EP0594600A1 - Immunosuppressive makrozyklische verbindungen - Google Patents

Immunosuppressive makrozyklische verbindungen

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Publication number
EP0594600A1
EP0594600A1 EP91905827A EP91905827A EP0594600A1 EP 0594600 A1 EP0594600 A1 EP 0594600A1 EP 91905827 A EP91905827 A EP 91905827A EP 91905827 A EP91905827 A EP 91905827A EP 0594600 A1 EP0594600 A1 EP 0594600A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
allyl
ene
dioxa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91905827A
Other languages
English (en)
French (fr)
Inventor
David Keith Donald
Mark Furber
Martin Edward Cooper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fisons Ltd
Original Assignee
Fisons Ltd
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 GB909005672A external-priority patent/GB9005672D0/en
Priority claimed from GB909008507A external-priority patent/GB9008507D0/en
Priority claimed from GB909008556A external-priority patent/GB9008556D0/en
Priority claimed from GB909009480A external-priority patent/GB9009480D0/en
Priority claimed from GB909017447A external-priority patent/GB9017447D0/en
Priority claimed from GB909023242A external-priority patent/GB9023242D0/en
Application filed by Fisons Ltd filed Critical Fisons Ltd
Publication of EP0594600A1 publication Critical patent/EP0594600A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • This invention relates to immunosuppressive macrocyclic compounds, processes for their preparation, their use as e medicaments, and compositions containing them.
  • European Patent Application 184162 discloses a number of macrocyclic compounds isolated from microorganisms belonging to the Q genus Streotomvces.
  • the macrolides are numbered FR-900506, FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described.
  • R 1 represents H, OH or alkoxy; c R 2 represents H; in addition, R 1 and R 2 may together represent a second bond between the carbon atoms to which they are attached;
  • R 3 represents methyl, ethyl, propyl or allyl
  • R 4 represents H, OH, alkyl, alkoxy, halogen, amino, Q S-alkyl, NHCHO or NHCO-alkyl; n represents 1 or 2;
  • X represents O, (H,OH) , (H,H) or - * NH;
  • Y represents a cyclic group of formula II
  • R 5 represents (H,H), (H,OH) , (H,methoxy) or 0
  • R 6 represents H, (R)-OH, (S)-OH, alkoxy, amino, alkylamino, alkanoylamino, formyloxy or halogen
  • R 7 represents H; and in addition R 5 and R 6 may together represent a second bond between the carbon atoms to which they are attached; or R 6 and R 7 may together represent a second bond between the carbon atoms to which they are attached; or a cyclic group of formula III,
  • R 6 represents (R)-OH; then X does not represent 0; b) when n represents 2; i) R 1 represents OH; R 3 represents methyl, ethyl, allyl or propyl; R 4 represents OH; R 5 represents (H,methoxy) ; and R 6 represents (R)-OH; then X does not represent 0; ii) when R 1 and R 2 together represent a second bond between the carbon atoms to which they are attached or each represent H; R 3 represents allyl or propyl; R 4 represents OH; R 5 represents (H,methoxy) ; and R 6 represents (R)-OH; then X does not represent O;
  • R 1 represents OH, methoxy or together with R 2 it represents a second bond between the carbon atoms to which they are attached;
  • R 3 represents allyl;
  • R 4 represents OH;
  • R 5 represents (H,methoxy) ;
  • R 6 represents methoxy; then X does not represent 0;
  • 25 represents OH; R 5 represents (H,0H) or (H,methoxy) ; and R 6 represents (R)-OH; then X does not represent (H,H) ; ix) when R 1 represents OH; R 3 represents ethyl; R 4 represents OH; R 5 represents (H,methoxy) ; and R 6 represents (R)-OH; then X does not represent (H,H) ; x) when R 1 represents OH; R 3 represents methyl, ethyl or allyl; R 4 represents OH; R 5 represents (H,OH) ; and R 6 represents (R)-OH; then X does not represent O; and 5 xi) when R 1 represents OH; R 3 represents allyl; R 4 represents OH; R 5 represents 0; and R 6 represents (R)-OH; then X does not represent 0; and pharmaceutically acceptable derivatives thereof.
  • esters which may b mentioned include esters, amides and salts of an carboxylic acid groups which may be present.
  • the ester and amides preferably contain up to 6 carbon atoms.
  • Salt include alkali metal and alkaline earth metal salts, fo
  • R 1 , R 4 , R 5 , R 6 , and R 8 represen carbon-containing groups, we prefer those groups to contai up to 10 carbon atoms, more preferably up to 6 carbo
  • Groups which R may represent include CHO and C0 2 H.
