N3O1 : 1127.6504, measured mass 1127.6474.
Anal. Calcd for C60H93N3O17 • 0.75 PI1CH3: C, 65.45; H, 8.33; N, 3.51
Found: C, 65,23; H, 8.32; N, 3.86
The following representative compounds can be prepared from rapamycin and the appropriate terminally-N-substituted amino acid by employing the method used to prepare the title compound in Example 1.
Rapamycin-42-ester with N-[(fluorenylmethoxy)carbonyl]-alanylserine Rapamycin-42-ester with N-[(fluorenylmethoxy)carbonyl]-glycylglycine Rapamycin-42-ester with N-[(ethoxy)carbonyl]-arginylmethionine Rapamycin-42-ester with N-[(4l-chlorophenoxy)carbonyl]-histidylarginine Rapamycin-42-ester with N-[(phenoxy)carbonyl]-tryptophanylleucine Rapamycin-42-ester with N-[(phenylmethoxy)carbonyl)]-N-methylglycyl-N- ethylalanine Rapamycin-42-ester with N-[(phenylmethoxy)carbonyl]-N-methyl-β- alanylphenylalanine
Rapamycin-42-ester with N-[(l,l-d-methylethoxy)carbonyl]-cysteinylglycine
Example 2
Rapamydn-31.42-diesterwith N-r(l.l-dimethylethoxy')carbonyl1-glycylglycine
The title compound (1.85 g, 42%) was separated from the 42-monoester as described in Example 1 and isolated as a three quarter toluene solvate. HPLC analysis showed that the diester is a 8.1: 1 mixture of conformers.
!H NMR (CDCI3, 400 MHz): δ 1.452 (m, 18H, COOBu*), 1.6612 (s, 3H, CH3C=C), 1.7815 (s, 3H, CH3C=C), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 4.52 (s, IH, OH), 4.79 (m, IH, 42- ΑO ); High Res. MS (neg. ion FAB): Calcd for C69H107N5O21 1341.7458, measured mass: 1341.7463.
Anal. Calcd for C69H107N5O21 • 0.75 PI1CH3: C, 63.17; H, 8.06; N, 4.96 Found: C, 62.83; H, 8.09; N, 5.00
The following representative compounds can be prepared from rapamycin and the appropriate terminally-N-substituted amino acid by employing the method used to prepare the title compound in Example 2.
Rapamycin-31 ,42-diester with N-[(fluorenylmethoxy)carbonyl]-alanylserine Rapamycin-31.42-diester with N-[(fluorenylmethoxy)carbonyl]-glycylglycine Rapamycin-31,42-diester with N-[(ethoxy)carbonyl]-arginylmethionine Rapamycin-31,42-diester with N-[(4'-chlorophenoxy)c-trbonyl]-histidylarginine Rapamycin-31,42-diester with N-[(phenoxy)carbonyl]-tryptophanylleucine Rapamycin-31,42-diester with N-[(phenylmethoxy)carbonyl)]-N-methylglycyl-N- ethyl-alanine
Rapamycin-31,42-diester with N-[(phenylmethoxy)carbonyl]-N-methyl-β- alanylphenyl- alanine Rapamycin-31 ,42-diester with N-[( 1 , 1 -dimethylethoxy)carbonyl] -cysteinylglycine Example 3
Rapamycin-31 ,42-diester with N-IY1.1 -dimethylethoxy)carbonyl1-N-methylglycine
Under anhydrous conditions, an ice cold solution of rapamycin (2 g, 2.18 mmole) and Nα-Boc sarcosine (1.65 g, 8.75 mmole) in 20 ml of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmole) followed by 4-dimethylaminopyridine (1 g, 8.7 mmole). 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 silica Merck 60, elution with hexane-ethylacetate 1:1, v/v) to provide the title compound (0.75 g, 27.4%) along with the 42-monoester of Example 4. HPLC analysis showed that the diester is a 19.8:1 mixture of two conformers. The multiplicity of the NMR peaks suggests the presence of amide rotamers.
IH NMR (CDC13, 400 MHz): δ 1.411, 1.438, 1.448 and 1.474 (m, 18 H, COOBut), 2.91 (m, 6H, NCH3), 3.14 (s, 3H, CH3O), 3.34 (s, 3H, CH3O), 3.37 (s, 3H, CH3O), 4.73 (broad, IH, 42-CHO), 4.82 (2s, IH, OH); High Res. MS (neg. ion FAB): Calcd. for C67H105N3O19 1255.7342, measured mass 1255.7289. Anal. Calcd for C67H105N3O19: C, 64.04; H, 8.42; N, 3.34
Found: C, 64.14; H, 8.74; N, 3.63
The following representative compounds can be prepared from rapamycin and the appropriate terminally-N-substituted amino acid by employing the method used to prepare the title compound in Example 3.
Rapamycin-31,42-diester with N-[(ethoxy)carbonyl]-tyrosine
Rapamycin-31 ,42-diester with N-[(fluorenylmethoxy)carbonyl]-phenylalanine
Rapamycin-31 ,42-diester with N-[(3',4',5'-trihydroxyphenoxy)carbonyl]-isoleucine Rapamycin-31,42-diester with N-[(l,l-dimethylethoxy)carbonyl)-glutamine Rapamycin-31,42-diester with N-[(phenoxy)carbonyl]-N-methylalanine Rapamycin-31,42-diester with N-[(propyloxy)carbonyl]-4-aminobutryic acid Rapamycin-31,42-diester with N-[(phenylmethoxy)carbonyl]-7-aminoheptanoic acid Rapamycin-31,42-diester with N-[(fluorenylmethoxy)carbonyl]-serine Example 4
Rapamycin-42-esterwith N-r(l.l-dimethylethoxy')carbonyn-N-methylglvcine
Under anhydrous conditions, an ice cold solution of rapamycin (0.95 g, 1.02 mmole) and Nα-Boc sarcosine (0.21 g, 1.1 mmole) in 20 mL of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide 0.21 g, 1 mmole) followed by 4-dimethylaminopyridine (0.12 g, 1 mmole). 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. Flash chromatography of the crude product (on silica Merck 60, elution with hexane- ethylacetate 1:1 v/v to remove the diester of Example 3, followed by chloroform- ethylacetate-methanol 75:25:1 v/v) provided partially purified title compound (0.38 g, 35%). Pure product was obtained by preparative HPLC (Waters Prep 500, silica gel, chloroforai-ethylacetate-methanol 75:25: 1 v/v, flow rate 250 mL min). HPLC analysis showed that the ester is a 6.6:1 mixture of two conformers. The multiplicity of NMR peaks suggests the presence of amide rotamers.
