WO2005097771A1 - Antiinflammatory lactones - Google Patents

Antiinflammatory lactones Download PDF

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Publication number
WO2005097771A1
WO2005097771A1 PCT/EP2005/003384 EP2005003384W WO2005097771A1 WO 2005097771 A1 WO2005097771 A1 WO 2005097771A1 EP 2005003384 W EP2005003384 W EP 2005003384W WO 2005097771 A1 WO2005097771 A1 WO 2005097771A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
present
salt
treatment
Prior art date
Application number
PCT/EP2005/003384
Other languages
French (fr)
Inventor
Josef Gottfried Meingassner
Klaus Thirring
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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 GB0407467A external-priority patent/GB0407467D0/en
Priority claimed from GB0407466A external-priority patent/GB0407466D0/en
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to CA002558244A priority Critical patent/CA2558244A1/en
Priority to DE602005006547T priority patent/DE602005006547D1/en
Priority to AU2005231939A priority patent/AU2005231939B2/en
Priority to PL05740303T priority patent/PL1735295T3/en
Priority to JP2007505504A priority patent/JP2007530630A/en
Priority to US10/594,098 priority patent/US7414074B2/en
Priority to BRPI0509494-1A priority patent/BRPI0509494A/en
Priority to EP05740303A priority patent/EP1735295B1/en
Publication of WO2005097771A1 publication Critical patent/WO2005097771A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to anti-inflammatory lactones.
  • the present invention provides a compound of formula
  • R is hydroxy or amino
  • a compound of formula I includes a compound of formula I'.
  • a compound of formula I Preferably in a compound of formula I
  • the present invention provides a compound of the present invention which is selected from the group consisting of
  • a compound of formula I includes a compound of formula I'.
  • a compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate.
  • the present invention provides a compound of the present invention in the form of a salt.
  • salts include preferably pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, e.g. for preparation / isolation / purification purposes.
  • a salt of a compound of the present invention includes a metal salt, e.g. or, where appropriate an acid addition salt.
  • Metal salts include for example alkali or earth alkali salts, preferably alkali, such as lithium, potassium, sodium, prefrably sodium.
  • a compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa.
  • a compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in non-solvated form; and vice versa.
  • a compound of of the present invention may exist in the form of isomers and mixtures thereof; e.g. optical isomers, diastereoisomers, cis/trans conformers.
  • a compound of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of enatiomers or diastereoisomers and mixtures thereof, e.g. racemates. Any substituent bound to an asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the tetrahydropyranyl ring and the nonadeca-alkenyl chain in a compound of formula I comprises asymmetric C-atoms and substitutents attached to such asymmetric C-atoms, such as sulfonyloxymethyl, methylcarbonyloxy, methyl groups, the pyranyl ring, may be in the (R)- or in the (S)- configuration, e.g. as set out in a compound of formula I' or in the selected group of compounds of the present invention.
  • a compound of formula I comprises double bonds in the nonadeca-alkenyl chain and substituents bound to such a double bond may be cis- or trans-confomers.
  • the configuration of substituents attached to asymmetric C-atoms of a compound of formula I and the confomers in a compound of formula I are the same as in a compound of formula I, if the starting material for its production, namely a compound of formula II (as set out below) is obtained by fermentation (see production process below).
  • Isomeric mixtures may be separated as appropriate, e.g. according, e.g. analogously, to a method as conventional, to obtain pure isomers.
  • the present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture.
  • the present invention also includes tautomers of a compound of formula I, where tautomers can exist.
  • the present invention provides a process for the production of a compound of formula I comprising sulfating or sulfamoylating a compound of formula
  • a compound of formula II includes a compound of formula II'.
  • Sulfation or sulfamoylation may be carried out as appropriate, e.g. according, e.g. analogously, to a process as conventional.
  • - sulfation is carried out by reaction of a compound of formula II with SO 3 -pyridine complex in organic solvent, e.g. polar organic solvent, such as N,N-dimethylformamide, and isolating a compound of formula I, wherein R is hydroxy from the reaction mixture;
  • organic solvent e.g. polar organic solvent, such as N,N-dimethylformamide
  • - sulfamoylation is carried out by treating of a compound of formula II with NaH and further treatment with CIS0 2 NH 2 (e.g. obtainable by reaction of chlorosulfonyl isocyanate with formic acid) in organic solvent, e.g. polar organic solvent, such as N,N-dimethylformamide, and isolating a compound of formula I, wherein R is amino, from the reaction mixture.
  • Salt formation may be carried out as appropriate, e.g. according, e.g. analogously to a method as conventional, e.g.
  • a compound of formula I may be treated with a base of formula MET-OH or of formula MET'OH 2 , wherein MET is an alkali ion and MET 1 is an earth alkali ion.
