WO2000056341A1 - Composés chimiques et leurs applications - Google Patents

Composés chimiques et leurs applications Download PDF

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Publication number
WO2000056341A1
WO2000056341A1 PCT/GB2000/001086 GB0001086W WO0056341A1 WO 2000056341 A1 WO2000056341 A1 WO 2000056341A1 GB 0001086 W GB0001086 W GB 0001086W WO 0056341 A1 WO0056341 A1 WO 0056341A1
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WIPO (PCT)
Prior art keywords
compound
disorders
treating
disorder
substituted
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PCT/GB2000/001086
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English (en)
Inventor
Maria Gabriella Santoro
Stanley Michael Roberts
Thierry Guyot
Original Assignee
Charterhouse Therapeutics Ltd.
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Publication date
Priority claimed from GBGB9906587.2A external-priority patent/GB9906587D0/en
Application filed by Charterhouse Therapeutics Ltd. filed Critical Charterhouse Therapeutics Ltd.
Priority to CA002366877A priority Critical patent/CA2366877A1/fr
Priority to NZ514522A priority patent/NZ514522A/xx
Priority to AU36657/00A priority patent/AU3665700A/en
Priority to EP00915293A priority patent/EP1165092A1/fr
Priority to JP2000606245A priority patent/JP2002539264A/ja
Publication of WO2000056341A1 publication Critical patent/WO2000056341A1/fr
Priority to HK02100880.1A priority patent/HK1041200A1/zh

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    • 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
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin

Definitions

  • the present invention relates to chemical compounds and their uses. More particularly, the present invention relates to cyclopentenones and to their uses in medicine.
  • cyclopentenone ring structure also known as the cyclopentenone nucleus
  • the heat shock response is a finely regulated and highly conserved mechanism to protect cells against different types of injury, including extreme temperatures, oxidative stress, exposure to toxins and viral infection (1).
  • triggering ofthe heat shock response requires activation of a transregulatory protein, the heat shock transcription factor type 1 (HSF 1), which controls the expression of cytoprotective heat shock proteins (HSPs) (1).
  • HSF 1 heat shock transcription factor type 1
  • HSPs cytoprotective heat shock proteins
  • HSP induction was at first interpreted as a signal for detection of physiological stress
  • HSPs are utilised by the cells as molecular chaperones in the repair process following different types of injury to prevent damage resulting from the accumulation and aggregation of non- native proteins (1).
  • a cytoprotective role ofthe heat shock protein HSP70 has now been described in a wide variety of human diseases, including ischemia, inflammation and viral infection (2-5).
  • HSF 1 is considered a novel, attractive target for cytoprotective and antiviral drugs.
  • PGs prostaglandins
  • HSP70 inducers via HSF1 activation (6,7).
  • PGAs prostaglandins ofthe A type
  • PG containing an ⁇ , ⁇ -unsaturated carbonyl group in the cyclopentane ring structure possess activity against a wide variety of DNA and RNA viruses, including herpes viruses, paramyxo viruses, orthomyxo viruses and retroviruses in in vitro and in vivo experimental models (9).
  • the mechanism ofthe antiviral activity is distinct from any other known antiviral agent and involves the induction of heat shock proteins and the inhibition ofthe transcription factor NF- ⁇ B (nuclear factor- ⁇ B) in the infected cell.
  • NF- ⁇ B is an inducible eukaryotic transcription factor which has a critical role in promoting inflammation and viral replication (11).
  • NF- ⁇ B exists in an inactive cytoplasmic complex, whose predominant form is a heterodimer composed of p50 and p65 subunits, bound to inhibitory proteins ofthe I ⁇ B family, usually I ⁇ B ⁇ , and is activated in response to primary (viruses, bacteria, UV) or secondary (inflammatory cytokines) pathogenic stimuli (12). Stimulation triggers rapid phosphorylation and degradation of I ⁇ B ⁇ , resulting in NF- ⁇ B translocation to the nucleus, where the factor binds to DNA at specific ⁇ B-sites, inducing a variety of genes encoding signalling proteins.
  • Target genes include inflammatory and chemotactic cytokines, cytokine receptors and viral genes.
  • NF- ⁇ B is involved in many pathological events including progression of AIDS by enhancing HIV-1 transcription, and is considered an attractive therapeutic target for novel antiviral and anti-inflammatory drugs (12).
  • Santoro et al. have shown that cyclopentenone prostaglandins inhibit NF- ⁇ B activation and NF- ⁇ B-dependent HIV-1 transcription in human cells, by preventing I ⁇ B ⁇ phosphorylation and degradation, and that this effect is strictly associated with HSF1 activation (11).
  • a compound for use in medicine that has the formula a), b), c) or d), as shown in Figure 1 ; wherein R], R 2 , R 3 , Rj, R 5 and R ⁇ 5 can (independently) be hydrogen or any other appropriate moiety and X can be any appropriate moiety.
