WO2008003978A2 - Dioxo-alkanes and dioxo-alkenes - Google Patents
Dioxo-alkanes and dioxo-alkenes Download PDFInfo
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- WO2008003978A2 WO2008003978A2 PCT/GB2007/002527 GB2007002527W WO2008003978A2 WO 2008003978 A2 WO2008003978 A2 WO 2008003978A2 GB 2007002527 W GB2007002527 W GB 2007002527W WO 2008003978 A2 WO2008003978 A2 WO 2008003978A2
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- optionally substituted
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- 0 *C(*)(C(*)=O)C(CCc1ccccc1)=O Chemical compound *C(*)(C(*)=O)C(CCc1ccccc1)=O 0.000 description 4
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Definitions
- the present invention relates to novel substituted dioxo-alkanes and dioxo-alkenes, as well as compositions and uses thereof.
- US Patent No. 4649157 (G D Searle & Co.), the disclosure of which is incorporated herein by reference, discloses certain generic definitions of phenyl-substituted dioxo- alkenes and substituted derivatives thereof which are said to possess activity as inhibitors of leukotriene biosynthesis.
- the compounds are proposed as agents against diseases and conditions associated with leukotrienes, such as allergic conditions, inflammatory conditions, certain skin disorders, hyperalgetic conditions and coronary vasoconstriction.
- EP-A-0402469 discloses certain generic definitions of catechol compounds which are said to possess activity as inhibitors of 5-lipoxygenase in leukotriene biosynthesis.
- the compounds are proposed as agents against diseases and conditions associated with leukotrienes, such as nephritis, hepatitis, rheumatism and gastric ulcers, as well as allergic diseases such as asthma and rhinitis.
- US Patent Application No. 2006/0148830 (Ono Pharmaceutical Co. Ltd), corresponding to WO-A-2004/0311 18, the disclosure of which is incorporated herein by reference, discloses certain generic and specific compound definitions which are said to engage in lysophosphatidic acid receptor bonding and antagonism and hence are useful for prevention and/or treatment of diseases such as urinary system disease, carcinoma- associated disease, proliferative disease, inflammation/immune system disease, disease by secretory dysfunction, brain related disease or chronic disease.
- diseases such as urinary system disease, carcinoma- associated disease, proliferative disease, inflammation/immune system disease, disease by secretory dysfunction, brain related disease or chronic disease.
- Examples 34 and 35 of this prior art describe the preparation of 2-[4-[3-oxo-5-phenyl-2-(3,4,5- trimethoxybenzoyl)-pentyl]-phenoxy]-benzoic acid benzyl ester and 2-[4-[3-oxo-5- phenyl-2-(3,4,5-trimethoxybenzoyl)-pentyl]-phenoxy]-benzoic acid.
- the prior art provides no biological data for these compounds, and there is no suggestion that any compounds similar to them would have activity.
- the present invention is based on our surprising finding that certain known and novel compounds have an unexpected combination of activities which provide advantageous use in the treatment or prophylaxis of hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain such as, for example but not limited to, asthma, cough, pruritus, food intolerance, psoriasis, croup, irritable bowel syndrome, tinnitus, Meniere's disease, stress-induced ulceration or acetylsalicylic acid-induced ulceration, primary dysmenorrhea, pre-term labour, preterm contractions, diarrhoea, gastrointestinal cramps, diverticular disease, achalasia, Hirschsprung's disease, gastro-oesophageal reflux disease, myotonic dystrophy, gallstone disease, constipation, post-surgical gastroparesis syndrome, paralytic ileus, post-operative ileus, diabetic gastroparesis, bowel paresis, intestinal pseudo-obstruction
- the compounds may be useful as non-pharmaceuticals, for example in foods or beverages (for example in a functional food or beverage), providing health benefits (whether for diseased or non-diseased humans or animals), for example health benefits relating to hypersensitivity, smooth muscle conditions, spasmodic conditions, the immune-system and/or pain, such as, but not limited to, the maintenance of normal gut function, as a calmative for the gut, to maintain normal breathing, to ease motion sickness and vertigo, to soothe sore throats and coughs, to ease nausea and vomiting, as an aid to maintain normal digestion, to ease upset stomachs, to warm hands and feet, to aid normal menstruation, to maintain normal blood pressure, to normalise bowel movement, to maintain a healthy immune system, to aid in the recovery from colds and flu, as a decongestant, to soothe headaches, to relieve muscle soreness, to ease mild aches and pains, to provide relief from toothache, to provide relief from mouth ulcers, to maintain healthy joints, to help limit c ellulite occurrence and as
- R 1 and R 2 are, independently of each other, selected from hydrogen, optionally substituted Ci -10 alkyl, optionally substituted -CO-(C) -10 alkyl), optionally substituted C 3-I0 cycloalkyl, optionally substituted -CO-(C 3-10 cycloalkyl), optionally substituted
- R 3 which may be the same as, or different from, either OfR 1 and R 2 , is selected from optionally substituted C 1-10 alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 2-10 alkenyl, and optionally substituted aryl;
- any optionally substituted C 1-10 alkyl or optionally substituted C 2-10 alkenyl for R 3 must have a branch point at one or more of the ⁇ and ⁇ positions counted from the carbonyl group (or tautomeric form thereof) to which R 3 is attached;
- the compound may particularly be used in the treatment or prophylaxis of hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain such as, for example but not limited to, asthma, cough, pruritus, food intolerance, psoriasis, croup, irritable bowel syndrome, tinnitus, Meniere's disease, stress-induced ulberation or acetylsalicylic acid-induced ulceration, primary dysmenorrhea, pre-term labour, pre-term contractions, diarrhoea, gastrointestinal cramps, diverticular disease, achalasia, Hirschsprung's disease, gastro- oesophageal reflux disease, myotonic dystrophy, gallstone disease, constipation, post- surgical gastroparesis syndrome, paralytic ileus, post-operative ileus, diabetic gastroparesis, bowel paresis, intestinal pseudo-obstruction, peripheral arterial diseases, Raynaud's syndrome and coronary
- a compound of formula I or a physiologically acceptable salt, complex or prodrug thereof in the treatment or prophylaxis of, or in the preparation of a medicament, foodstuff, beverage (for example in a functional food or beverage), food supplement, beverage supplement or other physiologically compatible composition for the treatment or prophylaxis of, hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain such as, for example but not limited to, asthma, cough, pruritus, food intolerance, psoriasis, croup, irritable bowel syndrome, tinnitus, Meniere's disease, stress-induced ulceration or acetylsalicylic acid- induced ulceration, primary dysmenorrhea, pre-term labour, pre-term contractions, diarrhoea, gastrointestinal cramps, diverticular disease, achalasia, Hirschsprung's disease, gastro-oesophageal reflux disease
- a method for treating or preventing hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain in a human or non-human subject in need thereof comprising administering to the subject an effective amount of a compound of formula I or a physiologically acceptable salt, complex or prodrug thereof.
