WO1993018043A1 - Nouveaux 42-sulfonates et (n-carboalcoxy)sulfamates de rapamycine utilises comme agents immunosuppresseurs - Google Patents

Nouveaux 42-sulfonates et (n-carboalcoxy)sulfamates de rapamycine utilises comme agents immunosuppresseurs Download PDF

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Publication number
WO1993018043A1
WO1993018043A1 PCT/US1993/001863 US9301863W WO9318043A1 WO 1993018043 A1 WO1993018043 A1 WO 1993018043A1 US 9301863 W US9301863 W US 9301863W WO 9318043 A1 WO9318043 A1 WO 9318043A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
alkoxy
alkyl
Prior art date
Application number
PCT/US1993/001863
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English (en)
Inventor
Amedeo Arturo Failli
Wenling Kao
Robert John Steffan
Robert Lewis Vogel
Original Assignee
American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/846,637 external-priority patent/US5177203A/en
Priority claimed from GB929223760A external-priority patent/GB9223760D0/en
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU37844/93A priority Critical patent/AU3784493A/en
Publication of WO1993018043A1 publication Critical patent/WO1993018043A1/fr

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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

Definitions

  • This invention relates rapamycin 42-sulfonates and a method for using them in the treatment of transplantation rejection, host versus graft disease, autoimmune diseases, diseases of inflammation, and fungal infections.
  • Rapamycin is a macrocyclic triene antibiotic produced by Streptomvces hvproscopicus. 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
  • 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.
  • 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,
  • This invention relates to rapamycin 42-sulfonates and 42-(N- carboalkoxy)sulfamates of general formula (I)
  • R 1 is Ci-C ⁇ alkyl, Ci-C ⁇ haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl or an aromatic moiety selected from phenyl, naphthyl and 4-(phenylaza)phenyl or a heteroaromatic group of 5 to 10 ring atoms containing oxygen, nitrogen and/or sulfur as heteroatoms(s) wherein said aromatic or heteroaromatic group is optionally substituted by one or more substituents selected from Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, hydroxy, amino, mono- or di(C ⁇ -C6) alkylamino, carboxy, (C1- 5 alkoxy)carbonyl, C2-C7 alkanoyl, (Ci-C ⁇ ) thioalkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy; or R 1 is NHCO2R 2 wherein R 2 is lower alkyl containing 1 to 6 carbon atom
  • alkyl for R 1 are straight or branched chain groups preferably of 1 to 4 carbon atoms such as methyl, ethyl, propyl and butyl.
  • haloalkyl are trifluoromethyl and 2-2-2-trifluoroethyl.
  • alkenyl are vinyl, alkyl, prop-1-enyl and but-2-enyl.
  • alkynyl are ethynyl and prop-2-ynyl.
  • R 1 examples of aromatic and heteroaromatic groups for R 1 are phenyl and naphth-1-yl, thienyl (e.g. thien-2-yl); fiiryl (e.g. furan-2-yl), pyridyl (e.g. pyrid-4-yl), quinolyl (e.g. quinol-8-yl) and isoquinolyl (e.g. isoquinol-4-yl).
  • thienyl e.g. thien-2-yl
  • fiiryl e.g. furan-2-yl
  • pyridyl e.g. pyrid-4-yl
  • quinolyl e.g. quinol-8-yl
  • isoquinolyl e.g. isoquinol-4-yl
  • substituents for aromatic or heteroaromatic R 1 groups are: straight or branched chain alkyl preferably of 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl; straight or branched chain alkoxy preferably of 1-4 carbon atoms such as methoxy, ethoxy, propoxy and butoxy; mono- or di-alkylamino such as methylamino, dimethylamino, ethylamino, methylethylamino; alkoxycarbonyl preferably of 2 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl; alkanoyl preferably of 2 to 4 carbon atoms such as acetyl, propionyl; thioalkyl such as MeS-; halo such as fluorine, chlorine and bromine.
  • R 1 are Ci-Cg alkyl, haloalkyl, C2-C6 alkenyl, C2- C ⁇ alkynyl, or a group selected from phenyl, 4-phenylazaphenyl, thienyl, quinolinyl and isoquinolinyl, each optionally substituted as described above, or R 1 is NHCO2R 2 where R 2 is as defined above.
  • This invention also provides processes for preparing the compounds of formula I.
  • the compounds are prepared by one of the following processes:
  • R 1 is as defined above and hal is a halogen such as chlorine or bromine;
  • R 2 is as defined above to give a corresponding compound of foimula I where R 1 is NHCO2R 2 where R 2 is as defined above; and if desired after each of the abovementioned processes isolating the compound of formula I in the form of a pharmaceutically acceptable salt thereof.
