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WO1994005685A1 - Macrocyclic compounds useful in therapy - Google Patents

Macrocyclic compounds useful in therapy Download PDF

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Publication number
WO1994005685A1
WO1994005685A1 PCT/GB1993/001850 GB9301850W WO9405685A1 WO 1994005685 A1 WO1994005685 A1 WO 1994005685A1 GB 9301850 W GB9301850 W GB 9301850W WO 9405685 A1 WO9405685 A1 WO 9405685A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
derivative
compounds
Prior art date
Application number
PCT/GB1993/001850
Other languages
French (fr)
Inventor
Mark Furber
Original Assignee
Fisons Plc
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Publication date
Application filed by Fisons Plc filed Critical Fisons Plc
Priority to AU49728/93A priority Critical patent/AU4972893A/en
Publication of WO1994005685A1 publication Critical patent/WO1994005685A1/en

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    • 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 novel macrocyclic compounds, their use as medicaments, and pharmaceutical formulations including 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.
  • European Patent Application 323042 and International Patent Application WO 91/02736 disclose many macrolides which may be derived from those dis ⁇ closed in European Patent Application 184162. The compounds are primarily indicated s as immunosuppressive agents.
  • European Patent Applications 349049, 349061 and 388153 disclose the 3,4-dihydroxycyclohexyl analogues of FR- 900506, FR-900520 and FR-900523 respectively and indicate them primarily as immunosuppressive agents.
  • European Patent Application 405994 discloses a method of converting compounds such as FR-900506 which contain a o piperidine ring into their pyrrolidine ring-containing analogues.
  • R 1 represents OH or OCH 3 ;
  • R 2 represents H or OH
  • R 3 represents methyl, ethyl, propyl, allyl or 2-oxopropyl
  • R 4 represents H or OH
  • X represents O, (H,OH) or (H,H); n represents 1 or 2; and pharmaceutically acceptable derivatives thereof (hereinafter referred to en bloc as
  • esters may be prepared by conventional methods, for example reaction with a carboxylic acid and a coupling agent, or an acyl chloride, and the carboxylic acid moiety preferably contains from 1-6 carbon atoms.
  • carbamates may also be prepared by conventional methods, for example reaction with an isocvanate, and the carbamic acid moiety preferably contains from 1-6 carbon atoms.
  • Specific esters and carbamates are CH 3 C0 2 -, H 5 C0 2 -, H 2 NC0 2 - and CH 3 NHC0 2 -.
  • R 4 represents H.
  • R ⁇ R 3 , R 4 , X and n are as defined above, and R 2 " represents H or protected hydroxy, followed where necessary by deprotection of R 2 ".
  • the reaction may be carried out using a mild dehydrating agent (for example l,3-dimethyl-2-fluoropyridinium 4- toluenesulphonate) in the presence of a base (for example triethylamine), in a solvent which does not adversely affect the reaction (for example dimethoxyethane), at a reduced temperature (for example 0°C).
  • a mild dehydrating agent for example l,3-dimethyl-2-fluoropyridinium 4- toluenesulphonate
  • a base for example triethylamine
  • a solvent which does not adversely affect the reaction for example dimethoxyethane
  • a reduced temperature for example 0°C
  • Protected hydroxy groups which R 23 may represent include silyl ethers (for example 'butyldimethylsilyloxy). Such silyl protecting groups may be removed using conventional methods (for example by the action of hydrofluoric acid). Other protected hydroxy groups are described in "Protective Groups in Organic Chemistry", ed: J W F McOmie, Plenum Press (1973), and “Protecting Groups in Organic Synthesis", 2nd edition, T W o Greene and P G M Wuts, Wiley & Son Inc (1991)]. In addition, EP 184162 describes the use of protecting groups in macrocyclic compounds. Compounds of formula II are either known from, or may be made by the methods of, the patent applications mentioned above.
  • the compounds of the invention are useful because they possesses pharmacological activity in animals, eg as indicated in Tests A-F below.
  • the compounds of the invention are indicated for use in the treatment or preven ⁇ tion of rejection of transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin, cornea, liver, medulla ossium, pancreas, intestinum ***, limb, muscle, nervus, etc; and of autoimmune, inflammatory, proliferative and hyperprohferative diseases (particularly of the skin), 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 (which is of particular interest), atopical s dermatitis, contact dermatitis and further eczematous dermatitides, seborrhoeic dermatitis,