- Therapeutic use of the compounds may be under medical or veterinary supervision or control, or may be self-administered (in the case of humans) or under the control of a person not veterinarily qualified (in the case of non-human animals).
- Non-therapeutic use of the compounds is also possible, and constitutes an embodiment of the third aspect of the present invention.
- Such non-therapeutic use will typically comprise the precautionary taking of the compound by a healthy human or the precautionary administration of the compound to a healthy non-human animal outside the context of medical or veterinary supervision and control, e.g. self-administration (in the case of humans), for example in foodstuffs to maintain normal blood pressure.
- a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt, complex or prodrug thereof and a physiologically acceptable carrier thereof.
- the pharmaceutical composition, foodstuff, beverage, food supplement, beverage supplement or the other physiologically compatible composition is preferably suitable and intended for use in the treatment or prophylaxis of hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain in a human or non-human subject, and the compound of formula I or a physiologically acceptable salt, complex or prodrug thereof is preferably present in an amount which is effective for that purpose when administered in an appropriate dosage to the subject.
- the pharmaceutical composition, foodstuff, beverage, food supplement, beverage supplement or the physiologically compatible composition may be provided in unit dosage form, whereby typically one or more unit dosages are administered to the subject.
- the pharmaceutical composition, foodstuff, beverage, food supplement, beverage supplement or the physiologically compatible composition may be provided in a form which does not comprise unit dosages, and in that case a suitable dosage is typically measured out for administration.
- a compound of general formula I or a physiologically acceptable salt, complex or prodrug thereof may, if desired, be used in association with one or more additional compounds of general formula I or physiologically acceptable salt, complex or prodrug thereof, or with one or more additional agent having activity against hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain or against side effects of such an agent.
- additional compounds of general formula I or physiologically acceptable salt, complex or prodrug thereof or with one or more additional agent having activity against hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain or against side effects of such an agent.
- active agents provided that the active agent as used in the present invention includes at least one compound of general formula I or a physiologically acceptable salt, complex or prodrug thereof.
- a method of manufacturing a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt, complex or prodrug thereof and a physiologically acceptable carrier therefor, the method comprising bringing into admixture the said compound of formula I or a physiologically acceptable salt, complex or prodrug thereof and the physiologically acceptable carrier therefor.
- the composition is preferably packaged with instructions for use in the treatment or prophylaxis of hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain in a human or non- human subject, the said instructions typically including dosage information, information concerning the appropriate administration route and protocol, and safety information relevant to the said intended use.
- R 1 and R 2 are, independently of each other, selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted -CO-(C 1- Io alkyl), optionally substituted C 3-IO cycloalkyl, optionally substituted -CO-(C 3-1 O cycloalkyl), optionally substituted C 2-10 alkenyl, optionally substituted -CO-(C 2- I 0 alkenyl), optionally substituted aryl, and optionally substituted -CO-aryl, or Ri and R 2 together represent an optionally substituted saturated or unsaturated Ci -10 alkylidene group, or an optionally substituted saturated or unsaturated C 3- io cycloalkylidene group, or Ri and R 2 together with the carbon atom to which they are attached represent an optionally substituted saturated or unsaturated organic ring containing 3, 4, 5, 6, 7 or 8 ring carbon atoms and optionally 1, 2 or 3 ring heteroatoms selected from O, N and S;
- R 3 which may be the same as, or different from, either of Ri and R 2 , is selected from optionally substituted Ci -10 alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 2-I0 alkenyl, and optionally substituted aryl;
- any optionally substituted Ci -I0 alkyl or optionally substituted C 2- io alkenyl for R 3 must have a branch point at one or more of the ⁇ and ⁇ positions counted from the carbonyl group (or tautomeric form thereof) to which R 3 is attached;
- physiologically unacceptable salts and complexes of the compounds of general formula I are new per se, and constitute a seventh aspect of the present invention. They may be used as intermediates in the preparation of the compounds of general formula I and their physiologically acceptable salts, complexes and prodrugs. In one embodiment of this aspect of the present invention, the physiologically unacceptable salts and complexes of the compounds of general formula Ia as defined above may be particularly mentioned.
- the compounds of formula I and their salts, complexes and physiologically acceptable prodrugs may be obtained from readily available starting materials by chemical reactions which will be well known and understood by those skilled in the art.
- the compounds are relatively simple organic molecules and their synthesis will present no undue difficulty to the skilled worker.
- a method of preparing a compound of general formula I as defined above or a salt, complex or physiologically acceptable prodrug thereof comprises selectively reducing the aliphatic carbon-carbon double bond marked * in a compound of general formula II:
- R 1 to R 6 are as defined above for general formula I, or a salt or complex thereof, to obtain the compound of general formula I.
- a suitable reducing agent for effecting the selective reduction is hydrogen in the presence of a metal catalyst such as Raney nickel or palladium on carbon.
- Functional groups such as the carbonyl groups, which are susceptible to reduction but are not desired to be reduced, may be protected for the reduction in a generally known manner.
- the protecting group(s) used will subsequently be removed in a conventional manner to provide the deprotected product.
- the reaction, and any subsequent deprotection that may be necessary, yields a compound of general formula I, which may be converted into a salt, complex or prodrug thereof by standard chemical reactions. If initially a salt or complex is formed which is not physiologically compatible, such a compound may subsequently be converted by standard chemical techniques into a physiologically acceptable salt or complex of the compound of general formula I, and optionally then to a physiologically acceptable prodrug.
- a method for preparing a compound of general formula I as defined above or a salt, complex or physiologically acceptable prodrug thereof comprises condensing a compound of general formula III with a compound of general formula IV:
- R 1 to R 6 are as defined above for general formula I, optionally in the presence of a chelating agent, to deactivate the carbon between the two carbonyl groups (or other tautomeric form) in formula IV in favour of the terminal methyl carbon atom, to obtain the compound of general formula I after reduction of the resulting double bond.
- chelating agents examples include boron trioxide and titanium tetrachloride.
