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WO1993016083A1 - Macrocyclic compounds and their use as pharmaceuticals - Google Patents

Macrocyclic compounds and their use as pharmaceuticals Download PDF

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Publication number
WO1993016083A1
WO1993016083A1 PCT/GB1993/000231 GB9300231W WO9316083A1 WO 1993016083 A1 WO1993016083 A1 WO 1993016083A1 GB 9300231 W GB9300231 W GB 9300231W WO 9316083 A1 WO9316083 A1 WO 9316083A1
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Prior art keywords
compound
formula
compounds
pharmaceutically acceptable
diseases
Prior art date
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PCT/GB1993/000231
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French (fr)
Inventor
Mark Furber
Original Assignee
Fisons Plc
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Publication of WO1993016083A1 publication Critical patent/WO1993016083A1/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
    • C07D498/22—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 four or more hetero rings
    • 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 a novel macrocyclic compound and its pharmaceutically acceptable derivatives, their use as pharmaceuticals, and pharmaceutical formulations containing them.
  • European Patent Application 184162 discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomyces. The compounds are numbered FR-900506, FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described. The compounds are indicated as immunosuppressive agents.
  • the compound of formula I may be prepared by the method of Example 1 below.
  • the compounds of the invention have the advantage that they are less toxic, more efficacious, longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed, are more soluble, or have other more useful physical or pharmacological properties, than compounds of the prior art.
  • esters may be prepared by conventional methods, for example reaction with a carboxylic acid and a coupling agent, or an acyl chloride.
  • carbamates may also be prepared by conventional methods, for example reaction with an isocyanate. Specific esters and carbamates are CH 3 CO 2 -, C 6 H 5 CO 2 -, H 2 NCO 2 - and CH 3 NHCO 2 -.
  • the compounds of the invention are useful because they possess pharmacological activity in animals: in particular they are useful because they possess immunosuppressive activity, e.g. as indicated in Tests A, B, C and D below.
  • the compounds of the invention 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, liver, medulla ossium, pancreas, intestinum ***, limb.
  • organs or tissues such as kidney, heart, lung, bone marrow, skin, cornea, liver, medulla ossium, pancreas, intestinum ***, limb.
  • 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.
  • the compounds of the invention are also indicated in the treatment of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease which latter includes conditions such as asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness), bronchitis and the like.
  • respiratory diseases for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease
  • respiratory diseases for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease which latter includes conditions such as asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-
  • the compound of the invention is also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy and the like.
  • eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy and the like.
  • the compounds of the invention are also indicated in the treatment of inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflarr-matory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases.
  • the compounds of the invention are also indicated in the treatment of renal diseases including interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases including multiple myositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; hematic diseases including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases such as osteoporosis; skin diseases including dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis;
  • the compounds of the invention are indicated in the treatment of diseases including 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.
  • diseases including 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 also have liver regenerating activity and/or activity in stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary s cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A non-B hepatitis and cirrhosis.
  • immunogenic diseases e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary s cirrhosis and sclerosing cholangitis
  • partial liver resection e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia
  • B-virus hepatitis e.g
  • the compounds of the invention are also indicated for use as antimicrobial agents, and o thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
  • the compounds of the invention are further indicated in the prophylactic treatment of acquired immunodeficiency syndrome (AIDS), by which we mean delay of the onset of 5 disease symptoms in patients infected with the human immunodeficiency virus (HIV)
  • AIDS acquired immunodeficiency syndrome
  • HAV human immunodeficiency virus
  • the dosage administered will, of course, vary with the mode of administration, the treatment desired (eg topical, parenteral or oral) and the disease indicated.
  • the compounds of the inventions are administered at a daily dosage of from 0.001 to 20mg per kg of animal body weight.
  • unit dosage forms suitable for adrninistration comprise from O.Olmg to 500mg, and preferably 0.5mg to lOOmg of a compound of the invention preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
  • a pharmaceutical formulation comprising preferably less than 80%, and more preferably less than 50% by weight, of a compound of the invention in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Suitable adjuvants, diluents or carriers are: 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; for inhalation formulations - coarse lactose.
  • the compounds of the invention are preferably in a form having a mass median diameter of from 0.01 to lO ⁇ m.
  • the formulations 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 formulated in sustained release form.
  • the compounds of the invention for the treatment of reversible obstructive airways disease, we prefer the compounds of the invention 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 the invention to a patient.
  • the compounds of the invention have a number of chiral centres and may exist in a variety of stereoisomers.
  • the invention provides all optical and stereoisomers.
  • the isomers may be resolved or separated by conventional techniques.
  • the MLR test was performed in microtitre plates, with each well containing 5x10 s
  • BALB/C stimulator cells H-2 d
  • BALB/C stimulator cells H-2 d
  • RPMI 1640 medium supplemented with 10% fetal calf serum, 2mM sodium hydrogen carbonate, penicillin (50 ⁇ g/ml) and streptomycin (50 ⁇ g/ml).
  • 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 compound of the invention was dissolved in ethanol s and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.l ⁇ g/ml or less.
  • 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% s 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.
  • graft versus Host Assay f GVH 0 Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 10 s cells/ml. 0.1ml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively). Recipient animals were dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay was te ⁇ ninated on day 7 when the popliteal lymph nodes of the animals were removed and weighed. The 5 increase in weight of the left node relative to the weight of the right gave a measure of the GVH response.
  • Example 1 The title compound of Example 1 was tested following the method of test D above, and s the concentration of the compound required to inhibit IL-2 secretion by 50% (IC ⁇ ) was found to be 5xlO- 10 M.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides the compound of formula (I), and its pharmaceutically acceptable derivatives, which are indicated inter alia as immunosuppressive agents.