  • the compounds of the invention are also indicated in the treatment or prophylaxis of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneu ⁇ monia and reversible obstructive airways diseases which latter term 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 5 hyper-responsiveness), bronchitis and the like.
  • the prophylaxis of asthma is of particu ⁇ lar interest.
  • the compounds of the invention are also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, 0 keratitis, herpetic keratitis. conical cornea, dystrophia epithelialis corneae, corneal leucoma, 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 ischaemic diseases and thrombosis, ischaemic bowel disease, inflammatory bowel disease, necrotiz- ing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4- s mediated diseases.
  • the compounds of the invention are also indicated in the treatment of renal diseases including interstitial nephritis, Goodpasture's syndrome, haemolytic-uraemic syndrome and diabetic nephropathy; nervous diseases including multiple myositis, Guillain-Barre 0 syndrome, Meniere's disease and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; haematic diseases including pure red cell aplasia, aplastic anaemia, hypoplastic anaemia, idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, agranulocytosis and anerythroplasia; bone diseases such as osteoporosis; skin diseases including dermatomyositis, leucoderma vulgaris, s ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases selected from arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteriti
  • 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 gastro-intestinal 25 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 gastro-intestinal 25 tract, for example migraine, rhinitis and eczema.
  • the compounds of the invention may also have liver regenerating activity and/or activity in stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are indicated in the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. 30 chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary 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 thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
  • a compound of the invention in the manufacture of a medicament for use as an immunosuppressive agent, in the manufacture of a medic ⁇ ament for the treatment of reversible obstructive airways diseases, and in the manufac- 0 ture of a medicament for the treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses.
  • Administration of a compound of the invention may be topical [for example by inhal ⁇ ation to the lung (particularly in the treatment of reversible obstructive airways diseases) s or application to the skin (particularly in the treatment of inflammatory or hyperprolifer ⁇ ative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses)], or systemic (for example by oral administration to the gastrointestinal tract).
  • the compounds of the invention may be inhaled o as a dry powder formulation which may be pressurized or non-pressurized.
  • a compound of the invention in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier, for example crystalline lactose.
  • Pressurized formulations may contain a compressed gas, eg nitrogen, or a liquefied gas propellant. Formulations of these types are described in 25 detail in International Patent Application WO 90/14826.
  • a suitable dose of active ingredient for administration by inhalation is in the range from 0.001 to O.lmg.kg '.day' 1 , and preferably O.Olmg.kg '.day "1 .
  • the formulation may be in the form of a lotion, 30 gel or cream, and preferably contains the compound of the invention in a concentration of 0.003-3% by weight.
  • Such formulations may be prepared by the methods described in European Patent Application 423714. Suitable doses for such topical administration are in the range from 0.05 to lOmg.kg '.day '1 , for example 0.5mg.kg ' '.day "1 .
  • the compound of the invention may be formu ⁇ lated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract.
  • Suitable doses for such oral administration are in the range from 0.003 to 0.3 mg.kg '.day '1 , for example 0.03mg.kg "1 .day '1 .
  • Such formulations may be prepared by the methods described by T Hondo et al, Transplantation Proceedings, 1987, XIX, Supp 6, 17-22.
  • the dosage to be administered will of course vary within the above limits with the particular compound of the invention, the condition to be treated and with its severity.
  • the compound of the invention may be administered as divided doses from 1 to 6, and preferably 2 to 4, times per day. Each dose may comprise 1 or more unit doses.