- the reaction yields a compound of general formula I, which may be converted into a salt, complex or physiologically acceptable prodrug thereof by standard chemical reactions. If initially a salt or complex is formed which is not physiologically compatible, such a compound may subsequently be converted by standard chemical techniques (salt or ligand displacement) into a physiologically acceptable salt or complex of the compound of general formula I, and optionally then to a physiologically acceptable prodrug.
- R 1 and R 2 are, independently of each other, selected from hydrogen, optionally substituted Ci -10 alkyl, optionally substituted -CO-(C 1-10 alkyl), optionally substituted C 3-10 cycloalkyl, optionally substituted -CO-(C 3-I0 cycloalkyl), optionally substituted C 2-10 alkenyl, optionally substituted -CO-(C 2-I0 alkenyl), optionally substituted aryl and optionally substituted -CO-aryl, or R 1 and R 2 together represent an optionally substituted saturated or unsaturated C 1-10 alkylidene group or an optionally substituted saturated or unsaturated organic ring containing 3, 4, 5, 6, 7 or 8 ring carbon atoms and optionally 1, 2 or 3 ring heteroatoms selected from O, N and S;
- R 3 which may be the same as, or different from, either of Ri and R 2 , is selected from optionally substituted Ci -I0 alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 2-10 alkenyl, and optionally substituted aryl;
- any optionally substituted C 1-10 alkyl or optionally substituted C 2-10 alkenyl for R 3 must have a branch point at one or more of the ⁇ and ⁇ positions counted from the carbonyl group (or tautomeric form thereof) to which R 3 is attached; and (b) R 3 cannot be unsubstituted phenyl.
- the protected forms of the compounds of general formula Ia and their salts and complexes which are initially prepared if a protected form of the compound of general formula Ha or a salt or complex thereof is used as starting material, are also novel per se, and these chemical compounds themselves constitute a further (eleventh) aspect of the present invention.
- a method for preparing a compound of general formula I or II as defined above or a salt or complex thereof in which one or both of Ri and R 2 is an alkyl group and the other of Ri and R 2 , if not an alkyl group, is a hydrogen atom comprising alkylating the corresponding compound of general formula I or II or salt thereof in which both of Ri and R 2 are hydrogen atoms by initially protecting any phenolic groups of the said compound using a base, (e.g. sodium hydride (NaH)) and a protecting group, (e.g. trimethylsilyl) in the presence of a suitable solvent (e.g.
- a base e.g. sodium hydride (NaH)
- a protecting group e.g. trimethylsilyl
- an alkylating agent e.g. an alkyl iodide, for example methyl iodide
- a base e.g. potassium carbonate, sodium hydride or potassium Z-butoxide
- a method for preparing a compound of general formula I or II as defined above or a salt or complex thereof comprising reacting a compound of general formula V
- R 1 , R 2 , R 4 , R 5 and R 6 are as defined respectively for formulae I and II, wherein represents a single or double bond and the wavy line represents either the (E) or (Z) isomer when is a double bond;
- the reaction may conveniently be carried out, for example, in the presence of lithium hexamethyldisylazide (LHMDS) as the base.
- LHMDS lithium hexamethyldisylazide
- the compounds of general formula I show activity in the modulation of the TRPVl receptor, modulation of smooth muscle tone, inhibition of tissue remodelling, and inhibition of inflammatory mediator production. From this, it is seen more generally that the compounds of general formula I and their salts, complexes and prodrugs have one or more of the following biological activities: (1) they modulate the TRPVl receptor; (2) they modulate smooth muscle tone; (3) they inhibit tissue remodeling; and (4) they have anti-inflammatory activity.
- the data show that the compounds of general formula I can bind to and modulate the TRPVl receptor and affect the release of calcitonin gene-related peptide (CGRP) in dorsal root ganglions (DRGs), and that the compounds can behave in this respect as agonists, partial agonists or antagonists of the TRPVl receptor.
- CGRP calcitonin gene-related peptide
- the compounds of general formula I have one or more of the following biological activities: modulation of the TRPVl receptor; modulation of smooth muscle tone; inhibition of tissue remodelling; and anti-inflammatory activity. More preferably, the compounds have at least two of these activities, for example at least three of the said activities. Most preferably, the compounds have all of the said activities.
- This combination of activities is strongly indicative of compounds that will provide for treatment or prophylaxis of hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain such as, for example but not limited to, asthma, cough, pruritus, food intolerance, psoriasis, croup, irritable bowel syndrome, tinnitus, Meniere's disease, stress-induced ulceration or acetylsalicylic acid-induced ulceration, primary dysmenorrhea, pre-term labour, preterm contractions, diarrhoea, gastrointestinal cramps, diverticular disease, achalasia, Hirschsprung's disease, gastro-oesophageal reflux disease, myotonic dystrophy, gallstone disease, constipation, post-surgical gastroparesis syndrome, paralytic ileus, post-operative ileus, diabetic gastroparesis, bowel paresis, intestinal pseudo-obstruction, peripheral arterial diseases, Raynaud's syndrome and coronary
- the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers.
- the compounds of general formula II and those compounds of general formula I and II that contain a double bond in one or more of the variable R groups are capable of double bond isomerism whereby each double bond may in principle exist in an (E) or a (Z) form.
- the present invention extends to all double bond isomers of such compounds, whether in the form of isomer mixtures in any relative proportion or as substantially pure isomers.
- the compounds of general formula I and II are capable of substitution position isomerism, for example in the locations of the groups R 4 , R 5 and R 6 and in the location of any optional substituents of the R groups.
- the present invention extends to all substitution position isomers of such compounds, whether in the form of isomer mixtures in any relative proportion or as substantially pure isomers.
- R 6 may be hydrogen, R 4 may be meta to the dioxo-containing chain and R 5 may be para to the dioxo-containing chain. It is most preferred that in this realisation R 4 represents an unsubstituted Ci -4 alkoxy group such as methoxy and R 5 represents hydroxyl.
- the compounds of general formulae I and II (and Ia and Ha) in which one or both of Ri and R 2 are hydrogen are capable of tautomerisation, particularly in solution, to form enols having a carbon-carbon double bond between one of the carbonyl carbon atoms and the central carbon atom between the carbonyl groups.
- Such enol tautomers of the compounds and their uses are included within the scope of the present application and subsequent patents.
- C x - y alkyl where x and y are any integers means an aliphatic hydrocarbon group having from x to y carbon atoms.
- the alkyl group may be straight or branched. "Branched” means that at least one carbon branch point is present in the group.
- the alkyl group is preferably a lower alkyl group.
- “Lower alkyl” means an alkyl group, straight or branched, having 1 to about 6 carbon atoms, e.g. 2, 3, 4, 5 or 6 carbon atoms.
