WO2014173957A2 - Composé - Google Patents

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WO2014173957A2
WO2014173957A2 PCT/EP2014/058248 EP2014058248W WO2014173957A2 WO 2014173957 A2 WO2014173957 A2 WO 2014173957A2 EP 2014058248 W EP2014058248 W EP 2014058248W WO 2014173957 A2 WO2014173957 A2 WO 2014173957A2
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compound
formula
ion
group
salt
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WO2014173957A3 (fr
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Nebojša SIMIC
Berit Johansen
Aleksandar Igic
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • This invention relates to a class of new compounds which have been found to exhibit ant i-inflammatory properties.
  • the invention also relates to a series of known compounds which have been surprisingly found to possess anti- inflammatory properties by affecting the activ ity PL .42 enzyme in the early stage of the inflammat ion cascade.
  • the inv ent ion also relates to a pharmaceutical composit ion comprising the compounds of the invention as well as the uses thereof in the treatment of inflammation and conditions associated with inflammation.
  • berberine is well known for its anti-inflammatory activity. It is present in a number of plants such as Hydrastis canadenis, Berberis vulgaris, Barberis aristata and Rhizoma coptidis.
  • quercetin belongs to tlavonoid class of compounds and is also anti- inflammatory in nature. It can be isolated from many plants, for instance Helminthostachys zeylanica. Some other classes of compounds showing ant i-in flammatory activ ity are terpenoids, phenols, polyphenols and some sulphur contai ning compounds.
  • the present inventors have developed a class of new ant i inflammatory drugs with an improved mode of act ion compared to exist ing drugs.
  • the compounds of the inv ent ion are inhibitors of cPLA2.
  • Most non-steroidal ant i- inflammatory drugs (NSAIDs) act on specific enzymes late i n the in flammat ion reaction pathway (e.g. COX-inhibitors ).
  • the problem with acting at such a late stage in the process is that it causes an imbalanced inflammation reduction due to over- activation of parallel pathways ( Figure 1).
  • Such an imbalance can cause severe side- effects such as heart attack, stroke and liver failure.
  • the use of existing NSAIDs therefore, has been notoriously linked w ith unwanted and serious side-effects.
  • the NSAID Rofecoxib (sold under the name Vioxx, Merck) was shown to give serious cardiovascular problems in patients having been prescribed the drug in the period 1999-2004 (between 88 000 and 139 000 heart attacks in US only, 30 to 40 % of which were probably fatal ). The drug was withdrawn from the market in 2004. These deaths could have been prevented if the drug had targeted enzymes earlier in the inflammation process.
  • the compounds of the presence invention affect ( reduce ) the activ ity of PLA2 enzyme although a complete mechanism and exact point of action has yet to be elucidated.
  • the core inv ention is the use of the compounds of the inv ention to interrupt the anti-inflammatory cascade by inhibiting PL A .
  • the inv ent ion relates to the characterisation of a new anti-inflammatory compound from a biological source and with that knowledge the design of a new class o f a n t i - i n 11 a m m a t o ry agents.
  • the preferred compound of the present invention derives from Sclerochloa dura which has prev iously been ident ified as hav ing medicinal uses.
  • This plant has a traditional use in smal l communities in South-East Guatemala for treatment of menstrual disorders characterised by excessive bleeding and pai n.
  • Oral intake of a boiled water extract of the plant allegedly results in pain relief and significantly reduces bleeding.
  • the present inventors have identified a series of chemical compounds present in S. dura, which have anti-inflammatory properties and based on this knowledge designed the claimed subject matter to achieve a new class of anti ⁇ inflammatory drugs with an improved mode of act ion and fewer side effects.
  • the PL A.> enzymes hydro Iyze fatty acids such as A A from the sn-2 ester bond of membrane glycerophospho l ipids. These enzymes are sorted into five main categories, namely cytosolic PLA >s (CPLA2), secretory PLA?s (SPLA2), C ' - independent PLAis (1PLA2), PAF acetyl hydrolases ( PAF-AH ). and lysosomal PLA2S. Apart fr m their role in normal physiological functions, the di fferent isotypes are implicated in a variety of diseases and thus there is currently great interest in the development of inhibitors that target specific PL A ? subtypes.