  • the invention further provides a pharmaceutical formulation including preferably less than 80%, and more preferably less than 50% by weight, of a compound of the inven ⁇ tion in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a method of effecting immunosuppression a method of treatment of reversible obstructive airways diseases, and a method of treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses, each of 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. All optical and stereoisomers are provided, as well as mixtures thereof. The isomers may be resolved or separated by conventional techniques. The preferred stereochemistry of various chiral carbon atoms is shown in formula la,
  • R 1"4 , X and n are as defined above.
  • 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 the compounds of the prior art.
  • the MLR test was performed in 96-well flat bottomed microtitre plates.
  • the test compound was dissolved in ethanol at 10 times the desired concentration, and 20 ⁇ l of the resulting solution added to each well. The ethanol was then allowed to evaporate.
  • Into each well was then placed 3x10 s C57BL/6 responder cells (H-2°), 3x10 s mitomycin C-treated (25 ⁇ g/ml mitomycin C at 37°C for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2°) in 0-2ml RPMI 1640 medium supplemented with 5% fetal calf serum, 2mM L-glutamine, 5xl0 '5 M 2-mercaptoethanol, 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 96 hours and pulsed with 3 H-thymidine (0-5 ⁇ Ci) 6 hours before the cells were collected. The level of radio- activity incorporated by the cells was then determined, which is a measure of T-cell proliferation.
  • the MLR test was performed in 96-well flat bottomed microtitre plates.
  • the compound under test was dissolved in ethanol to 10 times the desired concentration and 20 ⁇ l of the resulting solution placed in each well. The ethanol was then allowed to evaporate.
  • Into each well was then placed 1 -5x10 s cells from each of two responding donors in a final volume of 0-2ml RPMI 1640 medium supplemented with 10% human serum, 2mM L- glutamine and penicillin streptomycin. The cells were incubated at 37°C in a humidified atmosphere at 5% carbon dioxide for 120 hours. 3 H-thymidine (0-5 ⁇ Ci) was added for the final 6 hours of the incubation. The level of radioactivity incorporated by the cells was then determined, which is a measure of T-cell proliferation.
  • Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 10* cells/ml. 04ml of these suspensions were injected respectively into the left and right rear footpads of DAxLewis Fl rats. Recipient animals were 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 GNH response.
  • the compounds of the invention may be screened for their potential anti-psoriasis efficacy in the TPA-induced cutaneous inflammatory response screen described by R J Griffiths, B E Wood, S Li and A Blackham in 'Effects of cyclosporin and protein syn ⁇ thesis inhibitors on cutaneous inflammation in mouse skin', Skin Pharmacology, 2, 30-37, 1989.
  • the compounds of the invention may be screened for their potential anti-asthma efficacy in the mast cell model described by E Wells, S T Harper, C G Jackson, J Mann and R P Eady in 'Characterization of primate bronchoaiveolar mast cells: I. IgE-dependent release of histamine leukotrienes and prostaglandins', J Immunol 137(12): 3933-40, 1986; and 'Characterization of primate bronchoaiveolar mast cells: II. Inhibition of histamine LTC4 and PGD2 release from primate bronchoaiveolar mast cells and a comparison with rat peritoneal mast cells', J Immunol 137(12): 3941-3945, 1986.
  • step (a) To a stirred solution of the product of step (a) (2.485g) in dry dimethoxyethane (70ml) at 0°C under nitrogen, was added portionwise l,3-dimethyl-2-fluoropyridinium 4-toluene- sulphonate (3.02g). Dry triethylamine (1.83ml) was added and the mixture stirred at 0°C s for 30 minutes. Water (10ml) was added and stirring continued for 10 minutes. The mixture was poured into IN aqueous hydrochloric acid and the product was extracted with diethyl ether.
  • step (b) To a stirred solution of the product of step (b) (0.048g) in acetonitrile (5ml) was added a 40% aqueous solution of hydrofluoric acid (2 drops). The solution was stirred at room temperature for 30 minutes, then poured into saturated aqueous sodium bicarbonate solution and the product was extracted with diethyl ether. The extracts were dried (MgS0 4 ), concentrated in vacuo and chromatographed on silica gel eluting with
  • Example 2 The compound of Example 1 was tested in Test D above, and found to inhibit IL-2 secretion by 50% (IC 50 ) at a concentration of 4xl0 '9 M.