  • R 1 represents H or OH.
  • R 4 t 25 represent H, OH, alkyl, halogen or amino.
  • R represents (H,OH) or (H,methoxy) .
  • R represents H, (R)-OH or amino.
  • R 8 to represen an amide of a C0 2 H group or alkyl substituted by alkoxy.
  • Subgroups of compounds which may be mentioned include: compounds of formula I in which Y represents a cyclic group of formula III; compounds of formula I in which R 4 represents alkoxy; compounds of formula I in which R 4
  • R 4 represents H or alkyl
  • R 6 represents H, (S)-OH or halogen or together with R 5 represents a second bond between the carbon atoms to which
  • a preferred group of specific compounds which may be mentioned is: 5 17-allyl-l,14-dihydroxy-12-[2-(3-methoxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28- dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16- tetraone;
  • the compounds disclosed in the above-mentioned application may be used as starting materials for the production o compounds of the present invention. Alternatively, the may be prepared by total synthesis.
  • a process for the production of a compound o formula I as defined in claim 1, which comprises: (a) producing a compound of formula I in which R 1 an R 2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, by dehydration of a corresponding compound in which R 1 represents OH and R 2 represents H; (b) producing a compound of formula I in which R 1 and R 2 each represent hydrogen, by reduction of a corresponding compound in which R 1 and R 2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; (c) producing a compound of formula I in which X represents (H,OH), by reduction of a corresponding compound in which X represents 0;
  • ,- includes an aldehyde and an appropriate Wittig reagent.
  • the dehydration may be carried out in solvent which does not adversely affect the reaction (e toluene) , in the presence of a trace amount of acid (e 20 p-toluenesulphonic acid) , at a temperature of from 50 t lOO'C.
  • solvent which does not adversely affect the reaction (e toluene)
  • acid e 20 p-toluenesulphonic acid
  • the reduction may be carried ou catalytically using hydrogen.
  • Suitable catalysts include platinum catalysts (eg platinum black, platinum oxides) palladium catalysts (eg palladium oxides, palladium o charcoal) , nickel catalysts (eg nickel oxide, Rane Nickel) , and rhodium catalysts (eg rhodium on alumina)
  • Suitable solvents are those which do not adversely affect the reaction, and include methanol, ethanol, ethyl acetate, dichloromethane and dimethylformamide.
  • the reduction may be carried out at or around room temperature.
  • suitable reagents for the reduction include tri- n butyltin hydride in a solvent which does not adversely affect the reaction (eg toluene) at a temperature of from 50 to lOO'C, sodium borohydride, zinc in acetic acid at or around room temperature, sodium triacetoxyborohydride in acetic acid, L-Selectride
  • the reduction may be achieved by the action of H 2 S, preferably in the presence of pyridine or an amine (for example morpholine) , in a solvent which does not adversely affect the reaction (for example dimethylformamide, pyridine or methanol) , at or around room temperature.
  • pyridine or an amine for example morpholine
  • a solvent which does not adversely affect the reaction for example dimethylformamide, pyridine or methanol
  • the oxidation may be carried out in the presence of a suitable oxidizing agent, such as cupric acetate.
  • suitable solvents include those which do not adversely affect the reaction, for example methanol.
  • the reaction may be carried out up to the reflux temperature of the solvent.
  • the reaction may be carried out in the presence of a suitable acid catalyst, for example montmorillonite K10.
  • the solvent used may conveniently be the alkanol reagent, and the reaction may be carried out at or around room temperature.
  • suitable halogenating agents include diethylaminosulphur trifluoride and thionyl chloride.
  • the halogenation is preferably carried out in a solvent which does not adversely affect the reaction, for example dichloro ethane, at or below room temperature, and preferably under an inert atmosphere.
  • suitable organometallic reagents include lithium dialkyl copper reagents, which may be prepared from a copper halide and an alkyl lithium reagent.
  • R 4 preferably represents Cl in the starting material.
  • Suitable solvents include those which do not adversely affect the reaction, for example diethyl ether. The reaction is preferably carried out at reduced temperature.
  • suitable solvents include thos which do not adversely affect the reaction, for exampl diethyl ether.
  • R 4 preferably represents Cl in th starting material. The reaction may be carried out at o around room temperature.
  • suitable solvents include those which do not adversely affect the reaction, for example tetrahydrofuran (THF) .
  • R 4 preferably represents Cl in the starting material. The reaction may be carried out at or around room temperature.
  • the solvent is conveniently formic acid.