  • the present invention provides a compound of formula II, e.g. useful as an intermediate in the production of a compound of the present invention, e.g. in free base form or in the form of a salt, including salts as described above for a compound of the present invention.
  • a compound of formula II is herein designated also as “an intermediate of (according to) the present invention” in distinction to a compound of formula I "a compound of (according to) the present invention".
  • a compound of formula II may be obtained as appropriate, e.g. according, e.g. analogously, to a process as conventional, e.g. or as described herein.
  • the present invention provides a process for the preparation of a compound of formula II, comprising acylating a compound of formula
  • a compound of formula III includes a compound of formula IN'.
  • Acylation may be carried out as appropriate, e.g. according, e.g. analogously, to a method as conventional.
  • acylation is carried out by reaction of a compound of formula II with acetic acid anhydride in organic solvent, e.g. pyridine, and isolating a compound of formula II obtained from the reaction mixture.
  • organic solvent e.g. pyridine
  • salt formation of a compound of formula II may be carried out as appropriate, e.g. as described above for a compound of formula I.
  • a compound of formula III may be obtained as appropriate, e.g. according, e.g. analogously, to a process as conventional, e.g. e.g. by culturing a strain producing a compound of formula III, e.g. a strain of the genus Microsphaeropsis Hohn, such as the fungus strain NRRL
  • functional groups in an intermediate of formula II or in a compound of formula III (starting materials), optionally may be in protected form or in the form of a salt, if a salt- forming group is present.
  • Protecting groups, optionally present, may be removed at an appropriate stage, e.g. according, e.g. analogously, to a method as conventional.
  • any compound described herein may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein.
  • the compounds of the present invention e.g. including a compound of formula I and of formula I', exhibit pharmacological activity and are therefore useful as pharmaceuticals.
  • the compounds of the present invention show anti-inflammatory activity and are e.g. useful in diseases associated with inflammation.
  • Antiinflammatory activity may be tested in test systems in vivo, e.g. as described in Example 3 below.
  • the compounds of the present invention show therapeutic activity and are thus useful in the treatment of diseases associated with inflammation, e.g. for use as antiinflammatory agents, e.g. for use in the treatment of inflammatory disorders, such as in suppression of neoplastic diseases, e.g.
  • inflammatory skin diseases and autoimmune diseases such as: psoriasis, atopic dermatitis, contact dermatitis and related eczematous dermatitises, seborrheic dermatitis, phototoxic and photoallergic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous easinophilias, Lupus erythematosus, Alopecia areata and acne.
  • the present invention provides a compound of the present invention for use as a pharmaceutical, e.g. for the treatment of diseases associated with inflammation.
  • a compound of the present invention includes one or more, preferably one, compounds of the present invention, e.g. a combination of two or more compounds of the present invention.
  • the present invention provides the use of a compound of the present invention for the manufacture of a medicament, e.g. a pharmaceutical composition, for the treatment of diseases associated with inflammation.
  • the compounds of Examples 1 and 2 are preferred compounds of the present invention.
  • the compounds of the invention may be administered in similar manner to known standards for use in the treatment of diseases associated with inflammation.
  • the present invention provides a method of treatment of diseases which are associated with inflammation, which method comprises administering to a subject in need of such treatment an effective amount, e.g. an antiinflammatory effective amount, of a compound of the present invention; e.g. in the form of a pharmaceutical composition.
  • an effective amount e.g. an antiinflammatory effective amount
  • a compound of the present invention e.g. in the form of a pharmaceutical composition.
  • Treatment includes treatment and prophylaxis.
  • the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmakokinetic data of a compound of the present invention employed, the individual host, the mode of administration and the nature and severity of the conditions being treated.
  • an indicated daily dosage is in the range from about 5 mg to about 500 mg (ca. 0.06 mg/kg to ca. 20 mg/kg body weight), such as about 50 to about 1200 mg (ca. 4 mg/kg to ca. 15 mg/kg body weight) of a compound of the present invention; conveniently administered, for example, in divided doses up to 4 times a day.
  • a compound of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intramuscular, subcutanous administration; or topically; e.g. including epicutaneous, intranasal, intratracheal administration; e.g. in form of coated or uncoated tablets, capsules, (injectable) solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, suppositories.
  • enterally e.g. including nasal, buccal, rectal, oral, administration
  • parenterally e.g. including intravenous, intramuscular, subcutanous administration
  • topically e.g. including epicutaneous, intranasal, intratracheal administration
  • the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt, e.g. metal salt; or in free form; optionally in the form of a solvate.
  • a pharmaceutically acceptable salt e.g. metal salt
  • the compounds of the present invention in the form of a salt exhibit the same order of activity as the compounds of the present invention in free form; optionally in the form of a solvate.
  • a compound of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents.