  • CPLA2 cytosolic PLA >s
  • SPLA2 secretory PLA?s
  • PAF-AH PAF acetyl hydrolases
  • lysosomal PLA2S Apart fr m their role in normal physiological functions, the di fferent isotypes are implicated in a variety of diseases
  • the ⁇ 6 fatty acid (AA) is the substrate for eicosanoids such as prostaglandins and leukotrienes, which are potent lipid mediators of inflammation.
  • eicosanoids such as prostaglandins and leukotrienes
  • cPLAi group IVa cPLA.>-I Va
  • P LA > P LA > with a preference for AA in the sn-2 position, it is a central enzyme of eicosanoid production and thus considered to be a main
  • Pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interlcukin 1 ⁇ ( I L- 1 ⁇ )
  • TNF tumor necrosis factor
  • I L- 1 ⁇ interlcukin 1 ⁇
  • cPLAi-I Va Pro-inflammatory cytokines
  • Several studies using knockout mice or cPLA >-I Va inhibitors have highlighted the potential for targeting this enzyme in order to quench the inflammation and ameliorate disease.
  • the S. dura derived compounds that inhibit AA release exert an overall anti- inflammatory action.
  • the present inventors hav e isolated and elucidated compounds from
  • Sclerochloa dura The compounds expressed ant i-inflammatory activity by showing the inhibition of cPLA? in an in vitro AA release assay.
  • the invention further relates to the use of the information gleaned to devise a new group of anti- inflammatory agents as well as the possible organic synthesis of these molecules.
  • the invention provides a compound of formula
  • R is a C9-23 polyunsaturated alkenyl group
  • X is SO3R3, SO2R3, PO3R3, PO2R3, COCHai 3 , or COOR 3 ;
  • R] and R ? are each independently H, a CI -6 alkyi group optionally subst ituted with OH , C6- 10 aryl group optionally subst ituted with OH , C7- 12 arylalkyl group optional ly subst ituted with OH , COC 1 -6 alkyl group optionally siibst ituted with OH, COC6- 10 aryl group optionally substituted with OH, COC7- 12 arylalkyl. group optionally substituted with OH , or COO Iah group;
  • hal is halide, preferably F
  • each R 3 is independently H . Cl -6 alkyl, C6- 10 aryl, r C7- 12arylalkyi; or a salt thereof.
  • each substituent in formula (I) must bind a separate carbon atom in the six membered ring. It is not therefore possible for two substituents to bind the same carbon atom. The substituents can otherwise attach in any order.
  • the compound of formula (I) is a compound of formula (V)
  • each R.4 is H, OH, OR 3 , Cl-6alkyl, C6-10 aryl, C7- 12 aryialkyl or the group:
  • p 0-3;
  • n 1 to 3;
  • w 0 to 2;
  • R5 is a monosaccharide linked to the phenyl ring via a C-C bond or linked
  • R 6 is H, OH, CI -6 alkyl or OR 3 ;
  • R 7 is H or CI -6 alkyl; or salt thereof for use in the treatment f inflammation.
  • each Rs is H or a C I -6-aikyl
  • q is 0 to 3, such as 1 or 2;
  • each R 3 is as hereinbefore defined with at least one OR 3 group being OH; or a salt thereof; for use in the treatment of inflammation.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined and at least one carrier or excipient.
  • the invention provides a compound of formula (I) for use as a medicament.
  • the invention provides a compound of formula (I) for use in the treatment of inflammation.
  • the invention provides a compound of formula (I) to (IV) for use as an inhibitor of cPLA>.
  • the invent ion provides a compound of formula (I) to (IV) for use in the treatment of a clironic inflammatory disease such as acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, and vasculitis.
  • a clironic inflammatory disease such as acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, and vasculitis.
  • V iewed fr m another aspect the invention provides a compound of formula (I) to (IV) for use in the treatment of hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and cancer.
  • the invention provides the use of a compound of formula (I) to (IV) as hereinbefore defined in the manufacture of a medicament for the treatment of inflammation.
  • the invent ion provides a method of treating inflammation comprising administering to a patient in need thereof, such as a human, a therapeutically effective amount of a compound of formula (I) to (IV) as hereinbefore defined.
  • This invention relates to a group of compounds which possess antiinflammatory properties.
  • the compounds are defined by formula (I) to (IV).
  • Compounds of formula (I) are new.
  • Compounds of formula (II) to (IV) are new for use in the treatment of inflammatory conditions, e.g. v ia the inhibit ion of cPLA 2 .
  • aryialkyl comprises an alky! port ion and an aryl portion.