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Abstract

Compounds of formula (I), wherein R1 represents OH or OCH¿3; R?2 represents H or OH; R3 represents methyl, ethyl, propyl, allyl or 2-oxopropyl; R4 represents H or OH; X represents O, (H,OH) or (H,H); n represents 1 or 2; and pharmaceutically acceptable derivatives thereof; are disclosed. The compounds are useful inter alia as immunosuppressants, and in the treatement of reversible obstructive airways diseases and certain skin diseases.

Description

Macrocyclic compounds useful in therapy
This invention relates to novel macrocyclic compounds, their use as medicaments, and pharmaceutical formulations including 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.
European Patent Application 323042 and International Patent Application WO 91/02736 (both to Fisons pic) disclose many macrolides which may be derived from those dis¬ closed in European Patent Application 184162. The compounds are primarily indicated s as immunosuppressive agents. European Patent Applications 349049, 349061 and 388153 (to Merck & Co Inc) disclose the 3,4-dihydroxycyclohexyl analogues of FR- 900506, FR-900520 and FR-900523 respectively and indicate them primarily as immunosuppressive agents. European Patent Application 405994 (to Merck & Co Inc) discloses a method of converting compounds such as FR-900506 which contain a o piperidine ring into their pyrrolidine ring-containing analogues.
At the 6th National American Chemical Society Meeting (Medicinal Chemistry Sympo¬ sium) held in Buffalo NY, USA, in June 1992. 18-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)- l-methylvinyl-24,26-dimethoxy- 13,20,22,28-tetramethyl- 11,29-dioxa- 5 4,16-diazatricyclo[23.3.1.04,9]nonaconta-19-ene-2,3,10,17-tetraone was disclosed. A group of macrocyclic compounds possessing advantageous properties over this compound has now been found.
Thus, according to the invention, there is provided a compound of formula I, 0
Figure imgf000004_0001
wherein
R1 represents OH or OCH3;
R2 represents H or OH;
R3 represents methyl, ethyl, propyl, allyl or 2-oxopropyl;
R4 represents H or OH;
X represents O, (H,OH) or (H,H); n represents 1 or 2; and pharmaceutically acceptable derivatives thereof (hereinafter referred to en bloc as
"the compounds of the invention").
Pharmaceutically acceptable derivatives of compounds of formula I include prodrugs, i.e. compounds which may be metabolized 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, and the carboxylic acid moiety preferably contains from 1-6 carbon atoms. Such carbamates may also be prepared by conventional methods, for example reaction with an isocvanate, and the carbamic acid moiety preferably contains from 1-6 carbon atoms. Specific esters and carbamates are CH3C02-, H5C02-, H2NC02- and CH3NHC02-. Preferably, R4 represents H.
Compounds of formula I may be prepared by a Beckmann rearrangement of an E-oxime of formula II,
Figure imgf000005_0001
wherein R\ R3, R4, X and n are as defined above, and R2" represents H or protected hydroxy, followed where necessary by deprotection of R2". The reaction may be carried out using a mild dehydrating agent (for example l,3-dimethyl-2-fluoropyridinium 4- toluenesulphonate) in the presence of a base (for example triethylamine), in a solvent which does not adversely affect the reaction (for example dimethoxyethane), at a reduced temperature (for example 0°C).
s Protected hydroxy groups which R23 may represent include silyl ethers (for example 'butyldimethylsilyloxy). Such silyl protecting groups may be removed using conventional methods (for example by the action of hydrofluoric acid). Other protected hydroxy groups are described in "Protective Groups in Organic Chemistry", ed: J W F McOmie, Plenum Press (1973), and "Protecting Groups in Organic Synthesis", 2nd edition, T W o Greene and P G M Wuts, Wiley & Son Inc (1991)]. In addition, EP 184162 describes the use of protecting groups in macrocyclic compounds. Compounds of formula II are either known from, or may be made by the methods of, the patent applications mentioned above.
The compounds of the invention are useful because they possesses pharmacological activity in animals, eg as indicated in Tests A-F below.
Thus, the compounds of the invention are indicated for use in the treatment or preven¬ tion of rejection of 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 hyperprohferative diseases (particularly of the skin), 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 (which is of particular interest), atopical s dermatitis, contact dermatitis and further eczematous dermatitides, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, acne, Alopecia areata, eosinophilic fascitis, atherosclerosis and the like.
o The compounds of the invention are also indicated in the treatment or prophylaxis of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneu¬ monia and reversible obstructive airways diseases which latter term 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 5 hyper-responsiveness), bronchitis and the like. The prophylaxis of asthma is of particu¬ lar interest.
The compounds of the invention are also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, 0 keratitis, herpetic keratitis. conical cornea, dystrophia epithelialis corneae, corneal leucoma, 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 ischaemic diseases and thrombosis, ischaemic bowel disease, inflammatory bowel disease, necrotiz- ing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4- s mediated diseases.