  • Such other pharmaceutically active agents include e.g. other pharmaceutically active compounds which are active in the treatment of diseases associated with inflammation, e.g. and antibacterials.
  • Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co- administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention in association with at least one pharmaceutical excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
  • a pharmaceutical excipient e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
  • the present invention provides a pharmaceutical composition according to the present invention, further comprising another pharmaceutically active agent.
  • compositions may be manufactured according, e.g. analogously to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes.
  • Unit dosage forms may contain, for example, from about 50 mg to about 1000 mg, such as 100 mg to about 500 mg.
  • Antiinflammatory activity may be tested in test systems in vivo, namely in the IL-8 induced leucocytes emigration model, in the Topical ICD-TPA mouse model and in the ACD mouse model, e.g. as described below, wherein the following abbreviations are used:
  • Test compounds include compounds of the present invention of formula I, namely of formula
  • Human recombinant IL-8 is injected at 1 ⁇ g in 100 ⁇ l PBS i.p..
  • the cytospin preparation is done on the Shandon Cytocentrifuge "Cytospin" 2.
  • the blood smears and cytospin preparations are stained with Hemacolor (Merck). Differential cell counts of blood smears and peritoneal cells are performed under the microscope. Statistical evaluation (t-test) of the results is performed.
  • the compounds of the present invention show activity in the IL-8 induced leucocytes emigration model.
  • test animals 10 ⁇ l of a 0.01% TPA solution is epicutaneously applied to the inner surface of the right ear of 8 NMRI mice per group for elicitation of an inflammatory pinnal swelling.
  • the test animals are treated topically with 10 ⁇ l of a test compound (dissolved in DAE) 30 minutes before the application of TPA; control animals are treated similarly with the vehicle DAE alone.
  • the compounds of the present invention show activity in the ICD-TPA model.

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Abstract

Lactones of Formula (I) which are pharmaceutically active in diseases associated with inflammation.

Description

Antiinflammatory Lactones
The present invention relates to anti-inflammatory lactones.
In one aspect the present invention provides a compound of formula
Figure imgf000002_0001
such as a compound of formula
Figure imgf000002_0002
wherein R is hydroxy or amino.
A compound of formula I includes a compound of formula I'. Preferably in a compound of formula I
- R is hydroxy;
- Ris amino.
In another aspect the present invention provides a compound of the present invention which is selected from the group consisting of
Acetic acid 7-acetoxy-1-[1 -((2R,3R,4R,6R)-3,4-diacetoxy-4,-hydroxy-2'-oxo-6- sulfooxymethyl-S^.δ.θ-tetrahydro^.H.^'.H.-p.S'lbipyranyl-e'-y -l-methyl-ethyl]- 4,6,8, 12,14, 16-hexamethyl-octadeca-2,4,10,12-tetraenyl ester, e.g. includi ng Acetic acid (2E14E,10E,12E)-7-acetoxy-1-[1-((2R,3R,4R,6R)-3,4-diacetoxy-4'- ydroxy-2,- oxo-e-sulfooxymethyl-S^.δ.e-tetrahydro^.H.^'.H.-p.S'Jbipyranyl-e'-y -l-rriethyl-ethyl]- 4,6,8,12,14,16-hexamethyl-octadeca-2,4, 10,12-tetraenyl ester, and Acetic acid 7-acetoxy-1 -[1 -(3,4-diacetoxy-4'-hydroxy-2'-oxo-6-sulfamoyloxymethyl-3,4,5,6- tetrahydro-2.H.,2,.H.-[2)3,]bipyranyl-6,-yl)-1-methyl-ethyl]-4,6>8,12,14,16-hexamethyl- octadeca-2,4,10,12-tetraenyl ester, e.g. including
Acetic acid (2E,4E,10E,12E)-7-acetoxy-1-[1-((2R,3R,4Rl6R)-3>4-diacetoxy-4,-hydroxy-2'- oxo-δ-sulfamoyloxymethyl-S^.S.e-tetrahydro^.H.^'.H.-p.S'lbipyranyl-e'-y -l-methyl-ethyl]- 4,6,8,12,14,16-hexamethyl-octadeca-2,4,10,12-tetraenyl ester.
Compounds provided by the present invention are hereinafter designated as "compound(s) of (according to) the present invention". A compound of formula I includes a compound of formula I'. A compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate.
In another aspect the present invention provides a compound of the present invention in the form of a salt.
Such salts include preferably pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, e.g. for preparation / isolation / purification purposes. A salt of a compound of the present invention includes a metal salt, e.g. or, where appropriate an acid addition salt. Metal salts include for example alkali or earth alkali salts, preferably alkali, such as lithium, potassium, sodium, prefrably sodium. A compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in non-solvated form; and vice versa.