  • I t may l ink to another group either via the aryl portion or a Iky I portion.
  • this term covers the groups tolyl and benzyl for example.
  • the monosaccharide is linked to the phenyl ring d irect ly either via a C-C l ink from a saccharide carbon ring atom to a phenyl ring atom. It can also be linked via a C-0 link at the 1 -posit ion of the saccharide direct ly to a carbon atom of the phenyl ring.
  • I n general is preferably H or Ci-6-alkyl, such as 0 1-4 a Iky I, especially methyl, especially H .
  • polyunsaturated long chain hydrocarbon subst ituent in the isolated molecule of formula (X) as defined herein is based on iinolenic acid (C I 8, 3 double bonds), it will be appreciated that other polyunsaturated long chain side groups would also be suitable.
  • R groups of the invention there are at least 3, such as 3 to 6 double bonds, preferably 3 to 5 double bonds. Such double bonds are preferably not conjugated.
  • the last double bond (i.e. furthest from the 6 membered sugar ring) is preferably 3 carbons from the end of the chain, i.e. the side chain is preferably based on an omega-3 type structure.
  • the total number of carbons present in group R may range from 1 1 to 23, preferably 13 to 21 , such as 15 to 19. Preferably, there are an even number of carbon atoms in the side chain R when you include the CO carbon atom in the calculat ion.
  • the use of a lino leic side chain is preferred (when including the CO carbon atom - i.e. 18 carbon atoms).
  • the sugar ring is preferably in the alpha configurat ion at the anomeric carbon. It should also be in the pyranose configuration. Ideally, the hexose is based on a 6-deoxyglucose mo iety and ideal ly it is a D-glucopyranosyl ring, it will be appreciated that the glucose moiety is 6-deoxy in that the group at the 6-position is not OH but a group X as defined herein.
  • I t is preferred i the -OCOR group lies equatorial ly on the ring. Ideal ly that group is opposite the O atom (i.e. on the para position to that O atom).
  • the C3 ⁇ 4X group lies equatorial ly on the ring.
  • the ring is based on glucose and all substituents other than the anomeric carbon are equatorial.
  • the X group is preferably SO3R3, S0 2 R 3 , COCHai 3 , or COOR 3 . More preferably it is SO 3 R 3 , especial ly SO 3 H.
  • the R 3 ⁇ 4 group in the definition of X is preferably H or Me.
  • Ri and R ? are H. Ideally both are H . If not IT, it is preferred if R] or R > is a C 1 -6 alkyl. such as a C 1 -4 alkyl especial ly methyl group.
  • OR 3 in the compounds of formula (I) is preferably OH. If not OH , OR 3 is preferably OC l-6 alkyl such as OMe.
  • the glycero l based subst ituent group ideal ly sits axially on the ring.
  • the compound of formula (I) is a compound of formula (V)
  • R, and R r R ⁇ are as hereinbefore defined; or a salt thereof, e.g. where SO3R3 is S0 3 H.
  • the compound of the invention is one of formula (IX)
  • the compound of formula (I) is a compound of formula (X) as herein described or a salt thereof:
  • the invention provides a compound of formula (II) (II)
  • each R.( is H , -6alkyl, C6- 10 aryl, C7- 12 arylal kyl or the group:
  • p 0-3;
  • n 1 to 3;
  • w 0 to 2;
  • R 9 is Ci-6 aikyl
  • Rj is a monosaccharide linked to the phenyl ring via a C-C bond or l inked v ia a C-0 bond at the 1 -position of the saccharide, and
  • Re is H, OH , CI -6 a Iky I or OR 3 ;
  • the saccharide employed in compounds of formula (II) as subst it uent R> is glucose or deoxy glucose. It may also be a 1 -deoxy
  • the saccharide may be bound to the phenyl of the bicyciic ring via the anomeric oxygen of the sugar or via a direct C-C link, preferably at the 1 -position of the ring.
  • a further preferred compound f formula (II) is therefore of formula (XI) or
  • the sugar is bound at the position adjacent the OH group (ortho) or meta to the OH group.
  • the subscript n is preferably 1 or 3.
  • the R.i group may independently be OH or OC' i /.a lkyl such as OMe.
  • the group R may also preferably represent:
  • each R is preferably H or CI -6 alkyl and p can be 1 or 2.
  • the invention also relates to a compound of formula
  • R ⁇ is H or C I -6 alky I; or salt thereof for use in the treatment of inflammation.