  • the reaction may be carried out at or around room temperature, and in the presence of acetic anhydride.
  • Suitable solvents include those which do not adversely affect the reaction, for example methanol.
  • the reaction may be carried out at below room temperature.
  • suitable leaving groups include tosylate, mesylate and triflate
  • the leaving group may be introduced by reaction of a compound of formula I in which R 6 represents (R)-OH with a suitable reagent, for example trifluoro ethanesulphonic acid anhydride.
  • suitable leaving groups include tosylate, g mesylate and triflate.
  • Suitable sources of halide include tetra- n butylammonium halides, for example tetra- n butylammonium iodide.
  • Suitable solvents include those which do not adversely affect the reaction, for example benzene. The reaction may be carried out at at or around room temperature.
  • the elimination is preferably carried out by the action of powdered zinc.
  • the solvent is preferably acetic acid and the reaction may be carried out at or around room temperature.
  • suitable leaving groups include imidazol-l-yl(thiocabonyl)oxy, which may be introduced by reaction of a corresponding compound in which R 6 represents OH with l,l'-thiocarbonyldiimidazole.
  • Suitable sources of hydride include tributyltin hydride, and the reaction is preferably carried out in the presence of AIBN.
  • Suitable solvents include those which do not adversely affect the reaction, for example benzene. The reaction may be carried out up to the reflux temperature of the solvent.
  • suitable reducing agents include 1,3-propanedithiol.
  • suitable solvents include those whic do not adversely affect the reaction, for exampl methanol.
  • the reaction is preferably carried out in th presence of triethyla ine, and may be carried out at o around room temperature.
  • the azido compound may b produced by the action of azide ion on a correspondin compound in which R 6 represents a leaving group, fo example triflate.
  • suitable alkylating agents include methyl iodide
  • suitable acylating agents include acyl halides, for example acetyl chloride.
  • Suitable solvents include those which do not adversely affect the reaction, for example dichloromethane. The reaction may be carried out at or around room temperature.
  • suitable reducing agents include L-Selectride.
  • suitable solvents include those which do not adversely affect the reaction, for example THF.
  • the reaction is preferably carried out below room temperature.
  • suitable oxidizing agents include sodium chlorite, preferably in the presence of 1-methylcyclohex-l-ene.
  • Suitable solvents include those which do not adversely affect the reaction, for example -butanol. The reaction is preferably carried out at or around room temperature.
  • Suitable Wittig reagents include
  • Suitable solvents include those which do not adversely affect the reaction, for example toluene.
  • the reaction may be carried out at or around the reflux temperature of the solvent.
  • the compounds of formula I may be isolated from their reaction mixtures using conventional techniques.
  • the compounds of formula I are useful because they possess pharmacological activity in animals; in particular they are useful because they possess immunosuppressive activity, eg in the tests set out in Tests A, B, C and D.
  • the compounds are indicated for use in the treatment or prevention of resistance to transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin, cornea, etc; and of autoimmune, inflammatory, proliferative and hyperproliterative diseases, and of cutaneous manifestations of immunologically-mediated diseases: for example rheumatoid arthritis, lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitides, seborrheic dermatitis.
  • Lichen planus Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias. Alopecia areata, eosinophilic fasciitis, atherosclerosis etc.
  • the compounds of the invention are also indicated more generally in the treatment of respiratory diseases, for example reversible obstructive airways disease.
  • the compounds of the invention are indicated in the treatment of a disease selected from intestinal inflammations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; and food related allergic diseases which have symptomatic manifestation remote from the gasto-intestinal tract, for example migraine, rhinitis and eczema.
  • a disease selected from intestinal inflammations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis
  • food related allergic diseases which have symptomatic manifestation remote from the gasto-intestinal tract, for example migraine, rhinitis and eczema.
  • the compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
  • the dosa administered will, of course, vary with the compou employed, the mode of administration, the treatment desir (eg topical, parenteral or oral) and the disease indicate However, in general, satisfactory results are obtained wh the compounds are administered at a daily dosage of fr 0.001 to 20mg per kg of animal body weight.
  • the indicated total daily dosage is in the range from O.Olmg to lOOOmg and preferably from 0.5mg to lOOm which may be administered, for example twice weekly, or divided doses from 1 to 6 times a day or in sustain release form.
  • unit dosage forms suitable f o administration, eg oesophageally, comprise from O.Olmg to
  • a pharmaceuti composition comprising preferably less than 80%, and m preferably less than 50% by weight, of a compound of form I in combination with a pharmaceutically accepta - 20 -
  • adjuvant for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes; and for inhalation compositions - coarse lactose.