IH NMR (CDCI3, 400 MHz): δ 1.42-1.46 (ds, 9H, COOBu*), 2.91 (ds, 3H, NCH3), 1.644 (s, 3H, CH3C=C), 1.738 (s, 3H, CH3C=C), 3.12 (s, 3H, CH3O), 3.32 (s, 3H, CH3O), 3.35 (s. 3H, CH3O), 4.18 (d, IH, CHOH), 4.71 (broad, IH, 42-CHO), 4.78 (broad s, IH, OH); High Res. MS (neg. ion FAB): Calcd for C59H92N2O16 1084.6446, measured mass 1084.6503.
Anal. Calcd for C59H92N2O16- C, 65.29; 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 terminally-N-substituted amino acid by employing the method used to prepare the title compound in Example 4.
Rapamycin-42-ester with N-[(ethoxy)carbonyl]-tyrosine
Rapamycin-42-ester with N-[(fluorenylmethoxy)carbonyl]-phenylalanine Rapamycin-42-ester with N-[(3',4',5'-trihydroxyphenoxy)carbonyl]-isoleucine Rapamycin-42-ester with N-[(l,l-dimethylethoxy)carbonyl)-glutamine Rapamycin-42-ester with N-[(phenoxy)carbonyl]-N-methylalanine Rapamycin-42-ester with N-[(propyloxy)carbonyl]-4-aminobutryic acid
Rapamycin-42-ester with N-[(phenylmethoxy)carbonyl]-7-aminoheptanoic acid Rapamycin-31,42-diester with N-[(fluorenylmethoxy)carbonyl]serine
Example 5
Rapamycin-31.42-diester with 5-(l.l-dimethylethoxy)-2-rr(l.l-dimethylethoxy)- carbonynaminol-5-oxopentanoic acid
Under anhydrous conditions, an ice cold solution of rapamycin (4 g, 4.37 mmole) and L-glutamic acid Nα~Boc-γ-tert-butylester (4.9 g, 16.1 mmole) in 40 mL of dry dichloromethane was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmole) followed by 4-dimethylaminopyridine (1 g, 8.7 mmole). After stirring overnight at room temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to provide 11 g of an amorphous amber solid. The crude product was purified by flash chromatography (on silica Merck 60, gradient elution with hexane-ethylacetate from 2:1 to 1:1, v/v) to yield 4.52 g (69.6%) of the title compound along with the 42-monoester of Example 6. HPLC analysis showed that the diester consists of a 6.6: 1 mixture of two conformers. H NMR (CDCI3, 400 MHz): δ 1.42 (m, 36 H, COOBu1), 1.646 (s, 3H,
CH3C=C), 1.701 (s, 3H, CH3C=C), 3.13 (s, 3H, CH3O), 3.34 (s, 3H, CH3O), 3.36 (s, 3H, CH3O), 4.735 (m, 2H, OH+42-CH-O); High Res. MS (neg. ion FAB): calc. for C79H125N3O23 1483.8715, measured mass 1483.8714.
Anal. Calcd for C79H125N3O23: 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 appropriately terminally-N-substituted amino diacid monoester by employing the method used to prepare the title compound in Example 5.
Rapamycin-31,42-diester with 6-(phenylmethoxy)-2-[[fluorenylmethoxy)carbonyl]- amino]-6-oxohexanoic acid
Rapamycin-31 ,42-diester with 6-(4'-methylphenoxy)-3-[[(phenylmethoxy)carbonyl]- amino-6-oxohexanoic acid
Rapamycin-31,42-diester with 6-(ethoxy)-4-[[(phenoxy)carrx)nyl]amino]-6-oxo- hexanoic acid Rapamycin-31,42-diester with 6-(methoxy)-5-[[(ethoxy)carbonyl]amino]-6-oxo- hexanoic acid
Rapamycin-31,42-diester with 4-(phenoxy)-2-[N-[(l,l-dimethylethoxy)carbonyl]-N- methylamino]-4-oxobutanoic acid Rapamycin-31,42-diester with 4-(phenylmethoxy)-3-[N-[(methoxy)carbonyl]-N- ιι_ethylamino]-4-oxobutanoic acid
Example 6
Rapamycin-42-ester with 5-(l . l-dimethylethoxy)-2-rr(l . l-dimethylethoxyV carbonynaminol-5-oxopentanoic acid
The title compound (1.14 g, 20.6%) was separated from the 31,42-diester as described in Example 5 and isolated as the quarter hydrate/mono-ethyl acetate solvate. HPLC analysis showed that the monoester is a 11.5: 1 mixture of two conformers.
!H NMR (CDCI3, 400 MHz): δ 1.425 (m, 18H, COOBu1), 1.643 (s, 3H,
CH3C=C), 1.737 (s, 3H, CH3C=C), 3.13 (s, 3H, CH3O), 3.32 (s, 3H, CH3O),
3.36 (s, 3H, CH3O), 4.17 (d, IH, CHOH), 4.71 (M, IH, 42-CHO), 4.785 (s, IH, OH); High Resolution MS ( neg. ion FAB): Calc. for C65Hχo2N2θι 1198.7127, measured mass 1198.7077.
Anal. Calcd for C65H102N2O18 • CH3COOEt • 0.25 H2O: 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 appropriately terminally-N-substituted amino diacid monoester by employing the method used to prepare the title compound in Example 6.
Rapamycin-42-esterwit 6-(phenylmethoxy)-2-[[flucM«nylmethoxy)c--rbonyl]-a-i-ino]- 6-oxohexanoic acid
Rapamycin-42-ester with 6-(4'-methylphenoxy)-3-[[(phenylmethoxy)carbonyl]-amino- 6-oxohexanoic acid Rapamycin-42-iester with 6-(ethoxy)-4-[[(phenoxy)carbonyl]amino]-6-oxo- hexanoic acid
Rapamycin-42-ester with 6-(methoxy)-5-[[(ethoxy)carbonyl]amino]-6-oxo- hexanoic acid Rapamycin-42-ester with 4-(phenoxy)-2-[N-[(l,l-dimethylethoxy)carbonyl]-N- methylamino]-4-oxobutanoic acid
Rapamycin-42-ester with 4-(phenylmethoxy)-3-[N-[(methoxy)carbonyl]-N- me ylainino]-4-oxobutanoic acid
Example 7
Rapamycin-31.42-diester with 2-rr(l.l-dimethylethoxy')carbonynamino1-4-oxo-4- (phenylmethoxy) butanoic acid
Under anhydrous conditions, 295mg (1.21mmol) of 2,4,6 trichlorobenzoyl chloride was added to a solution of 391mg(1.21mmol) of Nα-Boc-L-aspartic acid-β- benzyl ester and 170μL (1.21mmol) of Et3N in 1 mL of THF at room temperature. After stirring for 30 minutes, 500 mg (0.55mmol) of rapamycin and 295 mg ( 2.42 mmol) of dimethylaminopyridine was added and the reaction was left to stir overnight. The reaction mixture was then filtered and the filtrate concentrated in vacuo. Pure product (200 mg, 25%) was obtained by preparative HPLC (5 cm column, 40 % ethyl acetate-hexane). The product was isolated as the heptahydrate.