A compound of of the present invention may exist in the form of isomers and mixtures thereof; e.g. optical isomers, diastereoisomers, cis/trans conformers. A compound of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of enatiomers or diastereoisomers and mixtures thereof, e.g. racemates. Any substituent bound to an asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. For example, the tetrahydropyranyl ring and the nonadeca-alkenyl chain in a compound of formula I comprises asymmetric C-atoms and substitutents attached to such asymmetric C-atoms, such as sulfonyloxymethyl, methylcarbonyloxy, methyl groups, the pyranyl ring, may be in the (R)- or in the (S)- configuration, e.g. as set out in a compound of formula I' or in the selected group of compounds of the present invention. Additionally a compound of formula I comprises double bonds in the nonadeca-alkenyl chain and substituents bound to such a double bond may be cis- or trans-confomers. Preferably the configuration of substituents attached to asymmetric C-atoms of a compound of formula I and the confomers in a compound of formula I are the same as in a compound of formula I, if the starting material for its production, namely a compound of formula II (as set out below) is obtained by fermentation (see production process below).
Isomeric mixtures may be separated as appropriate, e.g. according, e.g. analogously, to a method as conventional, to obtain pure isomers. The present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture. The present invention also includes tautomers of a compound of formula I, where tautomers can exist.
In another aspect the present invention provides a process for the production of a compound of formula I comprising sulfating or sulfamoylating a compound of formula
Figure imgf000004_0001
such as a compound of formula
Figure imgf000004_0002
and isolating a compound of formula I obtained from the reaction mixture; and, optionally, converting a compound of formula I obtained in another compound of formula I, for example
- converting a compound of formula I obtained into a salt thereof, or, - if a compound of formula I is obtained in the form of a salt, converting said salt into a free base of a compound of formula I.
A compound of formula II includes a compound of formula II'. Sulfation or sulfamoylation may be carried out as appropriate, e.g. according, e.g. analogously, to a process as conventional.
In a preferred aspect of the present invention
- sulfation is carried out by reaction of a compound of formula II with SO3-pyridine complex in organic solvent, e.g. polar organic solvent, such as N,N-dimethylformamide, and isolating a compound of formula I, wherein R is hydroxy from the reaction mixture;
- sulfamoylation is carried out by treating of a compound of formula II with NaH and further treatment with CIS02NH2 (e.g. obtainable by reaction of chlorosulfonyl isocyanate with formic acid) in organic solvent, e.g. polar organic solvent, such as N,N-dimethylformamide, and isolating a compound of formula I, wherein R is amino, from the reaction mixture. Salt formation may be carried out as appropriate, e.g. according, e.g. analogously to a method as conventional, e.g. for alkali or earth alkali metal salt formation a compound of formula I may be treated with a base of formula MET-OH or of formula MET'OH2, wherein MET is an alkali ion and MET1 is an earth alkali ion.
In another aspect the present invention provides a compound of formula II, e.g. useful as an intermediate in the production of a compound of the present invention, e.g. in free base form or in the form of a salt, including salts as described above for a compound of the present invention.
A compound of formula II is herein designated also as "an intermediate of (according to) the present invention" in distinction to a compound of formula I "a compound of (according to) the present invention".
A compound of formula II may be obtained as appropriate, e.g. according, e.g. analogously, to a process as conventional, e.g. or as described herein.
In another aspect the present invention provides a process for the preparation of a compound of formula II, comprising acylating a compound of formula
Figure imgf000006_0001
A compound of formula III includes a compound of formula IN'.
Acylation may be carried out as appropriate, e.g. according, e.g. analogously, to a method as conventional. In a preferred aspect of the present invention acylation is carried out by reaction of a compound of formula II with acetic acid anhydride in organic solvent, e.g. pyridine, and isolating a compound of formula II obtained from the reaction mixture. Optionally, and if desired, salt formation of a compound of formula II may be carried out as appropriate, e.g. as described above for a compound of formula I.
A compound of formula III may be obtained as appropriate, e.g. according, e.g. analogously, to a process as conventional, e.g. e.g. by culturing a strain producing a compound of formula III, e.g. a strain of the genus Microsphaeropsis Hohn, such as the fungus strain NRRL
15684, in the presence of a culture medium and recovering a compound of formula III from the culture medium, e.g. by chromatography, see e.g. US4753959.
In an intermediate of formula II or in a compound of formula III (starting materials), functional groups, if present, optionally may be in protected form or in the form of a salt, if a salt- forming group is present. Protecting groups, optionally present, may be removed at an appropriate stage, e.g. according, e.g. analogously, to a method as conventional.
Any compound described herein may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein. The compounds of the present invention, e.g. including a compound of formula I and of formula I', exhibit pharmacological activity and are therefore useful as pharmaceuticals. In particular we have found surprisingly that the compounds of the present invention show anti-inflammatory activity and are e.g. useful in diseases associated with inflammation.