Description

Macrocvclic compounds and their use as pharmaceuticals
This invention relates to a novel macrocyclic compound and its pharmaceutically acceptable derivatives, their use as pharmaceuticals, and pharmaceutical formulations containing them.
European Patent Application 184162 (to Fujisawa Pharmaceuticals Co Ltd) discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomyces. The compounds are numbered FR-900506, FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described. The compounds are indicated as immunosuppressive agents.
International Patent Applications Nos WO 89/05304 and WO 91/02736 and European Patent Application No 413532 (to Fisons pic), European Patent Application 353678 (to Fujisawa Pharmaceuticals Co Ltd), European Patent Applications 349049, 349061, 358508 and 388153 (to Merck & Co Inc) and European Patent Application 356399 and International Patent Application WO 90/15805 (to Sandoz AG) also disclose a number of macrocyclic compounds whose indications include immunosuppressive activity.
According to the invention, there is provided the compound of formula I,
Figure imgf000003_0001
and pharmaceutically acceptable derivatives thereof (hereinafter referred to en bloc as "the compounds of the invention".
The compound of formula I may be prepared by the method of Example 1 below.
The compounds of the invention have the advantage that they are less toxic, more efficacious, longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed, are more soluble, or have other more useful physical or pharmacological properties, than compounds of the prior art.
Pharmaceutically acceptable derivatives of the compound of formula I include prodrugs, i.e. compounds which may be metabolised in vivo to the compound of formula I. These include compounds which differ from the compound of formula I in that some or all of the OH groups are derivatized to esters or carbamates. Such esters may be prepared by conventional methods, for example reaction with a carboxylic acid and a coupling agent, or an acyl chloride. Such carbamates may also be prepared by conventional methods, for example reaction with an isocyanate. Specific esters and carbamates are CH3CO2-, C6H5CO2-, H2NCO2- and CH3NHCO2-.
The compounds of the invention are useful because they possess pharmacological activity in animals: in particular they are useful because they possess immunosuppressive activity, e.g. as indicated in Tests A, B, C and D below.
Thus the compounds of the invention 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, liver, medulla ossium, pancreas, intestinum tenue, limb. muscle, nervus, etc; and of autoimmune, inflammatory, proliferative and hyperproliferative 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, acne, Alopecia areata, eosinophilic fascϋtis, atherosclerosis and the like.
The compounds of the invention are also indicated in the treatment of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia and reversible obstructive airways disease which latter includes conditions such as asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness), bronchitis and the like.
The compound of the invention is also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy and the like.
The compounds of the invention are also indicated in the treatment of inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflarr-matory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases.
The compounds of the invention are also indicated in the treatment of renal diseases including interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases including multiple myositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; hematic diseases including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases such as osteoporosis; skin diseases including dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases including scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; periodontal disease; nephrotic syndrome: hemolytic-uremic syndrome; and male pattern alopecia and alopecia senilis.
s Further, the compounds of the invention are indicated in the treatment of diseases including 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. 0
The compounds of the invention also have liver regenerating activity and/or activity in stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary s cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A non-B hepatitis and cirrhosis.
The compounds of the invention are also indicated for use as antimicrobial agents, and o thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
The compounds of the invention are further indicated in the prophylactic treatment of acquired immunodeficiency syndrome (AIDS), by which we mean delay of the onset of 5 disease symptoms in patients infected with the human immunodeficiency virus (HIV)
We therefore provide the use of the compounds of the invention as pharmaceuticals.
Further, we provide the use of the compounds of the invention as active ingredients in o the manufacture of a medicament for use as an immunosuppressive agent.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the mode of administration, the treatment desired (eg topical, parenteral or oral) and the disease indicated. However, in general, satisfactory results are obtained when the compounds of the inventions are administered at a daily dosage of from 0.001 to 20mg per kg of animal body weight.
For man the indicated total daily dosage is in the range of from O.Olmg to lOOOmg and preferably from 0.5mg to lOOmg, which may be administered, for example twice weekly, or in divided doses from 1 to 6 times a day or in sustained release form. Thus unit dosage forms suitable for adrninistration, eg oesophageally, comprise from O.Olmg to 500mg, and preferably 0.5mg to lOOmg of a compound of the invention preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