  • the compound of formula I preferably is in a form having a mass median diameter of from 0.01 to lO ⁇ .
  • compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol) , sweetening and colouring agents and flavourings.
  • solubilisers eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol
  • sweetening and colouring agents and flavourings may, if desired, be
  • the compound of formula I for the treatment of reversible obstructive airways disease, we prefer the compound of formula I to be administered by inhalation to the lung, especially in the form of a powder.
  • a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula I, as defined above, to a patient.
  • the compounds of formula I have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds previously used in the therapeutic fields mentioned above.
  • the compounds of formula I have a number of chiral centres and may exist in a variety of stereoisomers.
  • the invention provides all optical and stereoisomers, as well as racemic mixtures.
  • the isomers may be resolved or separated by conventional techniques.
  • R 1 to R 4 , X and n are as first defined above, and Y represents a cyclic group of formula Ila or Ilia,
  • R to R 8 are as first defined above.
  • MLR Mixed Lymphocyte Reaction
  • the cells were incubated at 37"C in a humidified atmosphere of 5% carbon dioxide and 95% of air for 68 hours and pulsed with 3 H-thymidine (0.5 ⁇ Ci) 4 hours before the cells were collected.
  • the object compound of this invention was dissolved in ethanol and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.l ⁇ g/ml or less.
  • the MLR test was performed in 96-well microtitre plates with each well containing 3 x 10 5 cells from each of two responding donors in a final volume of 0.2ml RPMI 1640 medium supplemented with 10% human serum, L-glutamine and penicillin/streptomycin.
  • the compound under test was dissolved at lomg/ml in ethanol and further diluted in RPMI 1640.
  • the cells were incubated at 37°C in a humidified atmosphere at 5% carbon dioxide for 96 hours. 3H-thymidine (0.5 ⁇ Ci) was added for the final 24 hours of the incubation to provide a measure of proliferation.
  • Spleen cells from DA and DAxLewis Fl hybrid rats were o prepared at approximately 10° cells/ml. 0.1ml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively) . Recipient animals are dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay is terminated on day 7 when the popliteal lymph nodes of the animals are removed and weighed. The increase in weight of the left node relative to the weight of the right is a measure of the GVH response. Test D
  • Example 1 The invention is illustrated, but in no way limited, by the following Examples.
  • Example 1 The invention is illustrated, but in no way limited, by the following Examples.
  • step (a) The compound of step (a) (40mg) was dissolved in methanol (3ml) and to this was added cupric acetate (lOOmg) . The resulting suspension was stirred and heated to reflux for 30 minutes. The reaction mixture was then cooled, filtered and evaporated in vacuo. Column chromatography on silica gave the title compound (30mg) as an oil. MS (FAB): 902.5 [M+Rb] + ; 840.8 [M+Na] + ; 818.8 [M+H] + ; 800.8 [M+H] + ; 786.8 [M+H-CH 3 OH] +
  • Fraction A was further purified by chromatography on silica 0 using HPLC eluting with ethyl acetate to give the first title compound (92mg) as a foam.
  • Example 2 17-Allyl-1.14-dihydroxy-12-r2-(cyclopentyl- 3 -carboxaldehvde)
  • Example 10 To a solution of the product of Example 8 (15mg) in methanol (4ml) was added Pd-on-C (4mg, 10%) and the resulting suspension was then stirred in an atmosphere of hydrogen for 1 hour at 0 ⁇ C. The reaction mixture was then filtered and volatiles were removed in vacuo. Chromatography on silica then gave the title compound as a foam (13mg) .
  • Example 10 To a solution of the product of Example 8 (15mg) in methanol (4ml) was added Pd-on-C (4mg, 10%) and the resulting suspension was then stirred in an atmosphere of hydrogen for 1 hour at 0 ⁇ C. The reaction mixture was then filtered and volatiles were removed in vacuo. Chromatography on silica then gave the title compound as a foam (13mg) .
  • step (a) To a solution of the product of step (a) (150mg) in acetonitrile (20ml) was added 40% aqueous hydrofluoric acid (3ml) . After stirring for 1 hour at room temperature the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether. The organic extracts were then dried, (MgS0 4 ) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with acetone/hexane [1:3] then gave the title compound (130mg) as a foam. MS (plasma spray): 738.54 [M+H-2H 2 0] + ; 756.58 [M+H-H 2 0] + ; 774.6 [M+H] + ; 791.57 [M+NH 4 ] +
  • Example 14 To a solution of the product of Example 14 (20mg) in methanol (10ml) was added 10% Pd-on-C (4mg) and the resulting suspension was then stirred in an atmosphere of hydrogen for 2 hours at 0'C. The reaction mixture was then filtered and volatiles were removed in vacuo. Chromatography on silica then gave the title compound as a foam (17mg) .