  • alkyl in the compound of formula IV are groups having 1 to 6 carbon atoms e.g. methyl or ethyl.
  • rapamycin 42-sulfonates of this invention can be prepared by the standard literature procedure as outlined below.
  • the 42-(N-carboalkoxy)sulfamates of the present invention can also be prepared by reaction of rapamycin with an alkyl(carboxysulfamoyl)triethylammonium hydroxide inner salt (Burgess Salts; see G. M. Atkins Jr. and E. M. Burgess, J. Am.
  • the pharmaceutically acceptable salts may be formed from inorganic cations such as sodium, potassium, and the like.
  • This invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
  • Dabsylchloride (0.83 g) was added to a solution of 0.54 g rapamycin in 30 mL dry pyridine and the solution heated at 65-70°C for 24 hours. Upon cooling, the reaction mixture was partitioned between 200 mL 2N HCl and 50 mL ethyl acetate.
  • the comitogen-induced thymocyte proliferation procedure 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 were 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:
  • 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
  • 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:
  • 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 B ALB/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. BIOLOGICAL DATA
  • the compounds of this invention are useful in the prevention and treatment of transplant rejection such as heart, kidney, liver, bone marrow, and skin transplants; graft versus host disease; autoimmune and proliferative diseases such as, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, glomerular nephritis, Hashimoto's thyroiditis, myastenia gravis, uveitis and psoriasis; diseases of inflammation such as dermatitis, eczema, seborrhea and inflammatory bowel disease; and fungal infections.
  • transplant rejection such as heart, kidney, liver, bone marrow, and skin transplants
  • graft versus host disease autoimmune and proliferative diseases such as, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, glomerular nephritis, Hashimoto's thyroiditis
  • 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.
  • the carrier In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient
  • the 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 solidcairiers 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 earner 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés de la formule (I) dans laquelle R1 est un alkyle, alkényle, ou un alkynyle renfermant 1 à 6 atomes de carbone; ou une fraction aromatique choisie entre le phényle, le naphtyle et le 4-(phénylaza)phényle dans laquelle ledit groupe aromatique est facultativement remplacé par un ou plusieurs agents de substitution choisis entre C¿1?-C6alkyle, C1-C6alkoxy, hydroxy, amino, mono- ou di-(C1-C6)alkylamino, carboxy, (C1-C6alcoxy)carbonyle, C2-C7alcanoyle, (C1-C6)thioalkyle, halo, cyano, nitro, trifluorométhyle, trifluorométhoxy ou R?1¿ est un groupe hétéroaromatique de 5 à 10 atomes de liaison renfermant de l'oxygène, de l'azote et/ou du soufre comme hétéroatome(s) dans lequel ledit groupe hétéroaromatique est facultativement remplacé par un ou plusieurs substituants choisis entre C¿1?-C6alkyle, C1-C6alcoxy, hydroxy, amino, mono- ou di-(C1-C6)alkylamino, carboxy, (C1-C6alcoxy)carbonyle, C2-C7alcanoyle, (C1C6)thioalkyle, halo, cyano, nitro, trifluorométhyle, trifluorométhoxy ou R?1¿ est NHCO¿2R?2, dans lequel R2 est un alkyle inférieur renfermant de 1 à 6 atomes de carbone; ou leurs sels pharmaceutiquement acceptables, qui sont utilisés pour les traitements anti-rejet consécutifs aux transplantations, la réaction de l'hôte contre le greffon, les maladies autoimmunes et les maladies inflammatoires.
PCT/US1993/001863 1992-03-05 1993-03-03 Nouveaux 42-sulfonates et (n-carboalcoxy)sulfamates de rapamycine utilises comme agents immunosuppresseurs WO1993018043A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37844/93A AU3784493A (en) 1992-03-05 1993-03-03 Novel rapamycin 42-sulfonates and 42-(n-carboalkoxy)sulfamates useful as immunosuppressive agents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US07/846,637 US5177203A (en) 1992-03-05 1992-03-05 Rapamycin 42-sulfonates and 42-(N-carboalkoxy) sulfamates useful as immunosuppressive agents
US07/846,637 1992-03-05
GB9223760.1 1992-11-12
GB929223760A GB9223760D0 (en) 1992-11-12 1992-11-12 Novel rapamycin 42-sulfonates and 42-(n-carboalkoxy)sulfamates useful as immuno-suppressive agents