  • R ? groups are I I, preferably at least 3 R7 groups are H .
  • one of the R? groups on the Ph ring is CI -6 alkyl, ideally methyl.
  • the compound is:
  • the invention also prov ides a compound of formula (IV)
  • each R N is H or a ( ⁇ -6-alkyl
  • q is 0 to 3, such as 1 or 2;
  • each is as hereinbefore defined with at least one OR3 group being OH ; or a salt thereof; for use in the treatment of inflammation.
  • Preferred Rg groups arc C 1 -4 a Iky I groups, such as methyl.
  • Rio is preferably ethyl or especially methyl.
  • OR 3 groups in formula (IV) are OH, such as at least three groups OR s are OH . Ideally, all OR 3 groups are OH in formula (IV).
  • the hexose ring is again preferably based on glucose.
  • the compound is of formula (XVII)
  • I t is also possible however to synthesize the compounds of the invention, and in particular those of formula (I).
  • the compounds of formula (I) can be made synthetically using known protocols, in general, any synthesis of a compound of formula (X) and related molecules of formula (I) may start from the saccharide, e.g. glucose.
  • I ntroduction of the SO d l group at C-6 may be accomplished via conversion of the OH group to a good leaving group ( Br, CI, tosylate, mesylate, trifiate); reaction with thioacetate followed by oxidation.
  • glycerol substituent at C- l might involve an acetonide of glycerol.
  • the polyunsaturated fatty acid chain required is a readily available product which can be coupled to the sugar ring using know n chemistry with protection if required. Nucleophi!ic attack of the 3 -position hydroxyl group onto to an acid chloride modified fatty acid chain allows the side chain to be introduced.
  • Esterfieation of the 3-position-OH might occur via a mixed anhydride and there is also a set of methods which can be used on the linolenic acid directly. Possibly enzymatic react ions could have some benefit in offeri ng h igh
  • the specific compound of formula (X) can, however be iso lated from Sclerochloa dura (Linneaus) P Beauvois, also known as common hard grass.
  • the experimental section contains a detailed description of the isolation procedure.
  • a compound of formula (X) can be isolated from the aerial parts of the plant.
  • Compounds of formula (II) to (IV) are also isoiable from this plant.
  • Tlius viewed from another aspect the invention provides a process for the isolation of a compound of formula (X) comprising extracting said compound from Sclerochloa dur.
  • the compounds of the invention have surprisingly been found to hav e potential as anti-inflammatory agents. They have been found to be potent inhibitors of PL A.> in particular cPLA.> The compounds of the invention are therefore of use as possible therapies for chronic inflammatory condition that can generally be associated with PL.A> inhibition.
  • the compounds of the inv ention are able to reduce inflammation via inhibit ion of cPLA2 as opposed to some enzyme later in the inflammation reaction pathway.
  • Conditions of interest therefore include acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensit iv ities, inflammatory bowel disease , pelv ic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, and vasculitis.
  • the compounds of the invention may also have utility in the treatment of hay fev er, periodontitis, atherosclerosis, rheumatoid arthritis, and cancer.
  • the animal being treated will typically be a human although these compounds could also be used by a vet field to treat domest ic, farm or even wild animals.
  • the expression "pharmaceutically acceptable salts” refers to deriv atives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • the pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Any pharmaceutically acceptable salt can be used in the invention such as a
  • rifluoroacetatc sulphate, phosphate, acetate, fumarate, maleate, citrate, pyruvate, succinate, oxalate, methanesulphonate, p-toluenesulphonate, bisulphate, benzcncsulphonate, ethanesulphonatc, ma!onate.
  • naphthalene- 1 ,5-disu!f nate or naphthalene- 1 -( sulfonic acid)-5-suifonate edisylate (ethane- 1 ,2-d isulfonate or ethane- 1 -( sulfonic acid )-2-sulfonatc ), isethionate (2- hydroxyethylsulfonate), 2-mcsitylenesulphonate, 2-naphthalenesulphonate, D- mandelate or L-mandelate.
  • the salt may well be a base salt such as ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium.
  • a base salt such as ammonium salts such as tromethamine, meglumine, epolamine, etc.
  • metal salts such as sodium, potassium, calcium, zinc or magnesium.
  • treating or treatment is meant at least one of:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • I n general a skilled man can appreciate when "treatment" occurs.