  • Example 16 1.14-dihvdroxy-12-r2-(cvclopent ⁇ l-3-carboxylic acid) -1-methylvinyl1-23.25-dimethoxy-17-propyl-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclor22.3.1.0--- 9 -1octacos- 18-ene-2.3.10.16-tetraone
  • Example 18 17-Allyl-1.14-dihydroxy-12-r2-(cyclopentyl-3-methyl propenoate)-1-methylvinyll-23.25-dimethoxy-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricvclor22.3.1.0 ' 9 1 octacos-18-ene-2.3.10.16-tetraone
  • a solution of the product of Example 17 70mg
  • Q acetonitrile 10ml
  • lml 40% aqueous hydrofluoric acid
  • step (a) was deprotected following the method of Example 8(d) to give the title compound.
  • Example 20 1.14-dihvdroxy-12-r2-(cvclopentyl-3-methanol)-l-methylvinyll
  • Example 23 5 l-14-dihydroxy-12-[2-(cyclopentyl-3-methyl propenoate)-1- methylvinyl]-23.25-dimethoxy-17-ethyl-13.19.21.27-tetra methyl-11.28-dioxa-4-azatricvclor22.3.1.04.91octacos-18-ene- 2.3.10.16-tetraone Wittig reaction on the product of Example 19(a) following the method of Example 17 and then deprotection following the method of Example 18 gave the title compound.
  • Example 25 l-Hvdroxy-12-r2-(cyclopentyl-3-methanol)-1-methylvinyl]- 23.25-dimethoxy-17-propyl-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricvclor22.3.1.0 4 ' 9 ]octacos-18-ene-2.3.10.16- tetraone Reduction of the product of Example 24 following the method of Example 10(a) yielded the title compound.
  • step (a) A sample of the product from step (a) was dissolved in methanol (20ml) and 10% Pd-on-carbon (lOmg) was added. The mixture was stirred in an atmosphere of hydrogen for 1.5 hours at room temperature and pressure, and was then filtered through celite and evaporated to an oil in vacuo.
  • Example 31 l-Hydroxy-12-r2-(cvclopentyl-3-carboxylic acid)-l-methyl vinyll-23.25-dimethoxy-17-ethyl-13.19.21.27-tetramethyl- ll.28-dioxa-4-azatricvclor22.3.1.0 ' 9 1octacos-18-ene- 2.3.10.16-tetraone Oxidation of the product from Example 29 following the method of Example 12 gave the title compound.
  • Example 33 l-Hydroxy-12-r2-(cyclopentyl-3-methyl propenoate)-l- methvlvinvl1-23.25-dimethoxv-17-ethvl-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclor22.3.1.0 ' 9 1octacos- 18-ene-2.3.10.16-tetraone Wittig reaction of the product of Example 29 following the method of Example 17 gave the title compound.
  • step (b) To a cold (-10 ⁇ C) stirred solution of the product of step (b) (0.97g) in dry dichloromethane (25ml) under nitrogen was added trifluoromethanesulphonic anhydride (0.1ml). After stirring for 15 minutes at -10"C saturated aqueous sodium hydrogen carbonate solution was added and the reaction mixture was extracted with diethyl ether. The ether extracts were then washed with saturated aqueous sodium hydrogen carbonate solution, dilute aqueous hydrochloric acid (IN) , saturated aqueous sodium hydrogen carbonate solution and brine before being dried (MgS0 ) , filtered and concentrated in vacuo to give the title compound as an oil (0.95g) .
  • step (d) To a solution of the product of step (d) (0.28g) in acetonitrile (10 ml) was added 40% aqueous hydrofluoric acid (2ml) . After stirring for 1 hour at room temperature the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether. The organic extract was then dried (MgS0 4 ) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with acetone/hexane [1:2] then gave the title compound (0.22g) as a foam.
  • Example 39(a)-(d) the subtitle compound was prepared from l,l4-dihydroxy-12-[2-(4-hydroxy-3-methoxy cyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16-tetraone (FR-900520) .
  • Example 39(e) Using the method of Example 39(e) the title compound was prepared from the product of step (a) .