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WO1993018043A1 true WO1993018043A1 (fr) 1993-09-16

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995014023A1 (fr) * 1993-11-19 1995-05-26 Abbott Laboratories Analogues semi-synthetiques de rapamycine (macrolides) utilises comme immunomodulateurs
US5527907A (en) * 1993-11-19 1996-06-18 Abbott Laboratories Macrolide immunomodulators
WO2000058314A2 (fr) * 1999-03-31 2000-10-05 Abbott Laboratories Sulfamate contenant des immunomodulateurs macrocycliques
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7196192B2 (en) 1999-08-24 2007-03-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7345053B2 (en) 2002-12-16 2008-03-18 Nitromed, Inc. Nitrosated and nitrosylated rapamycin compounds, compositions and methods of use
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4650803A (en) * 1985-12-06 1987-03-17 University Of Kansas Prodrugs of rapamycin
EP0509795A2 (fr) * 1991-04-17 1992-10-21 American Home Products Corporation Carbamates de rapamycine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4650803A (en) * 1985-12-06 1987-03-17 University Of Kansas Prodrugs of rapamycin
EP0509795A2 (fr) * 1991-04-17 1992-10-21 American Home Products Corporation Carbamates de rapamycine

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008150389A (ja) * 1993-11-19 2008-07-03 Abbott Lab ラパミシン（マクロライド）の半合成類似体免疫調節剤
US5527907A (en) * 1993-11-19 1996-06-18 Abbott Laboratories Macrolide immunomodulators
US5583139A (en) * 1993-11-19 1996-12-10 Abbott Laboratories Marcolide immunomodulators
US5672605A (en) * 1993-11-19 1997-09-30 Abbott Laboratories Macrolide immunomodulators
JP2008174560A (ja) * 1993-11-19 2008-07-31 Abbott Lab ラパミシン（マクロライド）の半合成類似体免疫調節剤
WO1995014023A1 (fr) * 1993-11-19 1995-05-26 Abbott Laboratories Analogues semi-synthetiques de rapamycine (macrolides) utilises comme immunomodulateurs
JP2008156369A (ja) * 1993-11-19 2008-07-10 Abbott Lab ラパミシン（マクロライド）の半合成類似体免疫調節剤
JP2008150391A (ja) * 1993-11-19 2008-07-03 Abbott Lab ラパミシン（マクロライド）の半合成類似体免疫調節剤
JP2008150392A (ja) * 1993-11-19 2008-07-03 Abbott Lab ラパミシン（マクロライド）の半合成類似体免疫調節剤
JP2008150390A (ja) * 1993-11-19 2008-07-03 Abbott Lab ラパミシン（マクロライド）の半合成類似体免疫調節剤
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
US6649595B2 (en) 1995-06-07 2003-11-18 Ariad Gene Therapeutics, Inc. Regulation of biological events using novel compounds
WO2000058314A3 (fr) * 1999-03-31 2001-02-22 Abbott Lab Sulfamate contenant des immunomodulateurs macrocycliques
WO2000058314A2 (fr) * 1999-03-31 2000-10-05 Abbott Laboratories Sulfamate contenant des immunomodulateurs macrocycliques
US7196192B2 (en) 1999-08-24 2007-03-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7345053B2 (en) 2002-12-16 2008-03-18 Nitromed, Inc. Nitrosated and nitrosylated rapamycin compounds, compositions and methods of use
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation

Also Published As

Publication number Publication date
MX9301188A (es) 1994-07-29

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