  • I t is particularly preferred i f the compounds of the invention are used therapeutically, i.e. to treat a condit ion which has manifested rather than prophylactical ly. it may be that the compounds of the inv ention are more effect ive when used therapeutical ly than prophylact ically.
  • the compounds of the inv ent ion can be used on any animal subject, in particular a mammal and more particularly to a human or an an imal serving as a model for a disease ( e.g., mouse, monkey, etc.).
  • a “therapeutically effect ive amount” means the amount of a compound that, when adm inistered to an animal for treating a state, disorder or condit ion, is sufficient to effect such treatment.
  • the “therapeutically effect ive amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated and will be ultimately at the discretion of the attendant doctor.
  • Suitable dosage regimes can be prescribed by a physician.
  • a compound may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • carrier refers to a diluent, excipient, and/or v ehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier. Such pharmaceutical carriers arc well known in the art.
  • the pharmaceutical compositions may also comprise any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s) and so on.
  • the compositions can also contain other active components, e.g. other drugs for the treatment of inflammation.
  • compositions for use in accordance with the present invention may be in the form of oral, parenteral, transdermal, sublingual, topical, implant, nasal, or enterally administered (or other mucosally administered) suspensions, capsules or tablets, which may be formulated in conv entional manner using one or more pharmaceutically acceptable carriers r excipients.
  • the compositions of the invent ion could also be formulated as nanoparticie formulat ions.
  • compositions of the invent ion will preferably be applied topically. They may be in the form of ointments, gels, syrups, creams and so on. Any conventional topical formulation vehicle may be used.
  • compositions of the invention may contain from 0.01 to 99% weight of the activ e compound.
  • a therapeutically effect ive amount of the compound of the present invention can be determined by methods known in the art.
  • the therapeutically effective quant it ies will depend on the age and on the general physiological condit ion of the patient, the route of administration and the pharmaceutical formulation used.
  • the therapeutic doses will generally be between about 10 and 2000 mg/day and preferably between about 30 and 1500 mg/day. Other ranges may be used,
  • includi ng for example, 50-500 mg/day, 50-300 mg day, 100-200 mg/day.
  • Administration may be once a day. twice a day, or more often, and may be decreased during a maintenance phase of the disease or disorder, e.g. once every second or third day instead o every day or twice a day.
  • adm inistration frequency will depend on the cl inical signs, which confirm maintenance of the remission phase, with the reduction or absence of at least one or more preferably more than one clinical signs of the acute phase known to the person skil led in the art.
  • the compounds of the invention may be used to treat inflammation in combinat ion with other known pharmaceut icals f r said purpose and this forms a further aspect of the invention.
  • Other useful pharmaceuticals include
  • Figure 1 The inflammation process showing point of act ion f r both the compounds of the invent ion and most NSA lDs. Inhibit ion of one of the three parallel pathw ays late in the process gives an over-expression of the two other pathw ays, thus an unbalanced inhibit ion.
  • Figure 2 describes the IC5 0 v alue of compound 1.
  • Detection had been made by ELSD ( Sedex 75) and UV (Merck, 250nm) detectors.
  • ELSD Sedex 75
  • UV Merck, 250nm
  • Detection had been made by ELSD ( Sedex 75) and UV (Merck, 250nm) detectors.
  • For preparative HPLC Kromasil C18 250x50 mm 10 ⁇ was used as separation phase.
  • the human synovial sarcoma cell line SW982 was purchased from ATCC (UK).
  • Recombinant human I L- 1 [3 was purchased from Roche (UK); phosphate-buffered saline solution (PBS) was from Oxo id (UK); Dulbecco's Modified Eagle Medium (DM EM ), foetal bov ine serum (FBS), fatty acid-free bov ine serum albumin (fBSA), gentamicin and L-glutamine were from Sigma-Aldrich (USA). Labelled (5,6,8,9,1 1, 12, 14, 15- 3 H)-AA (specific activity 180-240 Ci/mmol) and liquid scintillation cocktail OptiPhase Supermix were from NEN Perk in Elmer (USA).
  • PBS phosphate-buffered saline solution
  • DM EM Dulbecco's Modified Eagle Medium
  • FBS foetal bov ine serum
  • fBSA fatty acid-free bov ine serum albumin
  • gentamicin and L-glutamine were from Sigma-Aldrich (
  • Sclerochloa dura (Linnaeus) P. Beauvois, known also as common hardgrass, belongs to family Poaceae Barnhart, which involves more than 700 genera and almost 50,000 species. Sclerochloa dura is an annual plant. It has:
  • pedicels stout up to 1 mm
  • Tlie plant is a common inhabitant of areas with heavy traffic, e.g. along dirty roads, on play yards and walking pathways. It is idely spread in the moderate climate zone on almost all the cont inents on North Hemisphere and introduced in
  • S. dura was collected in the city of Nis, Serbia, near Gabrov acka reka creek.