  • step (a) To a solution of the product of step (a) (30mg) i acetonitrile (7ml) was added 40% aqueous hydrofluoric aci (lml) . After stirring for 1 hour at room temperature the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether. The combined ether extracts were then washed with saturated aqueous sodium hydrogen carbonate solution and brine before being dried (MgS0 4 ) , filtered and concentrated to an oil in. vacuo. Chromatography on silica eluting with acetone/hexane [1:4] then gave the title compound (17mg) as a foam. MS (FAB): 870.74 [M-I+Rb] + ; 997.15 [M+Rb] +
  • step (a) A solution of the product of step (a) (105mg) in dry benzene (25ml) containing AIBN (2,2 '-bisisobutyronitrile) (3mg) was heated to 40'C under nitrogen. Tributyltin hydride (0.1ml) was then added dropwise by syringe. The 5 temperature was then raised to 60 ⁇ C over 5 minutes and a further 0.1 ml of tributyltin hydride was added. The temperature was then further raised to 90'C over 10 minutes and an additional 0.1ml of tributyltin hydride was added. After a further 10 minutes no starting material remained 0 and volatiles were removed in vacuo after cooling to room temperature.
  • AIBN 2,2 '-bisisobutyronitrile
  • step (c) 40mg
  • acetonitrile 8ml
  • 40% aqueous hydrofluoric acid lml
  • the 5 reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether.
  • the ether extracts were then dried (MgS0 4 ) , filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with hexane in an o increasing acetone gradient then gave the title compound as a foam (20mg) .
  • Example 45 1.14-dih ⁇ drox ⁇ -12-r2-(3-methoxycyclohexyl)- -methylvinyl1-
  • Example 47 l-Hydroxy-12-f2-(3-methoxycyclohexyl)-1-methylvinyl]-23.25- dimethoxy-17-propyl-13.19.21.27-tetramethyl-ll.28-dioxa-4- azatricyclor22.3.1.0 4 ' 9 1octacos-18-ene-2.3.10.16-tetraone
  • the title compound was prepared from l-hydroxy-12-[2- (4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-17-propyl-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16-tetraone (Example 12, WO 89/05304) following the method of Example 43.
  • Example 48 l-Hvdroxy-12-[2-(3-methoxycyclohexyl)-1-methylvinyl1-23.25- dimethoxy-17-ethyl-13.19.21.27-tetramethyl-ll.28-dioxa-4- azatricyclor22.3.1.0 ,9 1octacos-18-ene-2.3.10.16-tetraone a) 17-Ethyl-l-hvdroxy-12-r2-(4-hvdroxy-3-methoxycvclo hexyl)-1-methylvinyll-23.25-dimethoxy-13.19.21.27-tetra methyl-11.28-dioxa-4-azatricyclor22.3.1.0 4/9 ]octacosa-
  • step (a) A sample of the product from step (a) was dissolved in methanol (20ml) and 10% Pd-on-carbon (lOmg) was added. The mixture was stirred in an atmosphere of hydrogen for 1.5 hours at room temperature and pressure, and was then filtered through celite and evaporated to an oil in vacuo. Column chromatography on silica eluting with hexane/acetone [2:1] gave the title compound as a foam (50mg) .
  • step (a) 17-All ⁇ l-1.2-dihvdroxy-12-r2-(cvclohex-3-enyl)-l- 5 methylvinyl]-14--butyldimeth ⁇ lsilyloxy-23.25-dimethoxy- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricvclo r22.3.1.0 ' 9 1octacos-18-ene-3.10.16-trione To a solution of the product of step (a) (500mg) in glacial acetic acid (8ml) was added zinc dust.
  • step (c) To a solution of the product from step (c) (280mg) in acetonitrile (20ml) was added 40% aqueous hydrofluoric acid (4ml) . After stirring for 30 minutes at room temperature the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether. The combined ether extracts after washing with saturated aqueous sodium hydrogen carbonate solution were then dried (MgS0 ) , filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with hexane in an increasing acetone gradient then gave the title compound as a foam (0.227g).
  • Example 50 1.14-Dihvdroxy-12-r2-(cvclohex-3-enyl)-l-methylvinyll-23.25- dimethoxy-17-ethyl-13.19.21.27-tetramethyl-ll.28-dioxa-4- azatricyclor22.3.1.0 4 ' 9 ]octacos-18-ene-2.3.10.16-tetraone
  • Example 51 1.14-Dihvdroxy-12-r2-(cvclohex-3-enyl)-l-methylvinyll-23.25- dimethoxy-17-ethyl-13.19.21.27-tetramethyl-ll.28-dioxa-4- azatricyclor22.3.1.0 4 ' 9 ]octacos-18-ene-2.3.10.16-tetraone
  • the subtitle compound was prepared from 1,14-dihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-17-propyl-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16-tetraone 5 (Example 10, WO 89/05304) following the method of Example 39(a)-(d).