Antiinflammatory activity may be tested in test systems in vivo, e.g. as described in Example 3 below.
The compounds of the present invention show therapeutic activity and are thus useful in the treatment of diseases associated with inflammation, e.g. for use as antiinflammatory agents, e.g. for use in the treatment of inflammatory disorders, such as in suppression of neoplastic diseases, e.g. inflammatory skin diseases and autoimmune diseases, such as: psoriasis, atopic dermatitis, contact dermatitis and related eczematous dermatitises, seborrheic dermatitis, phototoxic and photoallergic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous easinophilias, Lupus erythematosus, Alopecia areata and acne.
In another aspect the present invention provides a compound of the present invention for use as a pharmaceutical, e.g. for the treatment of diseases associated with inflammation.
For pharmaceutical use a compound of the present invention includes one or more, preferably one, compounds of the present invention, e.g. a combination of two or more compounds of the present invention.
In another aspect the present invention provides the use of a compound of the present invention for the manufacture of a medicament, e.g. a pharmaceutical composition, for the treatment of diseases associated with inflammation.
The compounds of Examples 1 and 2 are preferred compounds of the present invention. The compounds of the invention may be administered in similar manner to known standards for use in the treatment of diseases associated with inflammation.
In a further aspect the present invention provides a method of treatment of diseases which are associated with inflammation, which method comprises administering to a subject in need of such treatment an effective amount, e.g. an antiinflammatory effective amount, of a compound of the present invention; e.g. in the form of a pharmaceutical composition.
Treatment includes treatment and prophylaxis. For such treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmakokinetic data of a compound of the present invention employed, the individual host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage is in the range from about 5 mg to about 500 mg (ca. 0.06 mg/kg to ca. 20 mg/kg body weight), such as about 50 to about 1200 mg (ca. 4 mg/kg to ca. 15 mg/kg body weight) of a compound of the present invention; conveniently administered, for example, in divided doses up to 4 times a day. A compound of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intramuscular, subcutanous administration; or topically; e.g. including epicutaneous, intranasal, intratracheal administration; e.g. in form of coated or uncoated tablets, capsules, (injectable) solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, suppositories.
The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt, e.g. metal salt; or in free form; optionally in the form of a solvate. The compounds of the present invention in the form of a salt exhibit the same order of activity as the compounds of the present invention in free form; optionally in the form of a solvate.
A compound of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include e.g. other pharmaceutically active compounds which are active in the treatment of diseases associated with inflammation, e.g. and antibacterials.
Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co- administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given.
In another aspect the present invention provides a pharmaceutical composition comprising a compound of the present invention in association with at least one pharmaceutical excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
In another aspect the present invention provides a pharmaceutical composition according to the present invention, further comprising another pharmaceutically active agent.
Such compositions may be manufactured according, e.g. analogously to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes. Unit dosage forms may contain, for example, from about 50 mg to about 1000 mg, such as 100 mg to about 500 mg.
In the following Examples all temperatures are in degrees Celsius (°C) and are uncorrected.
The following abbreviations are used: DMF N,N-dimethyiformamide
Example 1
Acetic acid 7-acetoxy-1 -[1 -(3,4-diace>toxy-4'-hydroxy-2'-oxo-6-sulfooxymethyl-3,4,5,6- tetrahydro-2.H.,2'.H.-[2,3,]bipyranyI-6,-yl)-1-methyl-ethyl]-4,6,8,12,14,16-hexamethyl- octadeca-2,4, 10,12-tetraenyl ester 1A. Acetic acid (2E,4E.10E,12E)-7-acetoxy-1-ri-((2R,3R.4R.6R)-3.4-diacetoxy-4'-hvdroxy-6- hvdroxymethyl-2'-oxo-3.4.5.6-tetrahvdro-2.H..2'.H.-r2.3'lbiPyranyl-6'-vn-1-methyl-ethvn- 4,6,8,12.14.16-hexamethyl-octade ca-2.4, 10,12-tetraenyl ester 5 g of (2R,3S,4R,6R)-6,-((3E,5E,11E,1 3E)-2,8-Dihydroxy-1 , 1 ,5,7,9, 13, 15,17-octamethyl- nonadeca-3,5,11 ,13-tetraenyl)-3,4,4'-trihydroxy-6-hydroxymethyl-3,4,5,6-tetrahydro-2.H.- [2,3']bipyranyl-2'-one, dissolved in 25 ml of pyridine and 25 ml of acetic anhydride, are stirred for 18 hours, solvent is evaporated, the evaporation residue obtained is dissolved in toluene and pyridinium salts are filtered off. From the filtrate obtained solvent is evporated and the evaporation residue obtained is dissolved in 100 ml of CH3OH. To the mixture obtained 4 ml of 33% aqueous NH3 are added, the mixture obtained is stirred for 18 hours, solvent is evaporated and the evaporation residue obtained is subjected to chromatography.