- Exemplary alkyl groups include methyl, ethyl, n-propyl, /-propyl, w-butyl, f-butyl, s- butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3- heptyl, 4-heptyl, 2-methyl-but-l-yl, 2-methyl-but-3-yl, 2-methyl-pent-l-yl, 2 -methyl - pent-3-yl.
- the alkyl group may be optionally substituted, e.g. as exemplified below.
- the phenylmethyl, phenylethyl and phenylpropyl groups are thus examples of substituted alkyl groups.
- C x . y cycloalkyl where x and y are any integers means a cyclic non-aromatic hydrocarbon group having from x to y carbon atoms.
- the cycloalkyl group may include non-aromatic unsaturation.
- the cycloalkyl group preferably has 3 to about 6 carbon atoms, e.g. 3, 4, 5 or 6 carbon atoms.
- Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl.
- the cycloalkyl group may be optionally substituted, as defined below, e.g. as exemplified below.
- C x-y alkenyl where x and y are any integers means an unsaturated aliphatic hydrocarbon group having from x to y carbon atoms. The unsaturation may include one or more double bond, one or more triple bond or any combination thereof.
- the alkenyl group may be straight or branched. "Branched" means that at least one carbon branch point is present in the group.
- Any double bond may, independently of any other double bond in the group, be in either the (E) or the (Z) configuration.
- the alkenyl group is preferably a lower alkenyl group.
- “Lower alkenyl” means an alkenyl group, straight or branched, having 2 to about 6 carbon atoms, e.g. 2, 3, 4, 5 or 6 carbon atoms.
- alkenyl groups include ethenyl, n-propenyl, /-propenyl, but-1-en-l-yl, but-2- en-l-yl, but-3-en-l-yl, pent-1-en-l-yl, pent-2-en-l-yl, pent-3-en-l-yl, pent-4-en-l-yl, pent-l-en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-l-en-3-yl, pent-2- en-3-yl, pentadien-1-yl, pentadien-2-yl, pentadien-3-yl.
- the alkenyl group may be optionally substituted, e.g. as exemplified below.
- Aryl means any aromatic group, preferably having up to about 12 carbon atoms, e.g. 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
- the aryl group may comprise one, two or more rings. Where two or more rings are present they may if desired be fused.
- the ring system of the aryl group may include one or more heteroatoms such as, for example, O, N and S.
- the aryl group preferably comprises one or more phenyl ring.
- exemplary aryl groups include phenyl, naphthyl, biphenyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, indolyl and purinyl.
- the aryl group may be optionally substituted, e.g. as exemplified below.
- Alkylidene means any alkyl or alkenyl group linked to the remainder of the molecule via a double bond.
- alkyl and alkenyl groups apply with appropriate modification also to alkylidene groups.
- Cycloalkylidene means any cycloalkyl group linked to the remainder of the molecule via a double bond.
- the definitions and illustrations provided herein for cycloalkyl groups apply with appropriate modification also to cycloalkylidene groups.
- organic ring containing x chain ring atoms and optionally y ring heteroatoms where x and y are integers means any cyclic organic group consisting of a ring of x carbon atoms and optionally y heteroatoms.
- the ring may comprise one or more branch point.
- the bonds between the atoms of the chain may be selected from single, double or triple bonds. At least some of the atoms of the chain will also be linked to side hydrogen atoms unless the chain is substituted or branched in such a way that side hydrogen atoms are not possible at that location.
- variable configurations of any double bond may, independently of any other double bond in the chain, be in either the (E) or the (Z) configuration.
- the organic chain is preferably a saturated or unsaturated alkylene group containing 2, 3, 4, 5 or 6 carbon atoms.
- Exemplary organic chains include ethylene, n-propylene, /-propylene, ⁇ i-butylene, s- butylene, n-pentylene.
- Optionally substituted as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different, preferably one or more substituents which individually have a size which is small in relation to the parent group being substituted (e.g. less than about 20% of the largest molecular dimension).
- a group cannot be a substituent of its own kind if it would thereby form a group of that kind which would then fall outside the definition of the compounds of formulae I and II (or Ia and Ha) (e.g. an alkyl group cannot be a substituent of another alkyl group so that an alkyl group having too many carbon atoms would result).
- Suitable substituents include halo (e.g. fluoro, chloro, bromo or iodo), Cj -6 alkyl, -C 2-6 cycloalkyl, hydroxy, C 1-6 alkoxy, C 2-6 alkoxy, amino, nitro, Ci -6 alkylamino, C 2-6 alkenylamino, di-C] -6 alkylamino, Ci -6 acylamino, di-Ci- 6 acylamino, C 6-I2 aryl, C 6-I2 arylamino, di-C 6- i 2 arylamino, C 6-I2 aroylamino, di-C 6- i 2 aroylamino, C 6-I2 arylamido, carboxy, Ci -6 alkoxycarbonyl or (C 6- I 2 ar)(Ci.io alkoxy)carbonyl, carbamoyl, or any of the above in which a hydrocarbyl moiety is itself substituted by halo
- acyl means an H-CO- or Ci -10 alkyl-CO- group wherein the alkyl group is as defined below.
- Preferred acyls contain a lower alkyl.
- Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl and butanoyl;
- Exemplary substituted alkyl groups include mono- or poly- aryl-substituted alkyl groups such as phenylmethyl, naphthylmethyl, diphenylmethyl, phenylethyl, naphthylethyl, diphenyl ethyl, phenylpropyl, naphthylpropyl, diphenylpropyl.
- Exemplary substituted cycloalkyl groups include mono- or poly- alkyl-substituted cycloalkyl groups such as 1 -methylcyclopropyl, 1-methylcyclobutyl, 1- methylcyclopentyl, 1 -methylcyclohexyl, 2-methylcyclopropyl, 2-methylcyclobutyl, 2- methylcyclopentyl, 2-methylcyclohexyl.
- Exemplary substituted aryl groups include, at any substitution position or combination of positions, C) -6 alkoxyphenyl such as methoxyphenyl, hydroxyphenyl,
- Ci -6 alkoxy)(hydroxy)phenyl such as methoxy-hydroxyphenyl
- Ci -6 alkylphenyl such as methylphenyl
- Ci. 6 alkyl (hydroxy)phenyl such as methyl -hydroxyphenyl
- monohalophenyl such as monofluorophenyl or monochlorophenyl
- dihalophenyl such as dichlorophenyl or chlorofluorophenyl
- carboxyphenyl Ci -6 alkoxycarbonylphenyl such as methoxycarbonylphenyl.