*H NMR (CDC13, 400 MHz) δ 7.347 (s, 10 H, Ar), 6.223, 5.126 (s, 4 H, CH2Ph), 4.698 (m, 1 H, CH-CO2), 4.587 (m, 2 H, NH), 3.353 (s, 3 H, CH3O), 3.337 (s, 3
H, CH3O), 3.301 (s, 3 H, CH3O), 2.775 (m, 4 H, CH2C02); IR (KBr) 3420 (OH),
2935 (CH), 2920 (CH), 1730 (C=O), 1650, 1500, 1455, 1370, 1170 cm"1; MS (neg. ion FAB) 1523 {Mr), 1433, 297, 248, 205, 148, 44, 25 (100).
Anal. Calcd for C83H1 ι7N3θ23-7H20 C, 60.40; H, 7.09; N, 2.54 Found: C, 60.54; H, 7.28; N, 2.56 Example 8
Rapamycin-31.42-diester with 3-rrfLl-dimethylethoxy)carbonyllamino1-4-oxo-4- (phenylmethoxy. butanoic acid
Under anhydrous conditions, 532 mg (2.18 mmol) of 2,4,6 trichlorobenzoyl chloride in 1 mL THF was added to a solution of 704 mg (2.18 mmol) of Nα-Boc-L- aspartic acid-α-benzyl ester and 303 μL (2.18 mmol) of Et3N in 5 mL of THF at room temperature. After stirring for 20 minutes, the reaction mixture was filtered over sintered glass, and the precipitate was washed with THF. The filtrate was concentrated in vacua 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 was added dropwise. The reaction was stirred for 2 hr, poured into ethyl acetate, and washed consecutively with 0.5 N HC1 and brine. The solution was dried over sodium sulfate, decanted, concentrated in vacua to give a white foamy solid, which was purified via flash chromatography on a 60 mm x 100 mm silica column (20- 40 % ethyl acetate/hexane as eluant) to give 532 mg (33 %) of the title compound which was isolated as the hydrate.
!H NMR (CDC13, 400 MHz) δ 7.362 (s, 10 H, Ar), 5.193 (s, 4 H, CH2Ph), 4.596 (m, 1 Η, CH-CO2), 4.586 (m, 2 Η, NH), 3.336 (s, 3 Η, CH5O), 3.306 (s, 3 Η, CH5O), 3.145 (s, 3 Η, CH3O); IR (KBr) 3410 (OΗ), 2950 (CΗ), 2920 (CΗ), 1735 (C=0), 1710 (C=0), 1640, 1490, 1445, 1350, 1150 cm -1; MS (neg. ion FAB) 1524 (M-), 1434, 297, 248, 232, 214, 205, 167, 148, 42 (100), 26.
Anal. Calcd for C83Η117Ν3O23 • H2O: C, 65.38; H, 7.73; N, 2.76 Found: C, 64.85; H, 7.67; N, 2.56
Example 9
Rapamvcin-42-ester with 3-rKl .l-dimethylethoxy)carbonyl1amino]-4-oxo-4- (phenylmethoxy) butanoic acid
The title compound (374 mg, 23%) was prepared by the method described in the previous Example and separated from the compound described in the previous Example by flash chromatography (20-40% ethyl acetate/hexane as the eluant) and isolated as the sesquihydrate. *H NMR (CDCI3, 400 MHz) δ 7.356 (s, 5 H, Ar), 5.185 (s, 2H, CH2Ph),
4.635 (m, 1 Η, CH-CO2), 4.582 (m, 1 Η, NH), 3.330 (s, 6Η, CH3O), 3.135 (s, 3
Η, CH3O); IR (KBr) 3410 (OΗ), 2950 (CΗ), 2920 (CΗ), 1735 (C=O), 1710 (C=O),
1640, 1490, 1445, 1350, 1150cm-1; MS (neg. ionFAB) 1218 (M-), 1127, 590, 168, 42, 25, 17 (100).
Anal. Calcd for Q57Η98Ν2O18 • 1.5 H2O: C, 63.64; H, 8.21; N, 2.22 Found: C, 63.64; H, 7.51; N, 2.13
Example 10
Rapamycin-42-ester with 5-(l.l-dimethyloxy)-4-rr(l.l-dimethylethoxy carbonyn aminol-5-oxopentanoic acid
Under anhydrous conditions, an ice cold solution of rapamycin (4 g, 4.37 mmole) and L-glutamic acid Nα-Boc-α-tert-butylester (4.9 g, 16.1 mmole) in 40 mL of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmole) followed by 4-dimethylamino pyridine (1 g, 8.7 mmole). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacua to give 9 g of an amorphous amber solid. The crude product was purified by flash chromatography (on silica Merck 60, gradient elution with hexane-ethylacetate from 2:1 to 3:2, v/v) to provide 1.35 g (25.7%) of the title compound along with the 31,42-diester of
Example 11. HPLC analysis showed that the monoester is a 7.5 :1 mixture of two conformers.
JH NMR (CDCI3, 400 MHz): δ 1.43 (s, 9H, COOBu1) and 1.46 (s, 9H, COOBut), 1.65 (s, 3H, CH3C=C), 1.75 (s, 3H, CH3C=C), 3.14 (s, 3H, CH3O), 3.34 (s, 3H, CH3O), 3.38 (s, 3H, CH3O), 4.18 (d, IH, CH-OH), 4.65 (m, IH, 42- CHO), 4.80 (s, IH, OH);
High Res. MS (neg. ion FAB): Calc. for C65H102N2O18. 1198.7126, measured mass 1198.7135.
Anal. Calcd for C65Hι02N2θι8: C, 65.09; H, 8.57; N, 2.34
Found C, 65.04; H, 8.33; N, 2.64 Example 11
Rapamvcin-31.42-diester with 5-(l.l-dimethylethoxyV4-rr(l.l-dimethylethox .- carbonyll- aminol-5-oxopentanoic acid
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.
*H NMR (CDCI3, 400 MHz): δ 1.43 (s, 18H, COOBu*), 1.46 (s, 18H,
COOBu1), 1.659 (s, 3H, CH3C=C), 1.759 (s, 3H, CH3C=C), 3.14 (s, 3H, CH3O),
3.34 (s, 3H, CH3O), 3.38 (s, 3H, CH3O), 4.66 (m, IH, 42-CHO), 4.72 (s, IH,
OH); High Res. MS (neg. ion FAB): Calcd for C79H125N3O23: 1483.8704, measured mass 1483.8636.