  • Ri, R 2 , R 3 and R 4 may, for example, (independently) be hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group.
  • Ri, R , R 3 or R 4 it is preferred that between 2 and 20 (more preferably between 3 and 15) carbon atoms are present.
  • Ri, R 2 , R 3 and Rj may comprise cyclic or non-cyclic groups.
  • a functional group e.g. a carboxylic acid group may be included.
  • Rj, R , R 3 and R 4 are not halogen.
  • R 5 and R 6 may, for example, (independently) be hydrogen or halogen.
  • Rj may be any moiety. Desirably it comprises one or more carbon atoms. Preferably it is a silicon-containing group or it contains another heteroatom (e.g. oxygen, nitrogen, or sulphur). If a heteroatom is present, desirably it is present as part of a chain (e.g. a hydrocarbyl chain). Most preferably X comprises one or more silicon atoms as part of a hydrocarbyl chain (which may optionally include one or more functional groups). An Si atom ofthe Si-containing group is preferably directly attached to the oxygen atom of O-X, although this is not essential, since a linker may be used.
  • X may be any moiety. Desirably it comprises one or more carbon atoms. Preferably it is a silicon-containing group or it contains another heteroatom (e.g. oxygen, nitrogen, or sulphur). If a heteroatom is present, desirably it is present as part of a chain (e.g. a hydrocarbyl chain). Most preferably
  • X therefore includes:
  • R 7 , R 8 and R are defined as for Rj, R 2 , R 3 and 4 above, but are preferably alkyl, substituted alkyl, aryl or substituted aryl; and wherein ⁇ is absent or is a moiety providing a linkage with the oxygen of -O-X (e.g. it is a hydrocarbyl linker, such as CH 2 , C 2 H 4 , or C 3 H ).
  • X is hydrophobic and/or lipophilic. It may, for example, have only 1, 2 or 3 carbon atoms. Desirably, however, it comprises at least 4 carbon atoms. A maximum number of carbon atoms for X has not been determined. However, without being bound by theory, it is envisaged that compounds with up to 50 or up to 20 carbon atoms (more preferably up to 12 carbon atoms and most preferably up to 8 carbon atoms) will normally be used in the present invention.
  • a side chain is present at positions R 3 and/or * shown in Figure 1 , then preferably it has no more than 7 carbon atoms. More preferably it has no more than 3 carbon atoms. However it is most preferred that R 3 and/or R_j are hydrogen.
  • compounds ofthe present invention includes various 4- and 5-oxacyclopent-2-en-l-ones .
  • An oxa moiety (provided by -O-X) may be present at both 4 and 5 positions ofthe cyclopentenone ring (in either cis or trans form).
  • the -O-X group may be provided twice at the 4 position and/or at the 5 position, if desired.
  • A indicates that one or more additional substituents may optionally be present on the cyclopentenone ring. If present, they are preferably small groups or atoms and desirably do not include more than 7 or more than 3 carbon atoms. However, it is preferred that additional substituents are not present - i.e. that A is absent.
  • Z is preferably H or halogen (e.g. chlorine).
  • R is a moiety incorporating up to 8 carbon atoms or a moiety incorporating one or more heteroatoms (preferably at least one Si atom) and up to 50 carbon atoms.
  • R is preferably a hydrocarbyl group that is optionally substituted.
  • R 1 and R 2 are such that either:-
  • At least one of R 1 and R 2 incorporates one or more heteroatoms (preferably at least one Si atom) and up to 30 or up to 50 carbon atoms, or
  • At least one of R 1 and R 2 comprises up to 8 carbon atoms.
  • At least one of R 1 and R 2 is an optionally substituted hydrocarbyl group.
  • R and R may also be an optionally substituted hydrocarbyl group, but this is not essential. It may for example be hydrogen or another atom or group.
  • R and R may be the same or different.
  • X and / or Y may be absent or may be groups or atoms providing a linkage between O and Si.
  • X and / or Y may, for example, be an optionally substituted hydrocarbyl group.
  • X and / or Y may be CH 2, C 2 H 4j or C 3 H 6.
  • X and Y may be the same or different.
  • R 1 and R 2 can be any appropriate moieties and may be the same or different.
  • at least one (desirably both) of R and R is a hydrocarbyl group.
  • the hydrocarbyl group may be optionally substituted.
  • the hydrocarbyl group preferably comprises up to 30 or up to 50 carbon atoms.
  • Preferred compounds for use in the present invention have higher activity than cyclopent-2-en-l-one in respect of one or more ofthe following:
  • Activity can be assayed by following the procedures set out in Example 1 (for a) and b)), in Example 2 (for c)) or in Example 3 (for d)).
  • Increased activity relative to cyclopent-2-en-l-one need not exist at all concentrations. It is however preferred that it exists over a range of 1 - 200 ⁇ M or over at least part of said range.
  • a level of activity can be obtained using compounds ofthe present invention that is at least twice the level of cyclopent-2-en-l-one. More preferably it is at least 10 times that of cyclopent-2-en-l-one.