- branch point refers to a carbon atom or heteroatom which is connected directly to 3 or 4 other atoms forming part of the skeleton of the compound, particularly carbon atoms or skeletal heteroatoms.
- branch points are denoted by the letter C: 2-methyl-but-1-yl
- a branch point which is at a carbon atom is referred to herein as a carbon branch point.
- branch point is denoted by the letter N (nitrogen)
- a branch point which is at a heteroatom is referred to herein as a heteroatom branch point.
- an atom is considered to form part of the compound (i.e. be "skeletal") if it itself links directly or indirectly to one or more carbon containing moieties.
- hydrogen atoms or carbon-free moieties are not considered to form part of the skeleton of the compound.
- any optionally substituted alkyl or optionally substituted alkenyl for R 3 must have a branch point at one or more of the ⁇ and ⁇ positions counted from the carbonyl group to which R 3 is attached does not exclude that other branch points may exist in the molecule or that more than one ⁇ branch point may exist in the molecule, optionally with or without an ⁇ branch point.
- Ri is selected from hydrogen and optionally substituted C] -I0 alkyl
- R 2 is selected from hydrogen and optionally substituted Ci -I0 alkyl
- R 3 is selected from optionally substituted C MO alkyl, optionally substituted C 3-10 cycloalkyl and optionally substituted aryl;
- R 4 is hydroxyl or optionally substituted Ci -4 alkoxy
- R 5 is hydroxyl or optionally substituted Ci -4 alkoxy
- R 6 is hydrogen.
- Ri is selected from hydrogen, unsubstituted Ci -6 alkyl and phenyl-substituted Cj -6 alkyl;
- R 2 is selected from hydrogen, unsubstituted Ci -6 alkyl and phenyl-substituted Ci -6 alkyl;
- R 3 is selected from unsubstituted Ci -6 alkyl, (C 3-6 cycloalkyl)- substituted Cj -6 alkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted phenyl, mono or poly phenyl-substituted phenyl, (Ci- 6 alkyl)- substituted phenyl, (C] -6 alkoxy)-substituted phenyl, mono or poly halo-substituted phenyl where polyhalo substituents may be the same or different, hydroxyl-substituted phenyl, (Ci -6 alkoxy)(hydroxyl)-disubstituted phenyl, (Ci -6 alkoxy) carbonyl-substituted phenyl and unsubstituted naphthyl; R 4 is unsubstituted methoxy;
- R 5 is hydroxyl; and R 6 is hydrogen.
- R 4 may be meta to the dioxo-containing chain and R 5 may be para to the dioxo- containing chain.
- halo groups in the mono or poly halo-substituted phenyl for R 3 may be selected from fluoro, chloro and iodo. Wherein R 3 a phenyl or naphthyl moiety is present, it may be linked at any carbon atom of the moiety and any substituent(s) may be at any other carbon atom(s) of the moiety.
- “Physiologically acceptable” means it is, within the scope of sound medical and veterinary judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. "Physiologically unacceptable” means it is not suitable for such use.
- Salt means the inorganic and organic acid addition salts, and base addition salts, of any compounds of the present invention where such salt formation is possible. These salts can be prepared in situ during the final isolation and purification of the compounds.
- acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. See, for example S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 66: p.1-19 (1977) which is incorporated herein by reference.
- Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed.
- Base addition salts include pharmaceutically acceptable metal and amine salts.
- Suitable acid addition salts are those formed with acids selected from hydrochloric, sulphuric, phosphoric and nitric acids.
- suitable base addition salts are those formed with bases selected from sodium hydroxide, potassium hydroxide and ammonium hydroxide.
- “Complex” means the chemical entity resulting from the non-covalent coordination of any suitable element, ion or compound with moieties of the compounds of general formulae I and II (or Ia and Ha) to provide a stable chemical entity.
- the compounds of general formulae I and II are ⁇ - diketones (or their tautomers), which are well known to complex with transition metal or alkaline earth metal atoms, ions and compounds.
- the complexes may further include one or more co-ligand, preferably containing an electron donating atom or group such as an oxygen or nitrogen atom.
- co-ligands can readily be selected from known chelating agents for the metals in question, and may include, for example, water and organic heterocycles containing nitrogen atoms.
- such complexes may be formed in generally known manner between the compounds of formulae I and II and the following metals: copper, nickel, iron, magnesium, calcium, strontium or barium, optionally with one or more suitable co- ligand.
- Prodrug means any compound that is rapidly transformed in vivo to yield the parent compound of the formula I by cleavage of one or more physiologically labile leaving group or by operation of a physiologically initiated chemical reaction, for example by hydrolysis in the gastrointestinal tract or in blood.
- certain functional groups can be pre-reacted with a carboxyl or other group to become chemically part of a prodrug form of the compound of formula I or II, and such groups may after administration to the patient be rapidly split off or transformed by metabolic processes in vivo (e.g. hydrolysis) to provide the compound of formula I or II in situ.
- a thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H.
- Protection refers to the use of protecting groups to protect reactive functional groups, for example hydroxyl, carboxy or carbonyl groups, where these are desired in the final product, to avoid unwanted participation in the reactions.
- the protecting group(s) will be removed after the reaction has been completed, to provide the final (“deprotected") compound.
- Conventional protecting groups may be introduced, removed and generally used in accordance with standard practice, for example see T.W. Green and P. G. M. Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991 ; J.F.W. McOmie in "Protective Groups in Organic Chemistry” Plenum Press, 1973.
- Me methyl
- Et ethyl
- Bn benzyl
- Ph phenyl
- Me methyl
- Napth 1-napthyl
- Ph phenyl
- the present invention thus enables and provides a method for treating or preventing hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain in a human or non-human animal.
- Such conditions include, for example, asthma, cough, pruritus, food intolerance, psoriasis, croup, irritable bowel syndrome, tinnitus, Meniere's disease, stress-induced ulceration or acetylsalicylic acid-induced ulceration, primary dysmenorrhea, pre-term labour, pre-term contractions, diarrhoea, gastrointestinal cramps, diverticular disease, achalasia, Hirschsprung's disease, gastro-oesophageal reflux disease, myotonic dystrophy, gallstone disease, constipation, post-surgical gastroparesis syndrome, paralytic ileus, post-operative ileus, diabetic gastroparesis, bowel paresis, intestinal pseudo-obstruction, peripheral arterial diseases, Raynaud's syndrome and coronary artery spasm, angina, peripheral arterial disease, hypertension, hypotension, vascular paresis and other vascular disorders, bladder disorders, nausea, allergic rhinitis, allergic dermatiti
- the compounds are also useful, for example, in the maintenance of normal gut function, as a calmative for the gut, to maintain normal breathing, to ease motion sickness and vertigo, to soothe sore throats and coughs, to ease nausea and vomiting, as an aid to maintain normal digestion, to ease upset stomachs, to warm hands and feet, to aid normal menstruation, to maintain normal blood pressure, to normalise bowel movement, to maintain a healthy immune system, to aid in the recovery from colds and flu, as a decongestant, to soothe headaches, to relieve muscle soreness, to ease mild aches and pains, to provide relief from toothache, to provide relief from mouth ulcers, to maintain healthy joints, to help limit cellulite occurrence and as an aid to weight loss.