Anal. Calcd for C79H125N3O23: C, 63.90; H, 8.49; N, 2.83 Found: C, 63.68; H, 8.60; N, 3.20
Example 12
Rapamvcin-42-ester with N-3-. NS-bisr(l.l-dimethylethoxy)carbonyn-L-lvsine
Under anhydrous conditions, a solution of rapamycin (3 g, 3.28 mmole) and
Nα, ISP-bis-Boc-L-lysine (4.5 g, 13 mmole) in 40 mL of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide (1.35 g, 6.56 mmole) followed by 4- dimethylaminopyridine (0.8 g, 6.56 m mole). After stirring overnight 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. Flash chromatography of the crude product (on silica Merck 60, elution with hexane- ethylacetate 1:1 v/v) gave partially purified title compound. Pure product (0.8 g, 19.6%) was obtained by preparative HPLC (Waters Prep 500, silica gel, hexane- ethylacetate 3:2 v/v, flow rate 250 mL min). HPLC analysis showed that the monoester is a 9: 1 mixture of two conformers. !H NMR (CDCI3, 400 MHz): δ 1.438 (m, 9H, COOBu1), 1.455 (s, 9H, COOBut), 652 (S, 3H, CH3C=C), 1.752 (s, 3H, CH3C=C), 3.14 (s, 3H, CH3O), 3.33(s, 3H, CH3O), 3.37 (s, 3H, CH3O), 4.18 (d, IH, CHOH), 4.72 (m, IH, 42- CHO), 4.79 (s, IH, OH); High Res. MS (neg. ion FAB): Calcd for C67Hκ)7N3θi8:
1241.7549, measured mass 1241.7604.
Anal. Calcd for C67H107N3O18 : C, 64.76; H, 8.68; N, 3.38
Found: C, 64.58; H, 9.01; N, 3.10
Example 13
Rapamycin-31.42-diester with N&. N----bisr(l.l-dimethylethoxy)c_trbonyl.-L-lvsine
Under a nitrogen atmosphere, a solution of Nα,Nε bis-Boc-L-lysine (1.038 g, 3 mmole) and triethylamine (0.42 mL, 3 mmmole) in 10 mL of anhydrous THF was treated in one portion with 2,4,6-trichlorobenzoyl chloride (0.73 g, 3 mmole). After stirring for 20 minutes at ambient temperature, 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 mmole) containing 4-dimethylamino pyridine (0.59 g, 4.8 mmole) in 10 mL of benzene. After stirring at ambient temperature overnight, the precipitated solid was collected and the filtrate was evaporated to dryness (yellow foam). The crude product was purified by flash chromatography ( on silica Merck 60, elution with hexane-ethylacetate 1:1) to provide title compound (1.15 g, 67%). HPLC analysis shows that the diester is a 9:1 mixture of two conformers.
IH NMR (CDCI3, 400 MHz): δ 1.426 (m, 9H, COOBut), 1.438 (s, 9H, COOBut),
1.443 (s, 9H, COOBut), 1.446 (s, 9H, COOBut), 3.141 (s, 3H, CH3O), 3.36 (s, 3H,
CH3O), 3.378 (s, 3H, CH3O), 4.68-4.76 (m, 2H, OH and 42-CHO); High res. MS
(neg. ion FAB): Calcd. for C83H135N5O23 1569.9526, measured mass 1569.9537. Anal. Calcd. for C83H135N5O23: C, 63.46; H, 8.66; N, 4.46
Found: C, 63.06; H, 8.84; N, 4.09 Example 14.
Rapamycin- 14.31 -42-tris(monobenzylsuccinate)
To a solution of 5.0 g (5.47 mmol) of rapamycin, 3.41 g (16.41 mmol) of monobenzylsuccinate, and 3.15 g (16.41 mmol) of l-(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 2 N HCl and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a light yellow foam. Hash 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, upon concentration, gave 330 mg (4.1 %) of pure rapamycin- 14,31, 42-tris- (monobenzylsuccinate).
*H NMR (CDC13, 400 MHz) δ 7.353 (bs, 15 H, arom), 5.168 (d, J = 2.0 Hz, 1 H, CH-O2C), 5.148 (m, 6 Η, CH2Ph), 4.672 (m, 1 Η, CO2CH-CΗOMe), 3.355 (s, 3 H, CH5O-), 3.337 (s, 3 Η, CH3O-), 3.327 (s, 3 Η, CH3O-), 2.697 ( m, 12 Η, θ2CCH2CH2Cθ2CΗ2Ph), 1.745 (s, 3 H, CH3C=C), 1.655 (s, 3 H, CH3C=C); IR (KBr) 3450 (OH), 2950 (CH), 1745 (C=0), 1650, 1460, 1385, 1360, 1160, 1105, 995 cm-1.
Analysis Calcd for C84Hi09NO2ι - 3 H20 C 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 half acid-ester by employing the method used to prepare the title compound in Example 14.
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(monobenzylsuccinate)
Fraction # 2, obtained from the procedure employed in Example 14, gave
1.25 g (17.7 %) of pure rapamycin-31,42-bis(monobenzylsuccinate) upon concen¬ tration. lH NMR (CDC13, 400 MHz) δ 7.351 (bs, 10 H, arom). 5.168 (d, J = 2.0 Hz, 1 H, CH-O2C), 5.125 (m, 4 Η, CH2Ph), 4.680 (m, 1 Η, CO2CH-CΗOMe), 3.356 (s, 3 H, CH3O-), 3.329 (s, 3 H, CH3O-), 3.146 (s, 3 Η, CH3O-), 2.639 ( m, 8 Η, O2CCH2CH2CO2CΗ2P--), 1.748 (s, 3 H, CHiC=C), 1.654 (s, 3 Η, CH3C=C); IR (KBr) 3450 (OΗ), 2940 (CΗ), 1740 (C=O), 1650, 1455, 1380, 1355, 1160, 1105, 995 cm-1; MS (neg. ion FAB) 1294 (M-), 1202, 1103, 1012, 590, 511, 475, 297, 207, 167, 148, 99 (100); High Res. MS (neg. ion FAB) Calcd for C73H99NO19 1293.68108, found 1293.6811.
Analysis Calcd for C73H99NO19 Η2O 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 half acid-ester by employing the method used to prepare the title compound in 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 (monobenzylthiodiglycolate)
Rapamycin-31 ,42-bis (monohexyldiglycolate)
Rapamycin-31 ,42-bis (monopropylphthalate) Rapamycin-31,42-bis (monoethyl-2',6'-pyridinedicarboxylate)
Example 16.
Rapamycin-42-(monobenzylsuccinate)
Fraction # 3, obtained from the procedure employed in Example 14, gave 930 mg (15.4 %) of pure rapamycin-42-monobenzylsuccinate upon concentration. iH NMR (CDCI3, 400 MHz) δ 7.355 (bs, 5 H, arom), 5.141 (m, 2 H, CH2Ph), 4.680 (m, 1 Η, CC^CH-CΗOMe), 3.364 (s, 3 H, CH3O-), 3.333 (s, 3 Η, CH3O-), 3.141 (s, 3 Η, CH5O-), 2.698 ( m, 4 Η, O2CCH2CH2CO2CΗ2PI1), 1.751 (s, 3 H, CH3C=C), 1.655 (s, 3 Η, CH3C=C); IR (KBr) 3450 (OΗ), 2940 (CΗ), 1740 (C=0), 1645, 1455, 1380, 1165, 1105, 990 cm-1; MS (neg. ion FAB) 1103 (M-), 1045, 1012, 624, 590, 167, 99 (100); High Res. MS (neg. ion FAB) Calcd for C 2H89NO16 1103.6181, found 1103.6048.