  • Particularly preferred compounds for use in the present invention include the R and S enantiomers of 4-tert-butyldimethylsiloxy-cyclopent-2-en-l-one (see Figures 2a) and 2b) respectively).
  • Both forms have unexpectedly high levels of activity, being at least 100 times more effective in activating HSF and inhibiting NF- ⁇ B than cyclopent-2-en-l-one. It is particularly surprising that the S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one enantiomer is so active, given that this isomeric form does not correspond with the form of prostaglandins that occurs in nature (the R-(+)-4-tert- butyldimethylsilyloxy-cyclopent-2-en- 1 -one form).
  • both R- and S-enantiomers of all compounds described in connection with the present invention are considered useful and may each be provided in a form substantially free ofthe other enantiomer (e.g. at least 75% free (w/w), at least 90% free (w/w) or at least 99% free (w/w)). Mixtures of these enantiomers (e.g. racemic mixtures) may however be used if desired.
  • anchor theory a theory referred to as the “anchor theory”, which is provided for the first time below. It is however important to note that the present invention does not rely upon this theory and therefore if it turns out to be incorrect this has no bearing upon the validity ofthe present invention.
  • prostaglandin molecules that stimulate HSP and inhibit NF- ⁇ B are the cyclopentenone ring structure. This is present in two classes of prostaglandins: the PGA series (see Fig 4a) and the PGJ series (see Fig 4b).
  • the anchor theory is that in vivo the cyclopentenone nucleus is put in place at or in close proximity to the active site of a receptor by a side chain anchoring it to a hydrophobic domain of a receptor.
  • the cyclopentenone nucleus can associate with and dissociate from the active site ofthe receptor.
  • the probability of association and/or the duration of association may be higher when a hydrophobic anchor is present.
  • the presence of a side chain at the S-position may provide an improved anchoring effect (see Fig 4d).
  • a similar effect is believed to occur with the Salbutamol derivative Salmeterol, which has a lipophilic "anchoring" side chain that aids binding and increases its effect on the target ⁇ - receptors.
  • O-X is present at the 4 and / or 5 positions of a cyclopent-2-en-l-one ring, wherein X is a silicon containing group (and is preferably also a hydrocarbyl group, optionally including one or more additional functional groups or heteroatoms).
  • X is a silicon containing group (and is preferably also a hydrocarbyl group, optionally including one or more additional functional groups or heteroatoms).
  • the presence of silicon at these positions may contribute to particular hydrophobicity characteristics leading to an improved anchoring effect.
  • Compounds ofthe present invention may be used for any desired therapeutic purpose.
  • Preferred treatments are human treatments, although veterinary treatments are also within the scope ofthe present invention.
  • the treatment may be prophylactic or may be in respect of an existing condition.
  • Treatments are desirably of disorders which can be treated in a host by the activation of a heat shock transcription factor (e.g. HSF1), by the induction of heat shock proteins (e.g. hsp70) and/or by the inhibition of NF- ⁇ B.
  • a heat shock transcription factor e.g. HSF1
  • hsp70 heat shock proteins
  • NF- ⁇ B is implicated in the pathogenesis of certain viral infections. It is known that heat shock proteins (e.g. HSP70) can offer protection against the pathogenesis of viral infection. Furthermore, it has now been shown that compounds ofthe present invention are surprisingly active in reducing the replication of viruses.
  • HSP70 heat shock proteins
  • R A viruses which may be single-stranded, negatively polarised RNA viruses
  • DNA viruses as well as disorders mediated by DNA viruses.
  • viral disorders examples include disorders mediated by: retroviruses (e.g. HIV-1), herpes viruses (e.g. HSV-1, CMV, HHV8, HSV-2), paramyxo and orthomyxo viruses (as illustrated by Sendai viruses and including influenza viruses), rhabdoviruses (e.g. vesicular stomatitis virus, rabies viruses), picornaviruses (e.g. rhinoviruses and hepatitis A viruses), hepadnaviruses (e.g. hepatitis B viruses), togaviruses (e.g. rubella viruses), or poxviruses (e.g. molluscum contagiosum virus).
  • retroviruses e.g. HIV-1
  • herpes viruses e.g. HSV-1, CMV, HHV8, HSV-2
  • paramyxo and orthomyxo viruses as illustrated by Sendai viruses and including influenza viruses
  • rhabdoviruses e
  • Additional viral disorders that can be treated using compounds ofthe present invention include: filoviruses (e.g. Ebola virus), bunyaviruses (e.g. hantaviruses), arenaviruses (e.g. lassa fever virus), flaviviruses (e.g. yellow fever and hepatitis C viruses).
  • filoviruses e.g. Ebola virus
  • bunyaviruses e.g. hantaviruses
  • arenaviruses e.g. lassa fever virus
  • flaviviruses e.g. yellow fever and hepatitis C viruses.