- the active agent according to the present invention may be administered in the form of a composition comprising the active agent and any suitable additional component.
- the composition may, for example, be a pharmaceutical composition (medicament).
- the composition may alternatively, for example, be a foodstuff, food supplement, beverage or beverage supplement.
- the composition is preferably adapted for oral administration, although all other administration routes are possible too, particularly, inhalation, parenteral (e.g. injection, implantation or infusion), topical, transdermal, rectal and vaginal.
- composition in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers.
- the composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms.
- compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.
- Techniques and formulations generally may be found in Remington, The Science and Practice of Pharmacy, Mack Publishing Co., Easton, PA, latest edition.
- Solid compositions preferably contain from 5 or 10 to about 70 percent by weight of the active ingredient.
- Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
- Liquid form preparations include solutions, suspensions, and emulsions.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colourants, flavours, stabilizing and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
- liquid forms include solutions, suspensions, and emulsions.
- These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternately, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon, or other volumetric container or apparatus. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition.
- the solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavourings, colourants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.
- the liquid utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol, and the like as well as mixtures thereof. Naturally, the liquid utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
- the terms "foodstuff, "food supplement”, “beverage” and “beverage supplement” used herein have the normal meanings for those terms, and are not restricted to pharmaceutical preparations.
- Other composition forms are also included within the present invention. These may, for example, include pure or substantially pure compound as such, a foodstuff precursor such as a rehydratable powder or a beverage precursor such as a powder dispersible in water, milk or
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with the smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
- the daily dose range may be from about 10 ⁇ g to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 ⁇ g to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 ⁇ g to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 ⁇ g to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 ⁇ g to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 ⁇ g to about 3 mg per kg of body weight of a human and non-human animal.
- the dosage may conveniently be between about 0.1 mg and about 2 g per day, for example between about 0.1 mg and about 1 g per day, preferably between about 1 mg and about 200 mg per day according to the particular application and the potency of the active ingredient.
- compositions can also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal antiinflammatory drugs (NSAIDs), peripheral analgesic agents such as diflunisal and the like.
- active ingredients such as cyclooxygenase inhibitors, non-steroidal antiinflammatory drugs (NSAIDs), peripheral analgesic agents such as diflunisal and the like.
- the weight ratio of the compound of the formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
- the weight ratio of the compound of the formula I to the NSAID will generally range from about 1000:1 to about 1 : 1000, preferably about 200:1 to about 1 :200.
- compositions comprising the formula I compounds may also contain, as the second active ingredient, antihistamine agents such as cetirizine, diphenhydrinate, chlorpheniramine, promethazine and the like.
- antihistamine agents such as cetirizine, diphenhydrinate, chlorpheniramine, promethazine and the like.
- they may include prostaglandin antagonists such as those disclosed in European Patent Application 1 1 ,067 or thromboxane antagonists such as those disclosed in U.S. Pat. No. 4,237,160.
- They may also contain histidine decarboxylase inhibitors such as ⁇ - fluoromethylhistidine, described in U.S. Pat. No. 4,325,961.
- the compounds of the formula I may also be advantageously combined with an H 1 or H 2 -receptor antagonist, such as for instance cimetidine, ranitidine, famotidine, temelastine, acrivastine, loratadine, cetrizine, tazifylline, azelastine, aminothiadiazoles disclosed in EP 81102976.8 and like compounds, such as those disclosed in U.S. Pat. Nos. 4,283,408; 4,362,736; 4,394,508 and European Patent Application No. 40,696.
- the pharmaceutical compositions may also contain a K + /H + ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.
- Modulation of the TRPVl receptor and/or modulation of smooth muscle tone and/or anti-remodelling and/or anti-inflammatory activity may be therapeutic (including prophylactic) or non-therapeutic.
- a therapeutic use of the method will typically comprise the treatment or prevention of a disease or disorder from which the human or non human animal is suffering or to which it is susceptible, such as, for example, hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain.
- the TRPVl receptor is a modestly calcium-selective ion channel and a member of the transient receptor potential family of ion channels.
- the TRPVl receptor functions as a polymodal nociceptor sensitive to signals such as heat, lipoxygenase products and protons, and exogenous compounds such as capsaicin. It is known that modulation (agonist and antagonist) of the TRPVl receptor has been exploited to treat a variety of conditions such as certain types of pain (Robbins, W., Clin. J. Pain, S86-S89, 16(2 Suppl), (2000); Rami, H. K. et al, DrugDiscov. Today, 97-104, 1(1), (2004)).
- the compounds described herein demonstrate effectiveness as good controllers of hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain in that they show modulation of some or all of the TRPVl receptor, modulation of smooth muscle tone, inhibition of tissue remodelling, and inhibition of inflammatory mediator production.
- This group of compounds represents a new series of agents which have potential therapeutic benefit in treating or preventing hypersensitivity, smooth muscle disorders, spasmodic conditions, allergic conditions, inflammatory conditions and/or pain in a human or non-human animal.
- the preparative method of the eighth aspect of the present invention involves selectively reducing the aliphatic carbon-carbon double bond in a compound of general formula II, to obtain the compound of general formula I.
- the process is essentially a selective catalytic reduction of the 5-(4-hydroxy-3- methoxyphenyl)-l ,3-dioxoalkenyl compound of formula II in the presence of hydrogen gas using either palladium on carbon or Raney nickel as catalyst.
- the reaction is preferably carried out in a suitable organic solvent such as a mixture of toluene and pyridine.
- the preparative method of the ninth aspect of the present invention preferably includes condensing a benzaldehyde compound of general formula III as defined above with a ⁇ - diketone compound of general formula IV as defined above, in the presence of a chelating agent to deactivate the carbon between the two carbonyl groups in formula IV in favour of the terminal methyl carbon atom, to obtain the compound of general formula II.