According to the invention there is also provided a pharmaceutical formulation comprising preferably less than 80%, and more preferably less than 50% by weight, of a compound of the invention in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
Examples of suitable adjuvants, diluents or carriers are: 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; for inhalation formulations - coarse lactose.
The compounds of the invention are preferably in a form having a mass median diameter of from 0.01 to lOμm. The formulations 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. The formulations may, if desired, be formulated in sustained release form.
For the treatment of reversible obstructive airways disease, we prefer the compounds of the invention to be administered by inhalation to the lung, especially in the form of a powder. According to a further aspect of the invention, there is provided a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of the invention to a patient.
The compounds of the invention have a number of chiral centres and may exist in a variety of stereoisomers. The invention provides all optical and stereoisomers. The isomers may be resolved or separated by conventional techniques.
However, the preferred configuration of certain chiral carbon atoms is shown in formula la,
Figure imgf000008_0001
Test A
Mixed Lymphocyte Reaction CMLR) I
The MLR test was performed in microtitre plates, with each well containing 5x10s
C57B1J6 responder cells (H-2b), 5x10s mitomycin C treated (25μg ml mitomycin C at
37°C for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2d) in 0.2ml RPMI 1640 medium supplemented with 10% fetal calf serum, 2mM sodium hydrogen carbonate, penicillin (50μg/ml) and streptomycin (50μg/ml). 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 3H-thymidine (0.5μCi) 4 hours before the cells were collected. The compound of the invention was dissolved in ethanol s and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.lμg/ml or less.
Test B
Mixed Lymphocyte Reaction fMLR^ II o The MLR test was performed in 96-well microtitre plates with each well containing
3x10s 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% s carbon dioxide for 96 hours. 3H-thymidine (0.5μCi) was added for the final 24 hours of the incubation to provide a measure of proliferation.
Test C
Graft versus Host Assay f GVH") 0 Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 10s cells/ml. 0.1ml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively). Recipient animals were dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay was teπninated on day 7 when the popliteal lymph nodes of the animals were removed and weighed. The 5 increase in weight of the left node relative to the weight of the right gave a measure of the GVH response.
Test D
Inhibition of Interleukin-2 (TL-2 secretion o The test was performed following the method of S Sawada et al, J Immunol (6), Vol 139, pp 1797- 1803, but using the Jurkat cell line. The invention is illustrated by the following Examples.
Example 1 fl4SVl-Hydroxy-12-[2-f4-hydroxy-3-methoxycyclohexylVl-methylvinyl]-24,26-dimethoxy- 18-ethyl-13.20,22.28-tetramethyl-ll,15.29-trioxa-4,16-diazatetracvclor23.3.1.1u l7.049] triaconta-16,19-diene-2,3,10-trione 16-N-oxide
a) l>14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexylVl-methylvinyl]-23.25- dimethoxy-17-ethyl-13,19,21.27-tetrametto^^ ene-2,3,10 6-tetraone C16 oxime
A solution of l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]- 23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 9] octacos-18-ene-2,3,10,16-tetraone (FR-900520, EP 184162) (71mg), hydroxylamine hydrochloride (80mg) and pyridine (0.2ml) in dry ethanol (5ml) was refluxed under an atmosphere of nitrogen for 2 hours. The reaction mixture was then cooled and poured into a mixture of dilute aqueous hydrochloric acid (IN) and ethyl acetate. The ethyl acetate extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgS04), filtered and evaporated in vacuo to an oil. Chromatograghy on silica eluting with hexane/acetone [2:1] then gave the Z-oxime of the title compound (7mg) followed by the E-oxime (lOmg).
MS (FAB): (E- and Z-oximes) 891 [M+Rb]+; 829 [M+Na]+; 807 [M+H]+; 789 [M-
OH]+
13C NMR (CDCI3) 6:
E-oxime 197.1 (C2); 169.3 (CIO); 165.3 (C3); 162 (C16); 138.1 (019); 132.7 (C29); 128 (C31); 125.8 (C18); 97.3 (Cl); 84.2 (C34); 39.7 (013); 39.1 (05); 24.3 (08); 21.4 (C6); 21 (07); 12 (C44); 9.9 (C39)
Z-oxime 169.5 (02); 169 (CIO); 165.3 (03); 161.7 (C16); 138 (C19); 132.6 (029); 128 (C31); 125.8 (018); 97.3 (Cl); 84.2 (C34); 9.5 (039)
b) (145)-l-Hydroxy-12-[2-f4-hydroxy-3-methoxycvclohexyl)-l-methylvinyl]-24.26- dimethoxy-18-ethyl- 13.20.22.28-tetramethyl-11.15.29-trioxa-4,16-diazatetracvclo r23.3.1.1u'17.04'&]triaconta-16.19-diene-2.3.10-trione 16-N-oxide To a solution of the compound of step (a) (0.2g) in dry dichloromethane (10ml) was added lead tetraacetate (0.131g). After stirring for 10 minutes at room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the reaction
~~ mixture was extracted with ethyl acetate. The organic extract was washed with saturated s aqueous sodium hydrogen carbonate solution, and this was dried (MgS0 ), filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with dichloromethane in an increasing acetone gradient then gave the title compound as a foam (86mg).
13C NMR (CDC13) δ: 196.7 (02); 168.8 (CIO); 166.4 (03); 138.8 (C19); 131.5 (C29);
128.7 (C31); 119.5 (C18); 118.1 (C16); 98.9 (Cl); 83.9 (034); 48.3 (C20); 38.9 (013); o 5.81 (039)
MS: 889.6 [M+Rb]+; 805.9 [M+H]+; 787.9 [M+H-H20]+
Example 2
The title compound of Example 1 was tested following the method of test D above, and s the concentration of the compound required to inhibit IL-2 secretion by 50% (IC^) was found to be 5xlO-10M.