  • the plant was air dried in the shade for ten days.
  • the dry plant material was packed in plastic bags and kept in a coolish and dark place until extraction.
  • Aerial plant parts were crushed into smaller pieces. Clean plant material weighing 1.4 kg was exhaustively extracted by soaking in methanol for 24 hours at room temperature twice. The extraction was aided by 90 minute of sonication. The obtained extracts were filtered ( Blue ribbon filter paper from Schleicher and Schuell) and combined. The volume was reduced on rotavapour and the concentrated solution transferred into separation funnels. Extraction with n-hexane (three times) was used for detailing and the separated methanoiic phase dried on rotav apour. The dry methanoiic extract yielded 1 70g (12.14%) and was used for further work.
  • Isolation was done by using a multistage fractionation approach by liquid chromatography.
  • the crude extract was subjected to pre fractionation by MPLC using a double inject ion, 85 g per injection.
  • the method used for MPLC is given in Table 1.
  • the obtained pre- fractions were tested on human synovial sarcoma ceil line SW982 to determine any effect on PLA2 activ ity by measuring A A release.
  • Three p re-fractions found very active were subsequently fractionated by 3 respective runs on preparative HPLC into 259 fractions.
  • the method used for preparative HPLC is giv en in Table 2. All the obtained fractions were tested for inhibit ion of PLA2 activity by measuring AA release.
  • fractions of pre- tract ion F were pooled into groups, e.g. F40-F44 as one group and F70-F74 as the other. These groups were subjected to semi-preparat ive HPLC runs.
  • the method used for semi preparat ive runs is given in Table 3.
  • fractions G50-G51 of pre-fraction G were pooled together and subjected to semi-preparative HPLC run.
  • the method used for semi-preparative run is given in Table 3.
  • the human synovial sarcoma cell line SW982 is used as a model system to determine cPLA > activity by measuring AA release.
  • SW982 cells are widely used as a model for rheumatoid synovial inflammation and express c LA.>-i Va and cytokines after inflammatory st imulat ion by e.g., IL- ⁇ ⁇ .
  • Cells were sub-cultured biweekly by routi ne trypsin detachment and kept in a sub-confluent state.
  • the cel ls were cultured in DM EM supplemented 10% FBS, 0.
  • the AA release assay determines the amount of AA released from ceils under inflammatory conditions.
  • the enzyme cPLA > is the only arachidonyl-specific PLA ) enzyme and thus the A A release mainly corresponds to the activity of cP LA.> that cleaves off AA in the sn-2 position of phospholipids.
  • the AA release is reduced, which is taken as evidence that the compound(s) target some level in the arachidonyl cascade, such as the cPLA ? enzyme.
  • SW982 cells were serum-starved and labelled overnight with Tl-AA ( 0.4 ⁇ / ⁇ ).
  • the cel ls Prior to the addition of S. dura fractions, the cel ls were washed with PBS containing fBSA (2 mg/ml) to remove un incorporated radioactivity.
  • Cells were pre-treated for 1 h with various dilutions ef fractions of the plant extract, followed by addit ion of 1 I .- 1 ⁇ (10 ng ml. ) to induce an in flammatory state.
  • the supematants were cleared of detached cel ls by centrifugat ion (13000 rpm, 10 min ).
  • Adherent cells were dissolved in 1M NaOH in order to measure the amount of labelled AA incorporated into the cells.
  • the activity in the supematants and cellular fractions was assessed by liquid scint i l lat ion count ing in LS 6500 u It i- Purpose Scint i llat ion Counter ( Beckman Coulter, Inc USA). The results are given as released Tl-AA in the supematants relative to total Tl-AA incorporated into the cells. Inhibition was calculated as AA release in inhibited relative to stimulated cells, normalized to control, subtracted by 100.
  • the carbons 1 -6 belonging to glucose moiety, had shift values for 13 C ranging from 6 54.4 to 100.3 ppm and for protons from ⁇ 2.92 to 4.77 ppm.