  • Compounds ofthe present invention may be particularly useful in treating viral and other disorders affecting aquatic organisms (e.g. fish, crustaceans, etc.). Such disorders include disorders mediated by the snout ulcer virus, by the iridovirus, by the lymphocystis disease virus, etc.
  • Compounds ofthe present invention may therefore be used in aquaculture. They may be used in food for aquatic organisms. Such food is within the scope ofthe present invention. It will generally be sold in sealed containers and labelled appropriately (e.g. as fish food, food for crustaceans, food for aquatic organisms, etc.) Alternatively, compounds ofthe present invention may be used for water treatment or for direct application to aquatic organisms. Such compounds do not therefore need to be present in foodstuffs in order to be useful in aquaculture.
  • Compounds ofthe present invention may also be useful in treating plant viral disorders. Given that the basic mechanisms ofthe heat shock response are believed to operate in a similar fashion in plants and animals and that it is reasonable to expect that direct antiviral effects will be produced by the compounds of invention in a similar fashion in plants and animals, the use of compounds ofthe present invention in treating viral infections of plants is within the scope ofthe present invention. These infections include, but are not limited to, infections of plants by geminiviruses, rhabdoviruses, caulimoviruses, bromoviruses, tobramoviruses, potyviruses and potexviruses. The use of compounds ofthe present invention in treating infections by viroids (including, but not limited to, potato spindle tuber viroid, hop stunt viroid, and coconut cadang cadang viroid) is also within the scope ofthe patent invention.
  • viroids including, but not limited to, potato spindle tuber viroid, hop stunt viroid, and coconut cadang cadang viroid
  • NF- ⁇ B is activated in response to bacterial infections.
  • Compounds ofthe present invention are useful in treating disorders arising from such infections - e.g. in treating NF- ⁇ B stimulated inflammation. Most commonly this will arise due to infection with Gram negative bacteria. However it may also arise due to infection with Gram positive bacteria (e.g. S. aureus).
  • NF- ⁇ B is activated in response to radiation (e.g. UV-radiation).
  • Compounds ofthe present invention are therefore useful in treating disorders mediated by radiation.
  • disorders include cell and tissue trauma, cell and tissue ageing and cancer (e.g. skin cancer). 4. Treatment of inflammation and of disorders ofthe immune system
  • NF- ⁇ B is activated in response to inflammatory cytokines. It is believed to be an early mediator ofthe immune and inflammatory responses.
  • Compounds ofthe present invention are useful in treating immune disorders (e.g. auto-immune disorders) and in treating inflammatory disorders.
  • Examples of specific inflammatory disorders and disorders ofthe immune system that can be treated with compounds ofthe present invention include rheumatoid arthritis, multiple sclerosis, inflammatory disorders ofthe airways, adult respiratory distress syndrome, pulmonary hypertension, hepatitis and/or cirrhosis, vascular inflammation (including lupus erythematosis disseminata), and inflammatory disorders ofthe gastrointestinal tract (e.g. ulcers).
  • NF- ⁇ B has been implicated in the pathogenesis of ischemia and arteriosclerosis.
  • Compounds ofthe present invention are therefore useful in treating such disorders.
  • These disorders include reperfusion damage (e.g. in the heart and or brain) and cardiac hypertrophy.
  • NF- ⁇ B is implicated in cell proliferation.
  • Compounds ofthe present invention are useful as anti-proliferatives. They are therefore useful in treating, inflammatory granulomas, neointimal proliferation in arterial and venous restenosis, and cancers (including lymphomas, leukemias, sarcomas, carcinomas and melanomas).
  • Heat shock proteins are known to provide a cytoprotective effect.
  • Compounds ofthe present invention are therefore useful in treating disorders involving damage to or killing of cells.
  • disorders include chemical toxicity (e.g. due to ingestion of toxins, such as paraquat, or to overdosing with medicaments, such as paracetamol), oxidative cell damage, cell and tissue ageing, trauma, hepatitis and diabetes.
  • chemical toxicity e.g. due to ingestion of toxins, such as paraquat, or to overdosing with medicaments, such as paracetamol
  • oxidative cell damage oxidative cell damage
  • cell and tissue ageing trauma, hepatitis and diabetes.
  • Cyclopentenone prostaglandins are of known utility in stimulating peroxisome proliferator activated receptors (PPARs). This is a further indication of the utility of compounds ofthe present invention in treating diabetes (including complications arising therefrom).
  • Compounds ofthe present invention can be used in the treatment of disorders in which calcium loss or deficiency is implicated or involved (including bone disorders, skeletal disorders, dental disorders, developmental disorders, etc.).
  • a compound ofthe present invention may be used in the manufacture of a medicament for one or more ofthe previously mentioned treatments.
  • a medicament will usually be supplied as part of a pharmaceutical composition, which may include a pharmaceutically acceptable carrier.