The compounds of the invention are also indicated in the treatment of renal diseases including interstitial nephritis, Goodpasture's syndrome, haemolytic-uraemic syndrome and diabetic nephropathy; nervous diseases including multiple myositis, Guillain-Barre 0 syndrome, Meniere's disease and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; haematic diseases including pure red cell aplasia, aplastic anaemia, hypoplastic anaemia, idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, agranulocytosis and anerythroplasia; bone diseases such as osteoporosis; skin diseases including dermatomyositis, leucoderma vulgaris, s 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; haemolytic- uraemic syndrome; and male pattern alopecia and alopecia senilis. 0
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 gastro-intestinal 25 tract, for example migraine, rhinitis and eczema.
The compounds of the invention may also have liver regenerating activity and/or activity in stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are indicated in the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. 30 chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary 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 thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
s We therefore provide the use of the compounds of the invention as pharmaceuticals.
Further, we provide the use of a compound of the invention in the manufacture of a medicament for use as an immunosuppressive agent, in the manufacture of a medic¬ ament for the treatment of reversible obstructive airways diseases, and in the manufac- 0 ture of a medicament for the treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses.
Administration of a compound of the invention may be topical [for example by inhal¬ ation to the lung (particularly in the treatment of reversible obstructive airways diseases) s or application to the skin (particularly in the treatment of inflammatory or hyperprolifer¬ ative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses)], or systemic (for example by oral administration to the gastrointestinal tract).
Dealing first with inhalation to the lung, the compounds of the invention may be inhaled o as a dry powder formulation which may be pressurized or non-pressurized. In non- pressurized powder formulations, a compound of the invention in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier, for example crystalline lactose. Pressurized formulations may contain a compressed gas, eg nitrogen, or a liquefied gas propellant. Formulations of these types are described in 25 detail in International Patent Application WO 90/14826. A suitable dose of active ingredient for administration by inhalation is in the range from 0.001 to O.lmg.kg '.day'1, and preferably O.Olmg.kg '.day"1.
For topical administration to the skin, the formulation may be in the form of a lotion, 30 gel or cream, and preferably contains the compound of the invention in a concentration of 0.003-3% by weight. Such formulations may be prepared by the methods described in European Patent Application 423714. Suitable doses for such topical administration are in the range from 0.05 to lOmg.kg '.day'1, for example 0.5mg.kg''.day"1. Turning now to systemic administration, the compound of the invention may be formu¬ lated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract. Suitable doses for such oral administration are in the range from 0.003 to 0.3 mg.kg '.day'1, for example 0.03mg.kg"1.day'1. Such formulations may be prepared by the methods described by T Hondo et al, Transplantation Proceedings, 1987, XIX, Supp 6, 17-22.
The dosage to be administered will of course vary within the above limits with the particular compound of the invention, the condition to be treated and with its severity.
The compound of the invention may be administered as divided doses from 1 to 6, and preferably 2 to 4, times per day. Each dose may comprise 1 or more unit doses.
The invention further provides a pharmaceutical formulation including preferably less than 80%, and more preferably less than 50% by weight, of a compound of the inven¬ tion in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
According to a further aspect of the invention, there is provided a method of effecting immunosuppression, a method of treatment of reversible obstructive airways diseases, and a method of treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses, each of 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. All optical and stereoisomers are provided, as well as mixtures thereof. The isomers may be resolved or separated by conventional techniques. The preferred stereochemistry of various chiral carbon atoms is shown in formula la,
Figure imgf000010_0001
wherein R1"4, X and n are as defined above.
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 the compounds of the prior art.
Test A
Murine Mixed Lymphocyte Reaction CMLR D
The MLR test was performed in 96-well flat bottomed microtitre plates. The test compound was dissolved in ethanol at 10 times the desired concentration, and 20μl of the resulting solution added to each well. The ethanol was then allowed to evaporate. Into each well was then placed 3x10s C57BL/6 responder cells (H-2°), 3x10s 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-2°) in 0-2ml RPMI 1640 medium supplemented with 5% fetal calf serum, 2mM L-glutamine, 5xl0'5M 2-mercaptoethanol, 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 96 hours and pulsed with 3H-thymidine (0-5μCi) 6 hours before the cells were collected. The level of radio- activity incorporated by the cells was then determined, which is a measure of T-cell proliferation.