  • the shift values of both I3 C and protons at C-6 indicated a direct attachment to an SO3H group, which was also confirmed by MS analysis.
  • H M BC correlat ion peak of H-3 (at ⁇ 3.65 ppm) of glucose and carbon C- l "(6 176.2 ppm) of the linolenoyl chain revealed the attachment position.
  • Glycerol moiety exhibited shift values for carbons ranging fr m ⁇ 64.4 to 72.7 ppm and protons from ⁇ 3.36 to 4.05 ppm.
  • the correlat ion peaks between carbon C- 1 of glucose and protons ⁇ ,. ⁇ - of glycerol in H M BC unambiguously revealed connect ivity between glucose and glycerol.
  • Compound 2 was identified as isovitexin. It was isolated as the main compound in fraction F-07 obtained by preparative HPLC run of pre fraction F (Table 2).
  • HRMS (ESI +) was 432.1055 which corresponded to molecular formula C21H20O10, ( theoretical value 432.1056).
  • the compound was identified by a a s of 1 D and 2D NMR experiments. The signal assignments for carbons and protons can be seen in Table 5. The NMR data were in agreement with those already published (Leong et a!., 2010).
  • Compound 3 was isolated as the main compound in fract ion F-51. This fraction was obtained by preparative H PLC run of pre fraction F (Table 2). Compound 3 was ident ified as tricin 4 -O-(erythro- -guaiacyiglyceryl) ether 7- ⁇ - ⁇ - glucopyranoside. H RMS (ESI +) found was 688.2003 ( theoretical value 688.2003) and it corresponded to the molecular formula C33H36O16. The NMR data of the compound (Table 5) fits the published ones (Bouaziz et al., 2002).
  • Compound 6 was the main compound in fraction F-32, obtained by preparative HPLC run o pre fraction F (Table 2). It was identified as trie in 7- glucoside. FIRMS (ESI +) 492.1268 for C23H24O12, found 492.1263. The NMR data of 6 (Table 5) fits to those reported earlier (Avvaad et al., 2008).
  • the m le percentage of compound 1 in the act ive fract ion was est imated to be 60%, based on integral ratio in ⁇ - M R spectrum. Therefore, the IC5 0 v alue of 1 from three independent experiments corresponds to 1 14. 1 ⁇ 31.1 ⁇ .
  • the obtained IC50 value shows that 1 has the potential to be used as a lead compound for the dev elopment o f a n t i- i n flam matory drugs.
  • the spectroscopic study f 1 shows unambiguous presence of an -SO3H group. The presence of sulfonyl group in 1 might be important for its bioact ivity.

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Abstract

L'invention concerne un composé de formule (I) dans laquelle R représente un groupe alcényle polyinsaturé C9-23 ; X représente SO3R3, SO2R3, PO3R3, PO2R3, COCHal3 ou COOR3 ; R1 et R2 représentent indépendamment H, un groupe iky I C1-6 facultativement substitué par OH, un groupe aryle C6-10 facultativement substituté par OH, un groupe arylalkyle C7-12 facultativement substitué par OH, un groupe alkyle COC1-6 facultativement substitué par OH, un groupe aryle COC6-10 facultativement substitué par OH, un groupe arylalkyle COC7-12 facultativement substitué par OH ou un groupe COCHaI3 ; hal représente halogénure, de préférence F ; chaque R3 représente indépendamment H, alkyle C1-6, aryle C6-10 ou arylalkyle C7-12 ; ou un sel de celui-ci.
PCT/EP2014/058248 2013-04-23 2014-04-23 Composé Ceased WO2014173957A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017031054A1 (fr) * 2015-08-20 2017-02-23 Antartina Llc Nouvelles molécules thérapeutiques et dérivés pour traiter le ccr
KR20170025977A (ko) * 2015-08-31 2017-03-08 재단법인차세대융합기술연구원 옥시리스 마리나로부터 분리된 신규 화합물

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* Cited by examiner, † Cited by third party
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CN103772312B (zh) * 2009-10-02 2016-08-17 埃维克辛公司 抗炎症的2-羰基噻唑和2-羰基恶唑

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017031054A1 (fr) * 2015-08-20 2017-02-23 Antartina Llc Nouvelles molécules thérapeutiques et dérivés pour traiter le ccr
KR20170025977A (ko) * 2015-08-31 2017-03-08 재단법인차세대융합기술연구원 옥시리스 마리나로부터 분리된 신규 화합물

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