  • This pharmaceutical composition will generally be provided in a sterile form. It may be provided in unit dosage form. It will generally be provided in a sealed container, and can be provided as part of a kit. Such a kit is within the scope ofthe present invention. It would normally (although not necessarily) include instructions for use.
  • a plurality of unit dosage forms may be provided.
  • compositions within the scope ofthe present invention may include one or more ofthe following: preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts (compounds ofthe present invention may themselves be provided in the form of a pharmaceutically acceptable salt - as explained in greater detail below), buffers, coating agents or antioxidants. They may also contain other therapeutically active agents in addition to a compound ofthe present invention.
  • Compounds ofthe present invention may themselves be provided in any suitable form - i.e. they may be used as such or may be used in the form of a pharmaceutically effective derivative.
  • Pharmaceutically acceptable salts include alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) aluminium salts, zinc salts, ammonium salts (e.g. tetra-alkyl ammonium salts), etc.
  • Inorganic acid addition salts e.g. hydrochlorides, sulphates, or phosphates
  • organic acid addition salts e.g. citrates, maleates, fumarates, succinates, lactates, propionates or tartrates
  • compositions ofthe present invention may be provided in controlled release form. This can be achieved by providing a pharmaceutically active agent in association with a substance that degrades under physiological conditions in a predetermined manner. Degradation may be enzymatic or may be pH-dependent. Pharmaceutical compositions may be designed to pass across the blood brain barrier (BBB).
  • a carrier such as a fatty acid, inositol or cholesterol may be selected that is able to penetrate the BBB.
  • the carrier may be a substance that enters the brain through a specific transport system in brain endothelial cells, such as insulin-like growth factor I or II.
  • the carrier may be coupled to the active agent or may contain / be in admixture with the active agent. Liposomes can be used to cross the BBB.
  • WO91/ 04014 describes a liposome delivery system in which an active agent can be encapsulated/embedded and in which molecules that are normally transported across the BBB (e.g. insulin or insulin-like growth factor I or II) are present on the liposome outer surface.
  • BBB insulin or insulin-like growth factor I or II
  • a pharmaceutical composition within the scope ofthe present invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes.
  • Such a composition may be prepared by any method known in the art of pharmacy, for example by admixing one or more active ingredients with a suitable carrier.
  • compositions adapted for oral administration may be provided as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions.
  • Tablets or hard gelatine capsules may comprise lactose, maize starch or derivatives thereof, stearic acid or salts thereof.
  • Soft gelatine capsules may comprise vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.
  • Solutions and syrups may comprise water, polyols and sugars.
  • suspensions oils e.g. vegetable oils
  • suspensions oils e.g. vegetable oils
  • An active agent intended for oral administration may be coated with or admixed with a material that delays disintegration and/or absorption ofthe active agent in the gastrointestinal tract (e.g. glyceryl monostearate or glyceryl distearate may be used).
  • a material that delays disintegration and/or absorption ofthe active agent in the gastrointestinal tract e.g. glyceryl monostearate or glyceryl distearate may be used.
  • a material that delays disintegration and/or absorption ofthe active agent in the gastrointestinal tract e.g. glyceryl monostearate or glyceryl distearate may be used.
  • glyceryl monostearate or glyceryl distearate may be used.
  • compositions adapted for transdermal administration may be provided as discrete patches intended to remain in intimate contact with the epidermis ofthe recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis.
  • iontophoresis is described in Pharmaceutical Research, 3(6):318 (1986).
  • Topical Administration is described in Pharmaceutical Research, 3(6):318 (1986).
  • compositions adapted for topical administration may be provided as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • a topical ointment or cream is preferably used.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water base or a water-in-oil base.
  • Pharmaceutical compositions adapted for topical administration to the eye include eye drops.
  • the active ingredient can be dissolved or suspended in a suitable carrier, e.g. in an aqueous solvent.
  • Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouthwashes.
  • compositions adapted for rectal administration may be provided as suppositories or enemas.
  • compositions adapted for nasal administration may use solid carriers - e.g. powders (preferably having a particle size in the range of 20 to 500 microns). Powders can be administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nose from a container of powder held close to the nose.
  • Compositions adopted for nasal administration may alternatively use liquid carriers - e.g. include nasal sprays or nasal drops. These may comprise aqueous or oil solutions ofthe active ingredient.
  • compositions for administration by inhalation may be supplied in specially adapted devices - e.g. in pressurised aerosols, nebulizers or insufflators. These devices can be constructed so as to provide predetermined dosages ofthe active ingredient.
  • compositions adapted for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions or suspensions. These may contain antioxidants, buffers, bacteriostats and solutes that render the compositions substantially isotonic with the blood of an intended recipient. Other components that may be present in such compositions include water, alcohols, polyols, glycerine and vegetable oils, for example.
  • Compositions adapted for parenteral administration may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, e.g. sterile water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions ofthe present invention can be formulated in many different ways.
  • preferred compositions ofthe present invention are in the form of topical formulations.