Analysis Calcd for C62H89NOi6 - H20 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 half acid-ester by employing the method used to prepare the title compound in Example 16.
Rapamycin-42-(monomethylsuccinate)
Rapamycin-42-monophenyl-3',3'-dimethylglutarate)
Rapamycin-42-(mono t-butyl-3'-methylglutarate)
Rapamycin-42-(monobenzylthiodiglycolate)
Rapamycin-42-(monohexyldiglycolate) Rapamycin-42-(monopropylphthalate)
Rapamycin-42-(monoethyl-2,,6'-pyridinedicarboxylate)
Example 17.
Rapamycin-31.42-bishemi lutarate
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 and the reaction mixture was allowed to reflux for 8 h. The solution was cooled to room temperature, poured into 2 N 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 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. JH NMR (CDCI3. 400 MHz) δ 5.398 (m, 1 H, -Cθ2CHCHOMe), 4.683 (m, 1 H, -CO2CHCHOMe), 3.364 (s, 3 H, CH30-), 3.362 (s, 3 H, CH3O-), 3.106 (s, 3 H, CH3O-), 2.407 (m, 8 H, -O2CCH2CH2CH2CO2H), 1.960 (m, 4 H, -O2CCH2CH2CH2CO2H), 1.770 (s, 3 H, CH3C--C), 1.653 (s, 3 H, CH3C=C); 1 C NMR (CDCI3, MHz) 211.45 (C=O), 206.84 (C=O), 200.44 (C=O), 177.83 (C=0), 177.04 (C=0), 172.43 (C=0), 171.20 (C=0), 165.27 (C=0), 159.08 (C=0); IR (KBr) 3430 (OH), 2940 (CH), 2880 (CH), 1745 (C=O), 1685, 1625, 1580, 1450, 1385, 1330, 1200, 1140, 1100, 990 cm-1; MS (neg. ion FAB) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; High Res. MS (neg. ion FAB) Calcd for C6ιH9oOι9N (M-H) 1140.6107, Found 1140.6106. Analysis Calcd for Q51H91O19N • H2O 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 by employing the method used to prepare the title compound in Example 17.
Rapamycin-31 ,42-bishemi-3'-methylglutarate Rapamycin-31 ,42-bishemi-3',3'-dimethylglutarate Rapamycin-31 ,42-bishemi-3'-oxoglutarate
Rapamycin-31,42-bishemi-3'-thioglutarate Rapamycin-31 ,42-bishemi-phthalate Rapamycin-31 ,42-bishemi-2',3'-pyridine dicarboxylate
Example 18.
Rapamycin-31.42-hemiglutarate bissodium salt
Purified bis-31,42-hemiglutarate of rapamycin (740 mg, 649 umol), prepared as described in Example 17, was dissolved in 5 mL of 95 % ethanol and 107 mg (1.27 mmol) of sodium bicarbonate was added. Water (1 mL) was added to completely dissolve the salt. Once dissolved, the light yellow solution was concentrated in vacuo to give a foamy yellow solid. The foam was dried in a drying pistol for 24 h, refluxing over acetone at reduced pressure to give 520 mg of the bissodium salt. *H NMR (d6-DMSO, 400 MHz) δ 5.235 (m, 1 H, -CHO2C), 4.498 (m, 1 Η, MeOCΗCHO2C-), 3.287 (s, 6 Η, 2 CH3O-), 3.236 (s, 3 Η, CH3O-), 2.245 (m, 8 Η, O2CCH2CΗ2CH2CO2-), 1.712 (s, 3 Η, CH3C=C), 1.593 (s, 3 Η, CH3C=C); IR (KBr) 3420 (OΗ), 2920 (CΗ), 1725 (C=O), 1675, 1620, 1560, 1450, 1400, 1375, 1230, 1195, 1130, 1090, 980 cm"1; MS (neg. ion FAB) 1112 (M-l, free acid), 994, 589, 475, 297, 167, 148, 117, 99 (100); High Res. MS (neg. ion FAB) Calcd for C6iH89θι9NNa (M-Na) 1162.5926, Found 1162.5899.
Analysis Calcd for C6iHs9θi9NNa2 - H2θ C 60.85; H 7.56; N 1.16 Found C 60.67; H 7.36; N 1.58
Example 19.
Rapamycin-31.42-bishemiglutarate bistromethamine salt
Purified bis-31,42 hemiglutarate of rapamycin (950 mg, 833 umol), prepared as described in Example 17, was dissolved in 5 mL of 95 % ethanol and 197 mg (1.63 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 900 mg (78 %) of the bistromethamine salt.
lH NMR (d6-DMSO, 400 MHz) δ 5.253 (m, 1 H, -CHO2C), 4.523 (m, 1 Η,
MeOCΗCH02C-), 3.347 (s, 6 Η, 2 CH3O-), 3.276 (s, 3 Η, CH3O-), 2.289 (m, 8 Η, O2CCH2CΗ2CH2CO2-), 1.681 (s, 3 Η, CH3C=C), 1.595 (s, 3 Η, CH3C=C); IR (KBr) 3400 (OΗ), 2920 (CΗ), 1730 (C=O), 1620, 1555, 1450, 1400, 1370, 1185, 1060, 980 cm-1; MS (neg. ion FAB) 1140 (M-Η, free acid), 1028, 167, 148, 131 (100), 113; High Res. MS (neg. ion FAB) Calcd for C 1H90O19N (M-H, free acid) 1140.6107, Found 1140.6069.
Analysis Calcd for C69Hιo3θ25N3 - 2 H2O C 58.77; H 7.58; N 2.98 Found C 58.47; H 7.94; N 3.58 Example 20.
Rapamvcin-42-hemi-3'-oxoglutarate
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 diglycolic anhydride followed by 1.32 mL (1.29 g, 16.4 mmol) of pyridine. To this was 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 2 N 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 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. l NMR (CDC13, 400 MHz) δ 4.768 (m, 1 H, CO2CH-CHOMe), 4.250 (m, 4 H, O2CCH2OCH2CO2), 3.356 (s, 3 Η, CH3O-), 3.331 (s, 3 Η, CH3O-), 3.139 (s, 3 Η, CH3 -), 1.759 (s, 3 Η, CH3C--C), 1.653 (s, 3 Η, CH3C=C); IR (KBr) 3420 (OΗ), 2920 (CΗ), 2875 (CΗ), 1740 (C=O), 1720 (C=O), 1640, 1625, 1445, 1370, 1320, 1200, 1135, 1095, 980 cm-1; MS (neg. ion FAB) 1028 (M - Η), 327, 167 (100), 148, 133, 115; High Res. MS (neg. ion FAB) Calcd for C55H82O17N (M - H) 1028.5597, Found 1028.5599.