  • Example 53 l-Hydroxy-12-r2-(cyclohex-3-enyl)-l-methylvinyl1-23.25- dimethoxy-17-ethyl-13.19.21.27-tetramethyl-ll.28-dioxa-4- azatricyclor22.3.1.0 4 •• 9 1octacos-18-ene-2.3.10.16-tetraone a) l-Hydroxy-12-f2-(4(S)-hydroxy-3-methoxycyclohexyl)- 1-methvlvinvl1-23.25-dimethoxy-17-ethyl-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclo[22.3.1.04.9]octacos- 18-ene-2.3.10.16-tetraone
  • the subtitle compound was prepared from 1-hydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23 ,25- dimethoxy-17-ethyl-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone [the product of Example 48(b)] following the method of Example 39(a)-(d).
  • Example 54 l-Hydroxy-12-r2-(cyclohex-3-enyl)-1-methylvinyl1-23,25- dimethoxy-17-propyl-13.19.21.27-tetramethyl-ll.28-dioxa-4- azatricyclor22.3.1.0 4 ' 9 1octacos-18-ene-2.3.10.16-tetraone a) l-Hydroxy-12-[2-(4-trifluoromethylsulphonyloxy-3- methoxycyclohexyl)-1-methylvinyl1-23.25-dimethoxy-17-prop ⁇ l- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricvclo f22.3.1.o 4 ' 9 1octacos-18-ene-2.3.10.16-tetraone To a cold (-10 ⁇ C) stirred solution of 1-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohe
  • Example 58 l-Hvdroxy-12-r2-cvclohexyl-l-methylvin ⁇ l]-23.25-dimethoxy- 17-propvl-13.19.21. 7-tetramethvl-ll.28-dioxa-4-azatricvclo r22.3.1.0 •9 ]octacos-18-ene-2.3.10.16-tetraone
  • the title compound was prepared from the product of Example 54 following the method of Example 55.
  • Example 59
  • step (e) 40mg
  • acetonitrile 8ml
  • 40% aqueous hydrofluoric acid lml
  • the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether.
  • the ether extracts were then dried (MgS0 4 ) , filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with hexane in an increasing acetone gradient then gave the subtitle compound as a foam (20mg) .
  • step (b) To a stirred solution of the product of step (b) (50mg) in dry, distilled methanol (5ml) under nitrogen was added 1,3-propanedithiol (0.03ml) and triethylamine (0.04ml) . After stirring for 1 hour at room temperature the reaction mixture was columned on silica eluting with hexane/acetone [3:1] to give the subtitle compound as a foam (37mg) .
  • step (b) To a solution of the product of step (b) (35 mg) in acetonitrile (7ml) was added 40% aqueous hydrofluoric acid (0.5ml). After stirring for 2.5 hours at room temperature the reaction mixture was poured into ethyl acetate and the separated organic extract was then washed with saturated aqueous sodium hydrogen carbonate solution and brine before being dried (MgS0 4 ) , filtered and evaporated to an oil in vacuo. Column chromatography on silica eluting with hexane/acetone [2:1] then gave the title compound (15mg) as a foam.
  • Example 62(b) To a solution of the product of Example 62(b) (20mg) in dry dichloromethane (3ml) was added pyridine (0.1ml) and acetyl chloride (0.1ml). After stirring for 10 minutes at room temperature the reaction mixture was poured into water and this was then extracted with diethyl ether. The organic extract was then washed with dilute aqueous hydrochloric acid and brine before being dried (MgS0 ) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with hexane/acetone [3:1] then gave the subtitle compound (15mg) as an oil.
  • step (a) A portion of the product from step (a) (13mg) was dissolved in acetonitrile (4ml) and to this was added 40% aqueous hydrofluoric acid (0.1ml). After stirring for 2 hours at room temperature the reaction mixture was poured into ethyl acetate and the separated organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution and brine before being dried (MgS0 4 ) , filtered and evaporated to an oil in vacuo. Column chromatography o silica eluting with hexane/acetone [2:1] then gave the title compound (8mg) as a foam.