  • Dosages of a compound ofthe present invention can vary between wide limits, depending upon the nature ofthe treatment, the age and condition ofthe individual to be treated, etc. and a physician will ultimately determine appropriate dosages to be used.
  • a daily dosage of a compound ofthe present invention of from lO ⁇ g to lOOmg/kg body weight may be suitable.
  • the dosage is from 5 to 50 mg/kg body weight/day.
  • the dosage may be repeated as often as appropriate. If side effects develop, the amount and or frequency of the dosage can be reduced, in accordance with good clinical practice.
  • Compounds ofthe present invention are useful in research. For example they can be used as research tools for the analysis of one or more ofthe following: HSF, NF- ⁇ B, the heat shock response, viral replication, viral-mediated disorders, bacterial-mediated disorders, disorders mediated by radiation (e.g. by UV-radiation), inflammatory disorders, disorders ofthe immune system, ischemia, arteriosclerosis, disorders involving cell proliferation (e.g. cancers), disorders involving damage to, or killing of cells (e.g. oxidative cell damage), and diabetes. Novel Compounds
  • Such compounds include novel compounds within the scope ofthe formulae shown in Figure 10.
  • the two compounds shown in Figure 2 are known and are therefore expressly excluded from the scope of novel compounds ofthe present invention. (However, for the avoidance of doubt it should be noted that pharmaceutical compositions comprising the compounds shown in Figure 2, as well as uses thereof, including medical uses, are included within the scope ofthe present invention.)
  • Figures 2a) and 2b) provide the structures of R-(+)-4-tert-butyldimethylsilyloxy- cyclopent-2-en- 1 -one and S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en- 1 -one respectively (referred to herein as CTC7 and CTC8 respectively).
  • FIG 3 a provides the structure of cyclopent-2-en-l-one (referred to herein as CTC1).
  • Figure 3b provides the structure of a punaglandin derivative disclosed in Japanese patent application number JP6205928.
  • Figure 4a provides the structure of PGA .
  • Figure 4b provides the structure of PGJ .
  • Figure 4c illustrates the S position of a side chain of a PGA-like molecule.
  • Figure 5 illustrates the effect of S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one (CTC8), R-(+)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l-one (CTC7) and cyclopent-2-en-l-one (CTC1) on the activity of transcription factors HSF and NF- KB.
  • Figure 6a illustrates the effect of S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one (CTC8), R-(+)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l-one (CTC7) and cyclopent-2-en-l-one (CTC1) on the replication of Herpes simplex virus type 1.
  • Figure 6b provides a comparison ofthe effect of S-(-)-4-tert-butyldimethylsilyloxy- cyclopent-2-en-l-one (CTC8) on HSV-1 replications with that of Aciclovir.
  • Figure 7 illustrates the effect of S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one (CTC8), R-(+)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l-one (CTC7) and cyclopent-2-en-l-one (CTC1) on the replication of Sendai virus.
  • Figure 8 illustrates the effect of S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one (CTC8) or nitrite formation at submicromolar cencentrations.
  • CTC8 S-(-)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one
  • FIG. 9 illustrates the effect of R-(+)-4-tert-butyldimethylsilyloxy-cyclopent-2-en-l- one (CTC7) infusion on the blood pressure of normal Wister rats, CTC8 is compared with the prostaglandin PG-E and with the cyclopentenone prostaglandin PG-A.
  • Figure 10 shows certain preferred compounds ofthe present invention (both R- and S- and cis- and tram-forms are covered and stereochemistry should therefore not be construed as limiting).
  • Example 1 Effect of CTC8. CTC7 and cyclopent-2-en-l-one (CTC1) on the activity of transcription factors HSF and NF- ⁇ B.
  • Human lymphoblastoid Jurkat T cells were grown at 37°C in a 5% CO2 atmosphere in RPMI 1640 medium (GIBCO BRL, Gaithersburg, MD) supplemented with 10% fetal calf serum (FCS, Hyclone Europe Ltd, UK), 2 mM glutamine and antibiotics according to the method described by A. Rossi et al. (Proc. Natl. Acad. Sci. USA 94: 746-750, 1997).
  • CTC8, CTC7 and cyclopent-2-en-l-one (CTC1) were stored as a 100% ethanolic stock solution (100 mM) and diluted to the appropriate concentration in culture medium at the time of use.
  • CTC8 and CTC7 are potent inducers of HSF and inhibitors of NF- ⁇ B, with CTC8 being more active than CTC7. Both compounds are shown to be at least 100 times more effective in activating HSF and inhibiting NF- ⁇ B than the originally described compound cyclopent-2-en-l-one (CTC1).
  • Example 2 Effect of CTC8, CTC7 and cvclopent-2-en-l-one (CTCl) on the replication of Herpes simplex virus type 1.