Acetic acid (2E,4E, 10E, 12E)-7-acetoxy-1 -[1 -((2R,3R,4R,6R)-3,4-diacetoxy-4'-hydroxy-6- hydroxymethyl-2'-oxo-3,4,5,6-tetrahydro-2.H.,2'.H.-[2,3']bipyranyl-6'-yl)-1-methyl-ethyl]-
4,6,8, 12,14, 16-hexamethyl-octadeca-2 ,4, 10,12-tetraenyl ester is obtained.
1H-NMR (CDCI3 / CD3OD 4:1) 6.30 (d, 1 H, H3, J = 15 Hz); 6.20 (d, 1H, Hn, J = 15.5 Hz); 5.91 (s, 1 H, Hff); 5.37-5.58 (m, 4H, H1ι2,6|10); 5.08-5.20 (m, 3H, H3-pyrany],4-pyranyi-ι3); 4.82 (d, 1 H, H2-pyranyi, J = 9.4 Hz); 4.75 (dd, 1 H, H-7, J = 4.4,7.8 Hz); 3.70-3.85 (m, 2H, Ha-acθt0χymethyi, Hb- acetoxymethyi); 3.61 (m, 1 H, H6-pyranyι); 2.88 (m, 1 H, H-6); 2.58 (m, 1 H, H-14); 2.24 (m, 1 H, H-5a. pyranyl); 2.20 (m, 1 H, H9a); 2.08 (s, 3H, COCH3), 2.04 (s, 3H, COCH3); 2.01 (s, 3H, COCH3), 2.00 (s, 3H, COCW3); 1.83 (m, 1H, H9b); 1.73-1.77 (m, 2H, H5b-Pyranvll H8); 1.73 (2xs, 6H, CH3- 4ι12); 1.17-1.30 (m, 3H, H15a,ι6, i7a); 1-24- (s, 3H, gem-CH3); 1.21 (s, 3H, gem-CH3); 1.05-1.18 (m, 2H, H15b,17b); 0.98 (d, 3H, CH3-6, J = 7 Hz); 0.93 (d, 3H, CH3-14, J = 7 Hz); 0.80-0.88 ( m, 9H, CH3.8|16ι18); MS-ESI m/e 829 (MH+, 100).
1 B. Acetic acid (2E.4E.10E.12E)-7-acetoxy-1-ri-((2R.3R.4R.6R)-3.4-diacetoxy-4'-hvdroxy- 2'-oxo-6-sulfooxymethyl-3.4.5.6-tetrahvdro-2.H..2'.H.-r2.3'lbipyranyl-6'-yl)-1-methyl- ethyll-4.6.8.12.14.16-hexamethyl-octadeca-2,4,10.12-tetraenyl ester 953 mg of S03-pyridine complex are added to 1g of acetic acid (2E,4E,10E,12E)-7-acetoxy- 1-[1-((2R,3R,4R,6R)-3,4-diacetoxy-4,-hydroxy-6-hydroxymethyl-2'-oxo-3,4,5,6-tetrahydro- 2.H.,2,.H.-[2,3']bipyranyl-6,-yl)-1-methyI-ethyl]-4,6,8,12,14,16-hexamethyl-octadeca- 2,4,10,12-tetraenyI ester in 90 ml of DMF and the resulting solution is stirred for 12 hours.
From the mixture obtained solvent is evaporated and the evaporation residue obtained is subjected to chromatography.