Analysis Calcd for C55H83θι7N - 3 H2O 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 half acid-ester by employing the method used to prepare the title compound in Example 20.
Rapamycin-42-hemi-3'-methylglutarate
Rapamycin-42-hemi-3l,3'-dimethylglutarate Rapamycin-42-hemi-3'-thioglutarate Rapamycin-42-hemi-phthalate Rapamycin-42-hemi-2',3,-pyridine dicarboxylate Example 21.
Rapamycin-31.42-bishemi-3'-oxoglutarate
To a solution of 5.0 g (5.47 mmol) of rapamycin in 20 mL of dry dichloromethane was added 3.17 g (27.3 mmol) of diglycolic anhydride followed by 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 at reflux for 24 h. The solution was cooled to room temperature, poured into 2 N 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 via reverse phase HPLC on a Ci8 column eluting starting with 60 % acetonitrile/water. After concentration, 1.75 g ( 28 %) of rapamycin-31,42-bishemi-3'-oxoglutarate was isolated. *H NMR (CDC13, 400 MHz) δ 4.785 (m, 1 H, CO2CHCHOMe), 4.260
(m, 8 H, O2CCH2OCH2CO2), 3.360 (s, 3 Η, CH3O-), 3.343 (s, 3 Η, CH3O-), 3.143 (s, 3 Η, CH3O-), 1.775 (s, 3 Η, CH3C=C), 1.656 (s, 3 Η, CH?C=C); 13C NMR (CDCI3, MHz) 211.12 (C=O), 207.73 (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=0), 1645, 1625, 1440, 1370, 1190, 11300, 980 cm"1; MS (neg. ion FAB) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; High Res. MS (neg. ion FAB) Calcd for C59H86O21N (M - H) 1144.5701, Found 1144.5702.
Analysis Calcd for C59H87O21N C 61.82; H 7.65; N 1.22 Found C 61.59; H 7.36; N 1.84
Example 22.
Rapamycin-31.42-bishemi-3'-oxoglutarate disodium salt
Purified bis-31,42 hemi-3'-oxoglutarate of rapamycin (720 mg, 629 umol) , prepared by the procedure employed in Example 21, was dissolved in 10 mL of 95 % ethanol and 106 mg (1.26 mmol) of sodium bicarbonate was added. Water (1 mL) was added to completely dissolve the salt. Once dissolved, the light yellow solution was concentrated in vacuo to give a foamy yellow solid. The foam was dried in a drying pistol for 48 h, refluxing over dichloromethane at reduced pressure to give 435 mg (58 %) of the disodium salt.
*H NMR (d6-DMSO, 400 MHz) δ 4.975 (m, 1 H, -CH02C), 4.593 (m, 1 H, MeOCHCHO2C-), 4.135 (s, 2 Η, -O2CCΗ2OCH2CO2R), 3.617 (s,2 Η, O2CCH2OCΗ2CO2R), 3.299 (s, 6 H, 2 CH3O-), 3.232 (s, 3 Η, CH3O-), 1.614
(s, 3 Η, CH3C=C), 1.553 (s, 3 Η, CH3C=C); IR (KBr) 3420 (OΗ), 2920 (CΗ), 1735 (C=O), 1615, 1445, 1395, 1380, 1320, 1220, 1130, 1090, 980 cm"1; MS (neg. ion FAB) 1188 (M-l), 1166 (M-Na), 1144, 1051, 1028, 590, 459, 167, 155 (100), 148, 133, 115. Analysis Calcd for C59Η85θ2iNNa2 • 2Η2O C 57.79; H 7.26; N 1.14
Found C 57.94; H 7.11; N 1.26
Example 23.
Raparnycin-31.42-bishemi-3'-oxoglutarate bistromethamine salt
Purified bis-31,42 hemi-3'-oxoglutarate of rapamycin (1.01 g, 882 umol), prepared by the procedure employed in Example 21, was dissolved in 10 mL of 95 % ethanol and 213 mg (1.76 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 48 h, refluxing over dichloromethane at reduced pressure to give 805 mg (66 %) of the bistromethamine salt.
*H NMR (d6-DMSO, 400 MHz) δ 4.955 (m, 1 H, -CHO2Q, 4.600 (m, 1 H, MeOCHCHO2C-), 4.149 (s, 2 Η, -O2CCΗ2OCH2CO2R), 3.770 (s, 2 Η, -O2CCH2OCΗ2CO2R), 3.407 (s, 6 H, 2 CH3O-), 3.257 (s, 3 Η, CH3O-), 1.806 (s, 3 Η, CH3C=C), 1.614 (s, 3 Η, CH3C=C); IR (KBr) 3400 (OΗ), 2920 (CΗ), 1730 (C=O), 1620, 1550, 1450, 1395, 1370, 1200, 1060, 985 cm"1; MS (neg. ion FAB) 1144 (M-Η, free acid), 1028, 167, 148, 133 (100), 115.
Analysis Calcd for C67Η109O27N3 • Η20 C 57.22; H 7.90; N 2.98 Found C 57.26; H 7.90; N 3.15 Example 24.
Rapamycin-31.42-bishemisuccinate.
To a solution of 2.0 g (2.2 mmol) of rapamycin in 10 mL of dry dichloro¬ methane was added 1.19 g (10.9 mmol) of succinic anhydride followed by 881 uL (861 mg, 10.9 mmol) of pyridine. To this was added 200 mg of 4-dimethylamino- pyridine and the reaction mixture refluxed for 24 h. The solution was cooled to room temperature, poured into 2 N 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 via reverse phase HPLC on a Cχ8 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.
*H NMR (d6-DMSO, 400 MHz) 5.231 (m, 1 H, -CHO2C), 4.554 (m, 1 Η, MeOCΗCHO2C-), 3.426 (s, 6 Η, 2 CH3O-), 3.249 (s, 3 Η, CH3O-), 2.431 (m, 8 Η, O2CCΗ2CΗ2CO2-), 1.700 (s, 3 H, CH3C=C), 1.554 (s, 3 Η, CH3C=C); 13C NMR (d6-DMSO, ) 211.28 (C=0), 205.23 (C=0), 199.59 (C=0), 174.86 (C=0), 173.62 (C=O), 171.72 (C=O), 171.50 (C=0), 166.56 (C=O), 166.53 (C=0); IR (KBr) 3420 (OΗ), 2940 (CΗ), 1735 (C=0), 1630, 1580, 1460, 1400, 1380, 1170, 1070, 990 cm-1; MS (neg. ion FAB) 1112 (M-l, free acid), 994, 589, 475, 297, 167, 148, 117, 99 (100).