Test B Human Mixed Lymphocyte Reaction (MLR ID
The MLR test was performed in 96-well flat bottomed microtitre plates. The compound under test was dissolved in ethanol to 10 times the desired concentration and 20μl of the resulting solution placed in each well. The ethanol was then allowed to evaporate. Into each well was then placed 1 -5x10s cells from each of two responding donors in a final volume of 0-2ml RPMI 1640 medium supplemented with 10% human serum, 2mM L- glutamine and penicillin streptomycin. The cells were incubated at 37°C in a humidified atmosphere at 5% carbon dioxide for 120 hours. 3H-thymidine (0-5μCi) was added for the final 6 hours of the incubation. The level of radioactivity incorporated by the cells was then determined, which is a measure of T-cell proliferation.
Test C
Graft versus Host Assay CG'VT-D
Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 10* cells/ml. 04ml of these suspensions were injected respectively into the left and right rear footpads of DAxLewis Fl rats. Recipient animals were 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 GNH response.
Test D
Inhibition of Interleukin-2 fIL-21 secretion
The test was performed following the method of D J Henderson et al, Immunology
1991, Nol 73, pp316-327.
Test E
The compounds of the invention may be screened for their potential anti-psoriasis efficacy in the TPA-induced cutaneous inflammatory response screen described by R J Griffiths, B E Wood, S Li and A Blackham in 'Effects of cyclosporin and protein syn¬ thesis inhibitors on cutaneous inflammation in mouse skin', Skin Pharmacology, 2, 30-37, 1989.
Test F
The compounds of the invention may be screened for their potential anti-asthma efficacy in the mast cell model described by E Wells, S T Harper, C G Jackson, J Mann and R P Eady in 'Characterization of primate bronchoaiveolar mast cells: I. IgE-dependent release of histamine leukotrienes and prostaglandins', J Immunol 137(12): 3933-40, 1986; and 'Characterization of primate bronchoaiveolar mast cells: II. Inhibition of histamine LTC4 and PGD2 release from primate bronchoaiveolar mast cells and a comparison with rat peritoneal mast cells', J Immunol 137(12): 3941-3945, 1986.
The invention is illustrated by the following examples.
Example 1
18-Allyl-1.14»dihvdroxy-12-f2-(4-hvdroxy-3-methoxycvclohexyl)-l-methylvinyl-24.26- dimethoxy-13.20.22.28-tetramethyl-11.29-dioxa-4,17-diazatricvclrf23 .1.04 >1nonaconta- 19-ene-2 ,10,l 6-tetraone
(a) 17-Allyl-14-'butyldimethylsilyloxy-l-hvdroxy-12-[2-('4-hvdroxy-3-methoxy cvclo- hexyπ-l-methylvinyl]-23.25-dimethoxy-13.19,21.27-tetramethyl-ll,28-dioxa-4-azatricyclo- [ 22.3.1.049]octacos-18-ene-2,3.10.16-tetraone C16 E-oxime
To a stirred solution of 17-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone C16 E-oxime (as prepared in Example 25, WO 89/05304, and separated from the Z-oxime by chromatography on silica) (2.745g) in dry dichloromethane (100ml) and dry 2,6-lutidine (2.35ml) was added slowly 'butyl- dimethylsilyltrifluoromethanesulphonate (3.82ml). After 20 minutes at room tempera¬ ture the solution was poured into IN aqueous hydrochloric acid solution and the product was extracted with diethyl ether. The extracts were dried (MgS04) and concentrated in vacuo to a foam (4.32g). The crude product was redissolved in methanol (75ml) and stirred with pyridinium toluenesulphonate (0.075g) for 2 days at room temperature and then for a further 3 days at 4°C. The mixture was poured into saturated sodium bicarbonate solution (150ml) and extracted with ethyl acetate. The extracts were washed with IN aqueous hydrochloric s acid followed by brine, dried (MgS04) and concentrated in vacuo to give the subtitle compound (2.488g) as a colourless foam.
(b) 18-Allyl-14-'butyldimethylsilyloxy-l-hvdroxy-12-[2- 4-hydroxy-3-methoxy- cvclohexylVl-methylvinyl-24.26-dimethoxy-13.20.22.28-tetramethyl-11.29-dioxa-4.17-diaza- o tricvclo[23.3.1.04-9]nonaconta-19-ene-2.3.10.16-tetraone
To a stirred solution of the product of step (a) (2.485g) in dry dimethoxyethane (70ml) at 0°C under nitrogen, was added portionwise l,3-dimethyl-2-fluoropyridinium 4-toluene- sulphonate (3.02g). Dry triethylamine (1.83ml) was added and the mixture stirred at 0°C s for 30 minutes. Water (10ml) was added and stirring continued for 10 minutes. The mixture was poured into IN aqueous hydrochloric acid and the product was extracted with diethyl ether. The extracts were washed with water then brine, dried (MgSO4), concentrated in vacuo and chromatographed on silica gel eluting with acetone/hexane [2:5] to give the subtitle compound (0.154g). 0
(c) 18-Allyl-1.14-dihvdroxy-12-[2-(,4-hvdroxy-3-methoxycvclohexylVl-methylvinyl- 24.26-dimethoxy-13.20.22.28-tetramethyl-11.29-dioxa-4.17-diazatricvclo 23.3.1.049]- nonaconta- 19-ene-2,3.10.16-tetraone
25 To a stirred solution of the product of step (b) (0.048g) in acetonitrile (5ml) was added a 40% aqueous solution of hydrofluoric acid (2 drops). The solution was stirred at room temperature for 30 minutes, then poured into saturated aqueous sodium bicarbonate solution and the product was extracted with diethyl ether. The extracts were dried (MgS04), concentrated in vacuo and chromatographed on silica gel eluting with
30 acetone/hexane [3:4] to give the title compound (0.028g) as a colourless foam.
Example 2 The compound of Example 1 was tested in Test D above, and found to inhibit IL-2 secretion by 50% (IC50) at a concentration of 4xl0'9M.