Claims

Claims;
The compound of formula I,
Figure imgf000012_0001
and pharmaceutically acceptable derivatives thereof.
2. A pharmaceutical formulation comprising the compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
3. The use of the compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, as a pharmacetical.
4. The use of the compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, as active ingredient in the manufacture of an immunosuppressive agent.
5. A method of effecting immunosuppression which comprises administering a therapeutically effective amount of the compound of formula I, as defined in claim 1, or a pharmceutically acceptable derivative thereof, to a patient.
6. The compound of formula I, as defined in claim 1, in which certain chiral carbon atoms have the configuration shown in formula la,
Figure imgf000013_0001
PCT/GB1993/000231 1992-02-15 1993-02-04 Macrocyclic compounds and their use as pharmaceuticals WO1993016083A1 (en)

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Cited By (4)

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EP0673646A2 (en) * 1994-03-22 1995-09-27 BEHRINGWERKE Aktiengesellschaft Use of Deoxypergualin in the manufacture of a medicament for the treatment of inflammatory-hyperresponsiveness diseases
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
US6346546B1 (en) 1997-06-13 2002-02-12 Galderma Research & Development Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection

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WO1989005304A1 (en) * 1987-12-09 1989-06-15 Fisons Plc Macrocyclic compounds
EP0413532A2 (en) * 1989-08-18 1991-02-20 FISONS plc Macrocyclic compounds
WO1992003441A1 (en) * 1990-08-18 1992-03-05 Fisons Plc Macrocyclic compounds

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Publication number Priority date Publication date Assignee Title
WO1989005304A1 (en) * 1987-12-09 1989-06-15 Fisons Plc Macrocyclic compounds
EP0413532A2 (en) * 1989-08-18 1991-02-20 FISONS plc Macrocyclic compounds
WO1992003441A1 (en) * 1990-08-18 1992-03-05 Fisons Plc Macrocyclic compounds

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EP0673646A2 (en) * 1994-03-22 1995-09-27 BEHRINGWERKE Aktiengesellschaft Use of Deoxypergualin in the manufacture of a medicament for the treatment of inflammatory-hyperresponsiveness diseases
EP0673646A3 (en) * 1994-03-22 1995-12-27 Behringwerke Ag Use of deoxyspergualin for the manufacture of a medicament for the treatment of inflammatory hyperreactive diseases.
US5496831A (en) * 1994-05-13 1996-03-05 The General Hospital Corporation Inhibition of insulin-induced adiposis
US6346546B1 (en) 1997-06-13 2002-02-12 Galderma Research & Development Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
US6849658B2 (en) 1997-06-13 2005-02-01 Galderma Research & Development Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection

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GB9203265D0 (en) 1992-04-01

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