Analysis Calcd for C 7Ηιo9θ25N3 - 2 Η2O C 57.80; H 8.12; N 3.01 Found C 57.91; H 8.21; N 2.37

Claims

CLAIMSWhat is claimed is:
1. A compound of the structure
Figure imgf000033_0001
wherein R1, R2> and R3 are each, independently, hydrogen, or R4;
O
II O II
R4 is [C(CH2)mCH(CH2)nN]pCO2R7 -C- (CH2)tX(CH2)uCO2Rπ or
I I
R5 R6
Figure imgf000033_0002
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
-(CH2)qC02R8, -(CH2)rNR9Cθ2R10, carbamylalkyl 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, hydroxyphenylmethyl, imidazoylmethyl 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; R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms;
R7, R8, and R10 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; R11 and R12 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;
R13
X is -C-, O, or S;
I R14
R13 and R14 are each, independently, hydrogen or alkyl of 1-6 carbon atoms;
Y is CH orN; m is 0 - 4; n is 0 - 4; p is 1 - 2; q is 0 - 4; r is 0 - 4; tis O - 4; u is 0 - 4;
O
II wherein R5, R6, m, and n are independent in each of the[C(CH2)mCH(CH2)nN]
I I
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2> and R3 are not all hydrogen, further provided that R1, R2> and R3 are not all O
II
- [C(CH2)mCH(CH2)nN]pCO2R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S.
O
II
2. A compound of claim 1 where R4 is — [C(CH2)mCH(CH2)nN]pCO2R7
I I
R5 R6 m = 0, n = 0, and p = 1 or a pharmaceutically acceptable salt thereof.
O
II
3. A compound of claim 1 where R4 is - [C(CH2)rnCH(CH2)nN]pCO2R7
I I
R5 R6 m = 0, n = 0, and p = 2 or a pharmaceutically acceptable salt thereof.
O
II
4. A compound of claim 1 where R4 is — [C(CH2)mCH(CH2)nN]pCO2R7
I I R5 R6 n = 0, and R5 is -(CH2)qCθ2R8 or a pharmaceutically acceptable salt thereof.
O
II
5. A compound of claim 1 where R4 is - [C(CH2)mCH(CH2)nN]pC02R7
I I
R5 R6 m = 0, n = 0, and R5 is -(CH2)rNR9CO2R10 or a pharmaceutically acceptable salt thereof.
O
II
6. A compound of claim 1 where R4 is - [C(CH2)mCH(CH2)nN]pC02R7
I I
R5 R6 m = 0, n = 0, and R5 is hydrogen or a pharmaceutically acceptable salt thereof. O
__ " 11
7. A compound of claim 1 where R4 is -C- (CH2)tX(CH2)uC02Rn or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 which is rapamycin-42-ester with N-[(l,l-dimethyleth- oxy)carbonyl]-glycylglycine or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 which is rapamycin-31,42-diester with N-[(l,l-di- methyl- ethoxy)carbonyl]-glycylglycine or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 which is rapamycin-31,42-diester with N-[(l,l-di- methylethoxy)carbonyl]-N-methylglyc_ne or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 which is rapamycin-42-ester with N-[(l,l-di- methylethoxy)carbonyl]-N-methylglycine or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1 which is rap amycin-31,42-diester with 5-(l,l- dimethylethoxy)-2-[[(l,l-dimethylethoxy)carbonyl]amino]-5-oxopentanoic acid or a pharmaceutically acceptable salt thereof.
13. A compound of claim 1 which is rapamycin-42-ester with 5-(l,l- dimethylethoxy)-2-[[(l,l-dimethylethoxy)carbonyl]amino]-5-oxopentanoic acid or a pharmaceutically acceptable salt thereof.
14. A compound of claim 1 which is rapamycin-31,42-diester with 2-[[(l,l- dimethylethoxy)carbonyl]amino]-4-oxo-4-(phenylmethoxy) butanoic acid or a pharma¬ ceutically acceptable salt thereof.
15. A compound of claim 1 which is rapamycin-31,42-diester with 3- [[(l,l-dimethylethoxy)carbonyl]amino]-4-oxo-4-(phenylmethoxy) butanoic acid or a pharmaceutically acceptable salt thereof.
16. A compound of claim 1 which is rapamycin-42-ester with 3- [[(l,l-dimethylethoxy)carbonyl]amino]-4-oxo-4-(phenylmethoxy) butanoic acid or a pharmaceutically acceptable salt thereof.
17. A compound of claim 1 which is rapamycin-42-ester with 5-(l,l-dimethyl- oxy)-4-[[(l,l-dimethylethoxy)carbonyl]amino]-5-oxopentanoic acid or a pharma¬ ceutically acceptable salt thereof.
18. A compound of claim 1 which is rapamycin-31,42-diester with 5-(l,l- dimethylethoxy)-4-[[(l,l-dimethylethoxy)carbonyl]amino]-5-oxopentanoic acid or a pharmaceutically acceptable salt thereof.
19. A compound of claim 1 which is rapamycin-42-ester with Nα, Nε-bis[(l,l- dimethylethoxy)carbonyl]-L-lysine or a pharmaceutically acceptable salt thereof.
20. A compound of claim 1 which is rapamycin-31,42-diester with Nα, Nε bis[(l,l-dimethylethoxy)carbonyl]-L-lysine or a pharmaceutically acceptable salt thereof.
21. A compound of claim 1 which is rapamycin- 14,31, 42-tris(monobenzyl- succinate) or a pharmaceutically acceptable salt thereof.
22. A compound of claim 1 which is rapamycin-31 ,42-bis(monobenzylsuccinate) or a pharmaceutically acceptable salt thereof.
23. A compound of claim 1 which is rapamycin-42-(monobenzylsuccinate) or a pharmaceutically acceptable salt thereof.
24. A compound of claim 1 which is rapamycin-31, 42-bishemiglutarate or a pharmaceutically acceptable salt thereof.
25. A compound of claim 1 which is rapamycin-31,42-hemiglutarate bissodium salt.
26. A compound of claim 1 which is rapamycin-31, 42-bishemiglutarate bistromethamine salt
27. A compound of claim 1 which is rapamycin-42-hemi-3'-oxoglutarate or a pharmaceutically acceptable salt thereof.
28. A compound of claim 1 which is rapamycin-31 ,42-bishemi-3'-oxoglutarate or a pharmaceutically acceptable salt thereof.