- the chelating agent may for example, be a boron or transition metal Lewis acid, by which is meant a chemical compound comprised of a central boron or transition metal atom and appropriate ligands, such that the central boron or metal atom can form chemical complexes by interaction with electron-rich atoms of other compounds.
- Suitable solvents for the reaction include alkanes, cycloalkanes, ethers, cyclic ethers such as tetrahydrofuran, aromatic hydrocarbons, and halocarbons such as chloroform, dichloromethane or ethylene dichloride.
- Co-ligands such as organic amines may also be present, as described in more detail in the US Patent mentioned above.
- compounds of formulae I or II which have an alkyl functionality at the central carbon between the two ketone groups or their tautomers can be produced by alkylation of the corresponding unalkylated compound (Reaction Scheme 3).
- the starting material e.g. compound 68 as shown in Reaction Scheme 3
- NaH sodium hydride
- TMSCl trimethylsilyl chloride
- THF tetrahydrofuran
- an alkylating agent such as an alkyl iodide (e.g. methyl iodide (MeI) as shown in Reaction Scheme 3) is used in the presence of a base such as potassium carbonate.
- the starting material 68 can, of course, also be selectively reduced analogously to the final stage of Reaction scheme 1. This option is also shown in Reaction Scheme 3, for completeness.
- the compounds of general formulae I or II which have an alkyl functionality at the central carbon between the two ketone groups (or their tautomers) can alternatively be produced by reaction of, for example, a 5-(4-hydroxy-3-methoxyphenyl)pent-4-en-3-one with the imidazole derivative of a carboxylic acid in the presence of base, analogously to the preparation of the compounds of general formula II as illustrated in Reaction Scheme 1.
- the compound thus prepared may be recovered from the reaction mixture by conventional means.
- FIG. 1 shows the results of the experimental work reported in Example 68.
- the effects of compound 2, compound 32, budesonide and montelukast on enhanced pause (penH) in the test animals is shown.
- n-butylamine (1.10 g, 0.015 mol) in dry ethyl acetate (5 ml) was then added dropwise over 15 min. Stirring was continued at 40°C for 24 h. Dilute hydrochloric acid (15 ml of 1.2 M) was added and the mixture rapidly stirred at 40°C for 1 h, cooled to room temperature and filtered. The solid was washed with ethyl acetate (50 ml), adding the washings to filtrate. The aqueous layer was separated and extracted with ethyl acetate (100 ml).
- 1,1-Carbonyldiimidazole (1.69 g, 10.4 mmol) was added to a stirred solution of 3,3- dimethylbutyric acid (1.32 ml, 10.4 mmol) in dry THF (50 ml) under a nitrogen atmosphere. Stirring was continued for 18 h.
- Solution A was then added dropwise over 30 min to solution B with ice cooling under a nitrogen atmosphere. Stirring was continued at low temperature for 3 h, and the solution then allowed to warm to room temperature slowly overnight. Ethyl acetate (50 ml) and dilute hydrochloric acid (50 ml, 2 M) were added and the mixture stirred for 10 min. The separated aqueous layer was extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts dried (Na 2 SO 4 ( ⁇ )), filtered and evaporated in vacuo to leave an orange oily solid.
- Toluene (10 ml) and pyridine (0.14 ml) were added to (E)-5-(4-(2-boc-aminoethoxy)-3- methoxyphenyl)-l-phenylpent-4-ene-l,3-dione (275 mg, 0.63 mmol) and 10% palladium on carbon (14 mg) and subjected to a balloon pressure of hydrogen with stirring for 18 h.
- the suspension was filtered through a pad of silica gel and flushed through with ethyl acetate.
- Wistar derived male rats (275 ⁇ 25 g) were suppressed by CO 2 overexposure.
- the vas deferens was removed, placed in Krebs solution, pH 7.4 (composition in g/1: NaCl 6.89, KCl 0.35, CaCl 2 0.277, KH 2 PO 4 0.163, MgSO 4 -7H 2 O 0.296, NaHCO 3 2.1 glucose 1.8) and excess fat and connective tissue removed.
- the portion of the vas deferens closest to the prostate was cut in half and each half was placed under 1 g tension in a 10 ml bath containing Krebs solution at 32°C.
- the tissue was contracted by electrical field stimulation (EFS; 60% of maximum stimulation, 0.015 Hz, 0.5 ms in duration) and contractile responses were measured.
- EFS electrical field stimulation
- DRG dorsal root ganglia
- Rat DRG sensory neurones were cultured by modification of a previously described method (Hall, A. K. et al, J. Neuroscl, 2775-2784, 17(8), (1997)).
- the culture used for this experiment contained sensory neurones, Schwann cells and fibroblasts.
- the effects of test compounds on CGRP release in the absence and presence of capsaicin were examined.
- the compounds 1, 2, 4, 6, 7, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 69, 71, 74, 76, 80, 81, 82, 83, 84 and 3- gingerdione were tested.
- the mature neurones were exposed to: (a) Vehicle (DMSO, 0.1%), (b) Test compounds (3 and 30 ⁇ M), (c) Capsaicin (1 ⁇ M), (d) Test compounds (3 and 30 ⁇ M) and capsaicin (1 ⁇ M).
- All the compounds modulated CGRP release, either by increasing CGRP release or inhibiting capsaicin-induced CGRP release.
- composition in g/1 NaCl 6.89, KCl 0.35, CaCl 2 0.277, KH 2 PO 4 0.163, MgSO 4 -7H 2 O 0.296, NaHCO 3 2.1 glucose 1.8.
- the solution was kept at 32°C and gassed with O 2 (95%)-CO 2 (5%) to maintain pH at 7.4.
- Mechanical activity was recorded by means of isotonic transducers. A resting tension of 1 g was applied to muscle strips before being equilibrated for 1 h, prior to test compound addition. Each preparation was washed twice at 15 min intervals during the equilibration.
- Histamine (1.7 ⁇ M; approximately EC 60-70 ) or 5-hydroxytryptamine (5-HT, 2.6 ⁇ M; approximately EC 60-70 ) was applied for 5 min and the amplitude of the contraction recorded.
- the histamine or 5-HT was then washed out until the ileal tissue returned to baseline.
- Five min after returning to baseline test compound (3 and 30 ⁇ M) was applied and the amplitude of the contraction (if any) was recorded.
- histamine or 5-HT was re-applied and the inhibition of the response was recorded.
- a human foetal lung fibroblast cell line (HFLl cells; ATCC accession number CCl-153) was used in this assay.