Acetic acid (2E,4E,10E,12E)-7-acetoxy-1-[1-((2R,3R,4R,6R)-3,4-diacetoxy-4,-hydroxy-2'- oxo-e-sulfooxymethyl-S^.δ.e-tetrahydro-Z. H.^'.H.-^.S'jbipyranyl-e'-y -l-methyl-ethyl]-
4,6,8, 12,14, 16-hexamethyl-octadeca-2,4,1 0,12-tetraenyI ester is obtained. H-NMR (CDCI3 / CD3OD 4:1 , 330K) 6.28 <d, 1H, H3, J = 15.5 Hz); 6.03 (d, 1H, Hn, J = 15.4
Hz); 5.75 (s, 1H, Hff); 5.56 (d, 1H, H1 f J = 7.6 Hz); 5.50 (d, 1H, H5, J = 7.5 Hz); 5.44-5.48 (m,
3H, H3-pyranyl,2,10); 5.14 (m, 1 H, H4-pyranyι); 5.1 2 (d, 1 H, H13, J = 9.6 Hz); 4.87 (d, 1 H, H2-pyranyι, J = 11.1 Hz); 4.77 (dd, 1H, H7, J = 5.3,6.9 Hz); ABX-system (μA = 4.37, Ha-aoetoXymethyι, MB = 4.08,
Hb.acetoxymethyi- Px = 4.02, H6-pyraπyι, JAB = 10.9 , JAX = 3.0, JBχ = 1.9 Hz); 2.89 (m, 1 H, H6); 2.55
(m, 1H, H14); 2.24 (m, 1 H, H9a); 2.20 (m, 1 H, H5a-pyranyι); 2.12 (m, 1 H, H5b-pyranyl); 2.05 (s, 3H,
COCH3), 2.02 (2xs, 6H, COCH3); 1.90 (m, 1H, H9b); 1 -87 (s, 3H, COCH3); 1.80 (m, 1H, H8);
1.72 (2xs, 6H, CH3 12); 1.22-1.30 (m, 3H, H15a, 16, 17a); 1.23 (s, 3H, gem-CH3); 1.18 (s, 3H, gem-CHs); 1.13 (m, 1 H, H17b); 1.08 (m, 1 H , H15b); 0.95 (d, 3H, CH3-6, J = 6.9 Hz); 0.93 (d, 3H,
CH3.15, J = 6.7 Hz); 0.82-0.87 ( m, 9H, CH3-8,i6,ι8); MS-ESI m/e 947 (MK+, 100).
Example 2
Acetic acid (2E,4E,10E,12E)-7-acetoxy-1 -[1-((2R,3R,4R,6R)-3,4-diacetoxy-4,-hydroxy-2"- oxo-e-sulfamoyloxymethyl-SΛδ.β-tetrahydro^.H.^'.H.-p.S'lbipyranyl-e'-y -l-methyl- ethyl]-4,6,8,12,14,16-hexamethyl-octadeca-2A10,12-tetraenyl ester
36 mg of NaH are added to 600 mg of acetic acid (2E,4E,10E,12E)-7-acetoxy-1-[1-
((2R,3R,4R,6R)-3,4-diacetoxy-4'-hydroxy-Θ-hydroxymethyl-2'-oxo-3,4,5,6-tetrahydro-
2.H.,2'.H.-[2,3']bipyranyl-6'-yl)-1-methyl-ethyl]-4,6,8,12,14,16-hexamethyl-octadeca- 2,4, 10,12-tetraenyl ester in 18 ml of DMF and the mixture obtained is stirred for 45 minutes. To the mixture obtained 432 mg of CIS02NJH2 are added and the resulting solution is stirred for further 2 hours. From the mixture obtained solvent is evaporated, the evaporation residue is treated with ethyl acetate and the organi c layer obtained is extracted with saturated sodium bicarbonate and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to chromatography.
Acetic acid (2E,4E,10E,12E)-7-acetoxy-1-[ 1-((2R,3R,4R,6R)-3,4-diacetoxy-4,-hydroxy-2'- oxo-6-sulfamoyloxymethyl-3,4,5,6-tetrahyd ro-2.H.,2'.H.-[2,3']bipyranyl-6,-yi)-1-methyl-ethyl]- 4,6,8,12,14,16-hexamethyl-octadeca-2,4,1 0,12-tetraenyl ester is obtained. 1H-NMR (CDCI3 / CD3OD 4:1) 6.26 (d, 1 H, H3, J = 15.5 Hz); 6.03 (d, 1H, Hn, J = 15.5 Hz); 5.77 (s, 1 H, H5.); 5.74 (m, 1 H, H3.pyranyι) 5.57 (d, 1H, H,, J = 7.5 Hz); 5.43-5.50 (m, 2H, H2,10); 5.47 (d, 1 H, H5, J = 7.8 Hz ); 5.10 (d, 1H, H13, J = 9.3 Hz); 5.09 (m, 1 H, H4-pyranyι); 4.80 (m, 1H, H2-pyrany,); 4.76 (dd, 1 H, H7, J = 4.6,7.6 Hz); ABX-system (μA = 4.37, Ha-aCetoxymet yι, MB = 4.20, Hb-acetoxymeihyι, Mx = 3.90, H6-pyranyι, JAB = 11.9, JAX = 2.5, JBX = 4.6 Hz); 2.90 (m, 1 H, H6); 2.58 (m, 1H, H14); 2.23 (m, 1H, H9a); 2.14 (m, 1H, H5a.pyranyl); 2.07 (s, 3H, COCH3), 2.03 (s, 3H, COCH3); 2.02 (s, 3H, COCH3); 1.93 (m,1 H, H5b-pyrany,); 1.89 <s, 3H, COCH3); 1.87 (m, 1 H, H9b); 1.79 (m, 1 H, H8); 1.74 (2xs, 6H, CH^,); 1.22-1.32 (m, 3H, H15a, 16, 17a); 1.23 (s, 3H, gem-CH3); 1.19 (s, 3H, gem-CH3); 1.13 (m, 1 H, H17b); 1.08 (m, 1 H, H15b); 0.96 (d, 3H, CH3-6, J = 7 Hz); 0.93 (d, 3H, CH3-15, J = 6.9 Hz); 0.82-0.87 ( m, 9H, CHM,16,ι8); MS-ESl m/e 908 (MH+, 50).