Claims

Claims:
1. A compound of formula I,
Figure imgf000015_0001
wherein
R1 represents OH or OCH3;
R2 represents H or OH; R3 represents methyl, ethyl, propyl, allyl or 2-oxopropyl;
R4 represents H or OH;
X represents O, (H,OH) or (H,H); n represents 1 or 2; and pharmaceutically acceptable derivatives thereof.
2. A compound as claimed in claim 1, wherein R4 represents H.
3. A compound as claimed in claim 1 or claim 2, which is 18-allyl-l,14-dihydroxy-
12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl-24,26-dimethoxy-13,20,22,28-tetra- methyl-ll,29-dioxa-4,17-diazatricyclo[23.3.1.04'9]nonaconta-19-ene-2,3,10,16-tetraone,or a pharmaceutically acceptable derivative thereof.
4. A pharmaceutical formulation including a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
5. A compound of formula I, as defined in claim 1, or a pharmaceutically accept¬ able derivative thereof, for use as a pharmaceutical.
6. A compound of formula I, as defined in claim 1, or a pharmaceutically accept¬ able derivative thereof, for use in the manufacture of an immunosuppressive medic- s ament.
7. A compound of formula I, as defined in claim 1, or a pharmaceutically accept¬ able derivative thereof, for use in the manufacture of a medicament for the treatment of reversible obstructive airways diseases.
8. A compound of formula I, as defined in claim 1, or a pharmaceutically accept- ιo able derivative thereof, for use in the manufacture of a medicament for the treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses.
9. A process for the production of a compound of formula I, or a pharmaceutically acceptable derivative thereof, which comprises a Beckmann rearrangement of an E- i5 oxime of formula II,
Figure imgf000016_0001
wherein Rl, R3, R4, X and n are as defined in claim 1 and R2* represents H or protected 20 hydroxy.
10. A method of effecting immunosuppression, which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, to a patient.
11. A method of treatment of reversible obstructive airways diseases, which com¬ prises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, to a patient.
12. A method of treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses, which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable derivative thereof, to a patient.
PCT/GB1993/001850 1992-09-04 1993-09-01 Macrocyclic compounds useful in therapy WO1994005685A1 (en)

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Publication number Priority date Publication date Assignee Title
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection

Citations (2)

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

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Title
M. FURBER ET AL.: "Studies Relating to the Immunosuppressive Activity of FK506", TETRAHEDRON LETT., vol. 34, no. 8, 1993, pages 1351 - 1354 *
R.V. BUNDICK ET AL.: "FK506 as an Agonist to Induce Inhibition of Interleukin 2 Production", TRANSPLANTATION, vol. 53, no. 5, May 1992 (1992-05-01), pages 1150 - 1153, XP000913592 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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