29. A compound of claim 1 which is rapamycin-31,42-bishemi-3'-oxoglutarate disodium salt.
30. A compound of claim 1 which is rapamycin-31,42-bishemi-3'-oxoglutarate bistromethamine salt.
31. A compound of claim 1 which is rapamycin-31,42-bishemisuccinate or a pharmaceutically acceptable salt thereof.
32. A compound of claim 1 which is rapamycin-31,42-bishemisuccinate bistromethane salt
33. A method of treating transplantation rejection, host vs. graft disease, autoimmune diseases, and diseases of inflammation in a mammal by administering an immunosuppressive amount of a compound having the structure
Figure imgf000038_0001
wherein R1, R2> and R3 are each, independently, hydrogen, or R4; o
II O
II
R4 is - [C(CH2)mCH(CH2)nN]pCO2R7 , -C- (CH2)tX(CH2)uCO2Rπ , or
I I
R5 R6
Figure imgf000039_0001
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, -(CH2)qC02R8, -(CH2)rNR9C02R10, carbamylalkyl 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, hydroxyphenylmethyl, imidazoylmethyl 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; R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R7, R8, and R10 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; R11 and R12 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;
ϊ13 X is -C-, O, or S;
I R14
R13 and R14 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; tis O - 4; u is 0 - 4;
O wherein R »5 , r R«6°, m, and n are independent in each of the[C(CH2)mCH(CH2)nN]
I I
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2> and R3 are not all hydrogen, further provided that R1, R2- and R3 are not all
O
II
- [C(CH2)mCH(CH2)nN]pCO2R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S.
34. A method of treating fungal infections which comprises administering an antifungal amount of a compound having the structure
Figure imgf000040_0001
wherein R1, R2> and R3 are each, independently, hydrogen, or R4; O
II °
R4 is -[C(CH2)mCH(CH2)nN]pC02R7 , -C-(CH2)tX(CH2)uC02R11 , or
I I
R5 R6
Figure imgf000041_0001
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
-(CH2)qC02R8, -(CH2)rNR9C02R10, carbamylalkyl 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, hydroxyphenylmethyl, imidazoylmethyl 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;
R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms;
R7, R8, and R10 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;
R11 and R12 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;
Figure imgf000041_0002
R13 and R14 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; ris O - 4; t is O - 4; u is 0 - 4;
O II wherein R5, R6, m, and n are independent in each of the[C(CH2)mCH(CH2)nN]
I I
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2> and R3 are not all hydrogen, further provided that R1, R2> and R3 are not all
O
II
- [C(CH2)mCH(CH2)-.N]pCO2R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S.
35. A pharmaceutical composition for the use in treating transplantation rejection, host vs. graft disease, autoimmune diseases, and diseases of inflammation in a mammal which comprises, an immunosuppressive amount of a compound having the structure
Figure imgf000043_0001
wherein R1, R2> and R3 are each, independently, hydrogen, or R4;
O
II O II
R4 is - [C(CH2)mCH(CH2)nN]pCO2R7 , -C-(CH2)tX(CH2)uCO2Rn , or
I I R5 R6
Figure imgf000043_0002
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
-(CH2)qC02R8, -(CH2)rNR9C02R10, carbamylalkyl 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, hydroxyphenylmethyl, imidazoylmethyl 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;
R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms;
R7, R8, and R10 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; R11 and R12 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;
R13 X is -C-, O, or S;
I R14
R13 and R14 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; tis 0 -4; u is 0 - 4;
O
II wherein R5, R6, m, and n are independent in each of the[C(CH2)mCH(CH2)nN]
I I
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2- and R3 are not all hydrogen, further provided that R1, R2- and R3 are not all
O
II
— [C(CH2)mCH(CH2)nN]pCO2R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S.
36. A pharmaceutical composition for the use in treating fungal infections, which comprises an antifungal amount of a compound having the structure
Figure imgf000045_0001
wherein R1, R2- and R3 are each, independently, hydrogen, or R4;
O
II O
II
R4 is -[C(CH2)mCH(CH2)nN]pCO2R7 , -C- (CH2)tX(CH2)uCO2R11 or
I I
R5 R6
Figure imgf000045_0002
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
-(CH2)qC02R8, -(CH2)rNR9Cθ2R10, carbamylalkyl 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, hydroxyphenylmethyl, imidazoylmethyl 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; R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R7, R8, and R10 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;
R11 and R12 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;
R13 Xis -C-, O, or S;
I R14
R13 and R14 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; Y is CH orN; 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;
O
II wherein R5, R6, m, and n are independent in each of the[C(CH2)mCH(CH2)nN]
I I
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2- and R3 are not all hydrogen, further provided that R1, R2> and R3 are not all
O
II
- [C(CH2)mCH(CH2)nN]pCO2R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S.
37. A process for preparing a compound of the formula
Figure imgf000047_0001
wherein R1, R2> and R3 are each, independently, hydrogen, or R4; O
II ?
R4 is - [C(CH2)mCH(CH2)nN]pCO2R7 , -C- (CH2)tX(CH2)uCO2Rn , or
I I R5 R6
Figure imgf000047_0002
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms,
-(CH2)qCO2R8, -(CH2)rNR9CO2R10, carbamylalkyl 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, hydroxyphenylmethyl, imidazoylmethyl 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;
R6 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms;
R7, R8, and R10 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; R11 and R12 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;
R13
X is -C-, O, or S;
I R14
R13 and R14 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; Y is CH orN; m is 0 - 4; n is 0 - 4; p is 1 - 2; q is 0 - 4; r is 0 - 4; tis O - 4; u is 0 - 4;
O
II wherein R5, R6, m, and n are independent in each of the[C(CH2)mCH(CH2)nN]
I I
R5 R6 subunits when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R1, R2- and R3 are not all hydrogen, further provided that R1, R2> and R3 are not all
O
II
- [C(CH2)mCH(CH2)nN]pC02R7 , and still further provided that t and u are not
I I
R5 R6 both 0 when X is O or S; which comprises (a) acylating rapamycin with an acylating agent or (b) sequentially acylating rapamycin with one or more acylating agents, said acylating agent(s) being selected from acids of formula: (CH2)tX(CH2)uCO2Rn , or
Figure imgf000049_0001
where Z is OH or reactive derivatives thereof, if desired protecting any of 42, 31 and 14 positions of rapamycin with an appropriate protecting group and removing said group as required, and further if desired isolating the product as a pharmaceutically acceptable salt
PCT/US1991/006824 1990-09-19 1991-09-19 Carboxylic acid esters of rapamycin WO1992005179A1 (en)

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US5247076A (en) * 1991-09-09 1993-09-21 Merck & Co., Inc. Imidazolidyl macrolides having immunosuppressive activity
US5258389A (en) * 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5262533A (en) * 1991-05-13 1993-11-16 Merck & Co., Inc. Amino O-aryl 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
EP0509795A3 (en) * 1991-04-17 1994-03-23 American Home Prod
EP0593227A1 (en) * 1992-10-13 1994-04-20 American Home Products Corporation Carbamates of rapamycin
US5310901A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynlheteroarylrapamycin derivatives
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IE913302A1 (en) 1992-02-25
MX9101139A (en) 1992-05-04
EP0549727A1 (en) 1993-07-07
AU8659991A (en) 1992-04-15
PT98990A (en) 1992-08-31
FI931203A0 (en) 1993-03-18
HUT65763A (en) 1994-07-28
AU653175B2 (en) 1994-09-22
FI931203A7 (en) 1993-03-18
HU9300776D0 (en) 1993-06-28

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