  • HEp-2 cell monolayers were infected with HSV-1 for 1 h at 37°C. After this time, virus inocula were removed and cells were incubated in RPMI 1640 medium containing 2% FCS. Different concentrations of CTC8, CTC7 or cyclopent- 2-en-l-one (CTC1) were added to the culture after the 1 h adsorption period, and maintained in the medium for the duration ofthe experiment. Control medium contained the same concentration of ethanol diluent, which did not affect cell metabolism or virus replication.
  • HSV-1 virus titres were determined 24 hours after infection by cytopathic effect 50% (CPE50%) assay on confluent VERO cells monolayers in 96-well tissue culture plates (six dilutions for each sample, eight wells for each dilution), as described by F. Pica et al. (Antiviral Res. 20: 193-208, 1993). The dilution that gives 50% cytopathic effect was determined by the interpolating procedure of Reed and Muench, as described by E. Rodriguez-Boulan (Methods Enzymol. 98: 486-501, 1983). Results from a representative experiment are shown. Each experiment was repeated at least 3 times.
  • S.I. selective index
  • Figure 6b provides a comparison ofthe antiviral activity of CTC8 with that of Aciclovir over a range of concentrations.
  • Table 1 below provides IC values based upon Figures 6a) to c).
  • Example 3 Effect of CTC8. CTC7 and cyclopent-2-en-l-one (CTC1) on the replication of Sendai virus.
  • Monkey kidney 37RC cells were grown at 37°C under the conditions described in Example 1 for T cells.
  • the parainfluenza Sendai virus (SV) was grown in the allantoic cavity of 10-day-old embryonated eggs.
  • Viral titre was expressed in haemagglutinating units (HAU) per ml; haemagglutinin titration was done according to standard procedures using human 0 Rh+ erythrocytes, as described in C. Amici et al. (J. Virol. 68: 6890-6899, 1994).
  • Confluent monolayers of 37RC cells were infected with SV virus (5 HAU/10 5 cells) for 1 h at 37°C, and then treated with different concentrations of CTC8, CTC7 or CTC1.
  • Virus yield at 24 hours after infection was determined in the supernatant of infected cells by HAU titration. Results from a representative experiment are shown. Each experiment was repeated at least 3 times.
  • Immune cells such as neutrophils and macrophages are activated in response to injury and infection. When activated they produce nitric oxide and superoxide radicals to kill foreign cells and cancer cells. They also produce a variety of cytokines and chemokines to cause further recruitment of immune cells in a cascade leading to the cardinal symptoms of inflammation; heat, redness, swelling, pain, and loss of function.
  • NF-KB transcription factor nuclear factor KB
  • NF- ⁇ B regulates the transcription of a spectrum of pro-inflammatory genes such as IL-1, IL-2, TNF- ⁇ , ICAM-1, VCAM-1, and E- selectin as well as the inducible form of nitric oxide synthase (iNOS) and cyclo- oxygenase II.
  • NF- ⁇ B occupies a critical position in the inflammatory cascade.
  • cyclopentenone prostaglandins are known to have anti-inflammatory actions (17)
  • the cyclopentenone derivative CTC-8 was tested for its effects on the induction of iNOS in a mouse macrophage model.
  • Mouse macrophages ofthe cell line RAW264.7 were stimulated with gamma interferon and 0.1 U/ml of bacterial lipopolysaccharide (LPS) in 96-well plates (17).
  • the induction of iNOS was measured by determination ofthe levels of nitrite (NO 2 " ) formed in the supernatant, using the Griess reagent.
  • the natural cyclopentenone prostaglandin PG-J 2 was used for comparison.
  • CTC-8 had a concentration-dependent inhibitory effect on nitrite formation at submicromolar concentrations (Fig. 8). At a concentration of 3 ⁇ g/ml the level of nitrites was reduced to background levels. PG-J had similar effects but was much less potent. No evidence of cytotoxicity was seen for either CTC-8 or PG-J . The results of this experiment indicated that the induction ofthe pro-inflammatory iNOS gene by interferon gamma and LPS treatment is suppressed by CTC-8. The most likely explanation is that CTC-8 is inhibiting the activation ofthe NF- ⁇ B pathway.
  • Table 3 shows IC50 values obtained for PGJ 2 and CTC-8 in respect ofthe inhibition of nitrite formation.
  • Prostaglandins Ai and Ei were used for comparison.
  • Prostaglandins Ai and Ei caused dose-dependent falls in blood pressure in doses from 30 ⁇ g/kg/min (Fig. 9).
  • CTC-8 at doses from 60-1200 ⁇ g/kg/min had no effect on blood pressure.
  • At the higher dose a small fall in blood pressure was observed but this was not different from that of solvent alone.
  • CTC-8 may be devoid ofthe generalised effects on smooth muscle characteristic of natural cyclopentenone prostaglandins.