- the cells were cultured in medium containing a low level of foetal bovine serum (FBS; 0.1%) for 24 h. After 24 h of culturing the medium was changed to: (a) Control medium (medium containing 10% FBS, 1% phosphate saline and 0.5 mM L-glutamine), (b) Control medium and transforming growth factor beta (TGF ⁇ ; 10 ng/ml), (c) Control medium and TGF ⁇ and test compounds (3 and 30 ⁇ M). The medium was collected after 24 h and the total mRNA extracted in Tri-reagent.
- Control medium medium containing 10% FBS, 1% phosphate saline and 0.5 mM L-glutamine
- TGF ⁇ transforming growth factor beta
- test compounds 3 and 30 ⁇ M
- ⁇ -smooth muscle actin ⁇ -smooth muscle actin
- rtRT-PCR real-time reverse transcription-polymerase chain reaction
- GADPH liver glyceraldehydes 3-phosphate dehydrogenase
- test compounds displayed a range of anti-remodelling activity at 3 and 30 ⁇ M.
- Human diploid lung fibroblasts (WI-38 cells) were incubated overnight in the presence of IL-I ⁇ (1 nM) and test compound (3 and 30 ⁇ M) in modified Eagle medium at pH 7.3 containing foetal bovine serum (10%) at 37°C. The supernatant was assayed by radioimmunoassay for released PGE 2 and the inhibition OfPGE 2 by test compound calculated (Table 10). The viability of the cells was then assessed by washing with Roswell Park Memorial Institute medium and adding Alamar Blue reagent before being incubated at 37 °C for 4 h. Living cells take up Alamar Blue and emit fluorescence when excited. Fluorescence intensity was measured using a SpectroFluor Plus plate reader with excitation at 530 nm and emission at 590 run (Table 10).
- test compounds displayed a range of anti-inflammatory activity, without altering cell viability, in WI-38 cells at 3 and 30 ⁇ M.
- Human peripheral blood mononuclear leukocytes were isolated using a Ficoll- Paque density gradient. Human peripheral blood mononuclear leukocytes (5x10 6 cells) were incubated with A23187 (30 ⁇ M), a divalent cation ionophore used to initiate the biosynthesis of arachidonic acid, and with vehicle (0.1% DMSO) or test compound (3 and 30 ⁇ M) in Hank's balanced salt solution (HBBS) buffer, pH 7.4 at 37°C for 15 min. The PBML solution was neutralised with NaOH (1 N) and centrifuged at 1000 g for 10 min and the supernatant collected.
- HBBS Hank's balanced salt solution
- LTB 4 leukotriene B 4
- concentration of leukotriene B 4 (LTB 4 ) in the supernatant was measured using an enzyme immunoassay kit (Assay Design Inc.).
- Test compounds displayed a range of anti-inflammatory activity in human PBMLs at 3 and 30 ⁇ M.
- Dunkin-Hartley guinea pigs were sensitised to ovalbumin using two interperitoneal injections of ovalbumin (20 ⁇ g) in Al(OH) 3 gel (1.65 mg) on days 1 and 11. On day 25 compound 2 was administered by oral gavage (30 mg/kg/day) for 7 days. On day 31, approximately 2 h after the last administration of compound 2, each guinea pig was anaesthetised with urethane (1750 mg/kg, i.p.) and artificially ventilated via a tracheal cannula connected to a Fleisch pneumotachograph (size 00) and a differential pressure transducer ( ⁇ 2 cm H 2 O; PT5, Grass Astro-Med Inc., USA).
- Total pulmonary resistance was calculated online by integration of flow, tidal volume and transpulmonary pressure. Pulmonary resistance was recorded for approximately 5 min before ovalbumin (300 ⁇ g/ml, i.v) challenge and for approximately 15 min following ovalbumin challenge and was recorded in real time using a computer data acquisition system (Po-ne-Mah, USA).
- mice (BALB/c from Harlan-Olac) were sensitised to ovalbumin using two interperitoneal injections of ovalbumin (10 ⁇ g) and alum (200 ⁇ l) on day 1 and 14 followed by a 20 min, daily exposure to a ovalbumin aerosol (5%) on days 19-23 and then a thrice weekly 20 min, exposure to a ovalbumin aerosol (5%) on days 24-55.
- compound 2 (3 mg/kg/day)
- compound 32 (30 mg/kg/day)
- mice were placed in BUXCO four chamber whole body plethysmographs and breathing-associated pressure changes were recorded which were then used to calculate enhanced pause (penH), a measurement of airways resistance, in response to a methacholine challenge.
- penH enhanced pause
- mice On day 55 the mice were killed and brochoalveolar lavage (BAL) fluid was collected and cytospins prepared to measure eosinophil infiltration. In addition, concentrations of interleukin-4 (IL-4) and interleukin-13 (IL-13) were measured in the BAL fluid.
- BAL brochoalveolar lavage
- lung samples were taken, examined by a histopathologist and scored using a grading system to describe the degree of lung remodelling.
- Compound 2, compound 32, budesonide and montelukast reduced eosinophil infiltration into the lung and IL- 13 concentrations in the BAL.
- compound 32, budenoside and montelukast reduced IL-4 concentration in the BAL.
- compound 2, compound 32, budesonide and montelukast reduced the amount of lung remodelling (Table 12).
- Table 12 Summary of the effect of compounds 2, 32, budesonide and montclukast on penH, eosinophil infiltration, IL-4 concentration, IL- 13 concentration and lung remodelling in ovalbumin-sensitised mice
Abstract
Description
Claims
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Also Published As
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GB0713117D0 (en) | 2007-08-15 |
WO2008003978A3 (en) | 2008-12-31 |
UY30468A1 (en) | 2008-05-31 |
GB2440034B (en) | 2011-02-16 |
PE20080274A1 (en) | 2008-04-10 |
GB2440034A (en) | 2008-01-16 |
JP2009544577A (en) | 2009-12-17 |
AU2007270951B2 (en) | 2013-04-11 |
US20080045591A1 (en) | 2008-02-21 |
JP5397903B2 (en) | 2014-01-22 |
CL2007001976A1 (en) | 2008-05-16 |
EP2046311A2 (en) | 2009-04-15 |
TW200819122A (en) | 2008-05-01 |
US7589123B2 (en) | 2009-09-15 |
CN101511350A (en) | 2009-08-19 |
GB0613518D0 (en) | 2006-08-16 |
CA2660182A1 (en) | 2008-01-10 |
HK1114600A1 (en) | 2008-11-07 |
AR061955A1 (en) | 2008-08-10 |
MX2009000283A (en) | 2009-01-26 |
AU2007270951A1 (en) | 2008-01-10 |
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