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Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5208228A (en) * 1989-11-13 1993-05-04 Merck & Co., Inc. Aminomacrolides and derivatives having immunosuppressive activity
US5143918A (en) * 1990-10-11 1992-09-01 Merck & Co., Inc. Halomacrolides and derivatives having immunosuppressive activity
WO1992020688A1 (en) * 1991-05-13 1992-11-26 Merck & Co., Inc. Amino o-aryl, o-alkyl, o-alkenyl and o-alkynyl macrolides
US5162334A (en) * 1991-05-13 1992-11-10 Merck & Co., Inc. Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity
US5250678A (en) * 1991-05-13 1993-10-05 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
US5565560A (en) * 1991-05-13 1996-10-15 Merck & Co., Inc. O-Aryl,O-alkyl,O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
US5189042A (en) * 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
ES2179823T3 (es) * 1991-09-05 2003-02-01 Abbott Lab Inmunosupresor macrolido.
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
GB9125660D0 (en) * 1991-12-03 1992-01-29 Smithkline Beecham Plc Novel compound
CA2091194A1 (en) * 1992-04-08 1993-10-09 Richard D. Connell 2-oxo-ethyl derivatives as immunosuppressants
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
US5258389A (en) * 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5310901A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynlheteroarylrapamycin derivatives
US5310903A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. Imidazolidyl rapamycin derivatives
MY110603A (en) * 1993-05-27 1998-08-29 Novartis Ag Tetrahydropyran derivatives
EP0711298A1 (de) * 1993-07-30 1996-05-15 Abbott Laboratories Macrolactam-derivate mit immun-modulierender wirkung
US5612350A (en) * 1993-11-30 1997-03-18 Abbott Laboratories Macrocyclic immunomodulators with novel cyclohexyl ring replacements
WO1995015328A1 (en) * 1993-11-30 1995-06-08 Abbott Laboratories Macrocyclic immunomodulators with novel cyclohexyl ring replacements
US5880280A (en) * 1994-06-15 1999-03-09 Merck & Co., Inc. Aryl, alkyl, alkenyl and alkynylmacrolides having immunosuppressive activity
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
GB9713730D0 (en) * 1997-06-30 1997-09-03 Ciba Geigy Ag Organic compounds
ME00189B (me) 1998-03-26 2011-02-10 Astellas Pharma Inc Preparati sa neprekidnim oslobađanjem
CA2326222C (en) * 1998-04-27 2008-09-23 Fujisawa Pharmaceutical Co., Ltd. Medicinal compositions
GB9826656D0 (en) 1998-12-03 1999-01-27 Novartis Ag Organic compounds
US7063857B1 (en) 1999-04-30 2006-06-20 Sucampo Ag Use of macrolide compounds for the treatment of dry eye
ATE264863T1 (de) 1999-08-24 2004-05-15 Ariad Gene Therapeutics Inc 28-epirapaloge
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
WO2006115509A2 (en) 2004-06-24 2006-11-02 Novartis Vaccines And Diagnostics Inc. Small molecule immunopotentiators and assays for their detection
US10143682B2 (en) 2014-10-28 2018-12-04 Koushi Yamaguchi Medicine for improving state of pregnancy, and use thereof
EP3426674A4 (de) 2016-03-09 2019-08-14 Blade Therapeutics, Inc. Cyclische keto-amid-verbindungen als calpain-modulatoren sowie verfahren zur herstellung und verwendung davon
AU2017292646A1 (en) 2016-07-05 2019-02-07 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
CN106074367A (zh) * 2016-07-20 2016-11-09 中山大学中山眼科中心 含fk506类化合物/fkbp蛋白二聚体的药物组合物及其制备方法
WO2018064119A1 (en) 2016-09-28 2018-04-05 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
US20210228551A1 (en) 2018-08-10 2021-07-29 Koushi Yamaguchi Therapeutic agent for humoral immunity-related diseases in maternofetal relationship
CN120053439A (zh) 2018-12-18 2025-05-30 山口晃史 用于改善不孕不育症或妊娠状态的药物
MX2021008824A (es) * 2019-01-23 2021-10-13 Univ Johns Hopkins Análogos no inmunosupresores de tacrolimus (fk506) y uso de los mismos.

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894366A (en) * 1984-12-03 1990-01-16 Fujisawa Pharmaceutical Company, Ltd. Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same
WO1989005304A1 (en) * 1987-12-09 1989-06-15 Fisons Plc Macrocyclic compounds
EP0356399A3 (de) * 1988-08-26 1991-03-20 Sandoz Ag Substituierte 4-Azatricyclo (22.3.1.04.9) octacos-18-en-Derivate, Verfahren zu ihrer Herstellung und die sie enthaltenden pharmazeutischen Zusammensetzungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9113889A1 *

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