Example 3: Antiinflammatory activity
Antiinflammatory activity may be tested in test systems in vivo, namely in the IL-8 induced leucocytes emigration model, in the Topical ICD-TPA mouse model and in the ACD mouse model, e.g. as described below, wherein the following abbreviations are used:
ACD allergic contact dermatitis
DAE mixture of acetylacetamide, ethanol and acetone
ICD isocitric dehydrogenase IL-8 interleukin-8
PBS phosphate buffered saline
TPA 12-O-tetradecanoyl phorbol-13-acetate (phorbol-12-myristate)
Test compounds include compounds of the present invention of formula I, namely of formula
I'.
TEST SYSTEMS a. IL-8 induced leucocytes emigration model
Comprise 24 to 36 female Balb/c mice, 18 - 20 g; IL-8 control group; reference group; buffer control group and 3 to 6 test groups. Human recombinant IL-8 is injected at 1 μg in 100 μl PBS i.p..
5 mg of a test compound, or reference compound, respectively, are dissolved in 1 ml of
PBS. Immediately after i.p. injection of IL-8 100 μl of the test compound-solution are injected i.v. (= 500 μg/mouse). 4 hours after IL-8 injection the mice are anaesthetized and blood is collected by orbital puncture. The mice are sacrificed and perito neal exudate cells harvested as follows: 5 ml of PBS are injected i.p. and after 1 minute as much of it as possible is recovered. Total cell counts of blood and peritoneal cells are performed on the Toa-Counter
(Coulter).
The cytospin preparation is done on the Shandon Cytocentrifuge "Cytospin" 2. The blood smears and cytospin preparations are stained with Hemacolor (Merck). Differential cell counts of blood smears and peritoneal cells are performed under the microscope. Statistical evaluation (t-test) of the results is performed.
The compounds of the present invention show activity in the IL-8 induced leucocytes emigration model.
b. Topical ICD-TPA mouse model (TPA-induced irritant contact dermatitis)
10 μl of a 0.01% TPA solution is epicutaneously applied to the inner surface of the right ear of 8 NMRI mice per group for elicitation of an inflammatory pinnal swelling.The test animals are treated topically with 10 μl of a test compound (dissolved in DAE) 30 minutes before the application of TPA; control animals are treated similarly with the vehicle DAE alone.
6 hours after TPA-treatment the animals are sacrificed, b oth ear lobes cut off at the basis and weighed. Difference in auricular weights are taken as a measure of inflammatory swelling [right (treated, irritated) vs left (untreated, non irritated) ears, in %]. The compounds of the present invention show activity in the ICD-TPA model.
c. Topical ACD-model (oxazolone-sensitized mice)
10 μl of 2% oxazolone are epicutaneously applied to the inner surface of the right ear of 8 NMRI mice per group which mice are sensitized against oxazolone. After 30 minutes the test animals are treated topically with 10 μl of a test compoum d (dissolved in DAE). 24 hours later the animals are sacrificed. Inflammatory swelling is measured as set out under point "b. Topical ICD-TPA mouse model" above. The compounds of the present invention show activity in the topical ACD model.

Claims

Patent Claims
1. A compound of formula
Figure imgf000014_0001
wherein R is hydroxy or amino.
2. A compound of claim 1 wherein R is hydroxy.
3. A compound of claim 1 , wherein R is amino.
4. A compound of any one of claims 1 to 3 in the form of a salt.
5. A compound of claim 4 in the form of an alkali salt.
6. A compound of claim 5, which is a sodium salt.
7. A compound of claim 6 wherein R is amino.
8. A compound of any one of claims 1 to 7 for use as a pharmaceutical.
9. A pharmaceutical composition comprising a compound of any one of claims 1 to 7 beside at least one pharmaceutically acceptable excipient.
10. Use of a compound of any one of claims 1 to 7 for the manufacture of a medicament for the treatment of diseases associated with inflammation.
1. A method of treatment of diseases associated with inflammation, which treatment comprises administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 7.
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US4753959A (en) * 1984-02-08 1988-06-28 Sandoz Ltd. Antibiotic lactone compound

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M. H. PARKER ET. AL.: "Synthesis of Carba-beta-L-Fructopyranose and Carbacyclic Analogs og Topiramate, an Anticonvulsant Agent. p", SYNLETT, no. 12, 2004, pages 2095 - 2098, XP002342677 *

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