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Abstract

Des 4- et 5-oxacyclopent-2-en-1-ones font montre d'un activité significative en activant HSF et en inhibant NF-λB. L'on estime qu'ils se révéleront des plus utiles pour traiter une large gamme d'états pathologiques, au nombre desquels, des états pathologiques provoqués par des virus et par des bactéries, des états pathologiques déclenchés par un rayonnement (par exemple. par le rayonnement ultraviolet), des maladies inflammatoires, des maladies du système immunitaire, l'ischémie, l'artériosclérose, des maladies à prolifération cellulaire (des cancers notamment), des maladies entraînant des dommages aux cellules ou provoquant leur mort (par exemple, altérations cellulaire due à des oxydants) et le diabète.
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WO2003051807A2 (fr) * 2001-12-14 2003-06-26 Charterhouse Therapeutics Limited Ameliorations relatives a des compositions pharmaceutiques
WO2003051893A2 (fr) * 2001-12-14 2003-06-26 Charterhouse Therapeutics Limited Ameliorations apportees a des compositions pharmaceutiques
US6613780B2 (en) * 1997-06-27 2003-09-02 Kaneka Corporation Heat shock factor activity inhibitor
WO2004013077A2 (fr) * 2002-08-06 2004-02-12 Charterhouse Therapeutics Ltd Ameliorations relatives a des composes pharmaceutiquement utiles
WO2004016253A1 (fr) * 2002-08-14 2004-02-26 Janssen Pharmaceutica N.V. Utilisation d'inhibiteurs du nf-kappa b pour le traitement de la mastite
WO2009038842A3 (fr) * 2007-06-15 2009-12-30 Mission Pharmacal Co. Procédés et compositions pour inhiber le facteur d'œdème et l'adénylylcyclase
US9101601B2 (en) 2012-01-09 2015-08-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of treating or preventing insulin resistance and associated diseases and conditions
US9517224B2 (en) 2012-11-15 2016-12-13 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Methods of treating patients infected with HIV and HTLV
US9701664B2 (en) 2013-10-04 2017-07-11 Cancer Research Technology Limited Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1
US10647678B2 (en) 2015-04-01 2020-05-12 Cancer Research Technology Limited Quinoline derivatives as inhibitors of heat shock factor 1 pathway activity
US11814370B2 (en) 2016-10-07 2023-11-14 Cancer Research Technology Limited Deuterated N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6613780B2 (en) * 1997-06-27 2003-09-02 Kaneka Corporation Heat shock factor activity inhibitor
WO2003051807A2 (fr) * 2001-12-14 2003-06-26 Charterhouse Therapeutics Limited Ameliorations relatives a des compositions pharmaceutiques
WO2003051893A2 (fr) * 2001-12-14 2003-06-26 Charterhouse Therapeutics Limited Ameliorations apportees a des compositions pharmaceutiques
WO2003051893A3 (fr) * 2001-12-14 2003-09-18 Charterhouse Therapeutics Ltd Ameliorations apportees a des compositions pharmaceutiques
WO2003051807A3 (fr) * 2001-12-14 2003-09-18 Charterhouse Therapeutics Ltd Ameliorations relatives a des compositions pharmaceutiques
US7183440B2 (en) * 2002-08-06 2007-02-27 Charterhouse Therapeutics Ltd Pharmaceutically useful compounds
WO2004013077A3 (fr) * 2002-08-06 2004-04-22 Charterhouse Therapeutics Ltd Ameliorations relatives a des composes pharmaceutiquement utiles
WO2004013077A2 (fr) * 2002-08-06 2004-02-12 Charterhouse Therapeutics Ltd Ameliorations relatives a des composes pharmaceutiquement utiles
WO2004016253A1 (fr) * 2002-08-14 2004-02-26 Janssen Pharmaceutica N.V. Utilisation d'inhibiteurs du nf-kappa b pour le traitement de la mastite
WO2009038842A3 (fr) * 2007-06-15 2009-12-30 Mission Pharmacal Co. Procédés et compositions pour inhiber le facteur d'œdème et l'adénylylcyclase
US8003692B2 (en) 2007-06-15 2011-08-23 Board Of Regents, The University Of Texas System Methods and compositions to inhibit edema factor and adenylyl cyclase
US9101601B2 (en) 2012-01-09 2015-08-11 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods of treating or preventing insulin resistance and associated diseases and conditions
US9517224B2 (en) 2012-11-15 2016-12-13 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Methods of treating patients infected with HIV and HTLV
US9701664B2 (en) 2013-10-04 2017-07-11 Cancer Research Technology Limited Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1
US10189821B2 (en) 2013-10-04 2019-01-29 Cancer Research Technology Limited Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor I
US11124501B2 (en) 2013-10-04 2021-09-21 Cancer Research Technology Limited Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor I
US11787786B2 (en) 2013-10-04 2023-10-17 Cancer Research Technology Limited Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1
US10647678B2 (en) 2015-04-01 2020-05-12 Cancer Research Technology Limited Quinoline derivatives as inhibitors of heat shock factor 1 pathway activity
US11814370B2 (en) 2016-10-07 2023-11-14 Cancer Research Technology Limited Deuterated N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-fluorophenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide

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