BR112012018792A2 - compostos anticoagulantes, composição e formulação farmacêutica, produto de combinação, kit, combinação e uso - Google Patents

Abstract

  COMPOSTOS ANTICOAGULANTES, COMPOSIÇÃO E FORMULAÇÃO FARMACÊUTICA, PRODUTO DE COMBINAÇÃ O, KIT, COMBINAÇÃO E USO. A presente invenção refere-se a um composto de fórmula (I): (I) em que R 1 , R 2 , R 3 e n têm significados dados na descrição, ou um solvato farmaceuticamente aceitável sal ou profármaco do mesmo para uso como um anticoagulante.

Description

Relatório Descritivo da Patente de Invenção para "COMPOS- TOS ANTICOAGULANTES, COMPOSIÇÃO E FORMULAÇÃO FARMA- CÊUTICA, PRODUTO DE COMBINAÇÃO, KIT, COMBINAÇÃO E USO". A presente invenção refere-se a compostos anticoagulantes e a 5 aplicações dos mesmos.

Anticoagulantes são administrados para interromper coagulação sanguínea inadequada, e distúrbios resultantes da mesma, e podem ser u- sados entre outros na prevenção de trombose venosa profunda, embolismo pulmonar, enfartes do miocárdio e derrames, mantendo a função mecânica da válvula cardíaca depois de substituição de válvula cardíaca mecânica, xeno-, homo- ou autóloga e prevenção da formação de coágulo durante ci- rurgia.

Varfarina e heparina são anticoagulantes usados comumente, com hemorragia sendo a complicação mais comum de sua uso terapêutica.

Foi agora surpreendentemente visto que alguns compostos de naftoquinona têm a capacidade de agir como anticoagulantes.

Portanto, a presente invenção se refere a um anticoagulante alternativo.

De acordo com a presente invenção, é proporcionado um com- posto de fórmula (I):

(I) em que: R representa hidrogênio, halogênio, ciano, trifluorometila, nitro, -ORa, SRa, SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, - CORa, -CO2Ra, -CONRaRb, ou um grupo hidrocarboneto compreendendo um grupo de cadeia reta, ramificado ou cíclico, cada um contendo até 18 átomos de carbono, ou um grupo heterocíclico contendo até 18 átomos de carbono e

Órgãos Govemamentais Federais. EStadtmis e Municipais no Brasil, incbindo cj instiWtQ Nacional da propnedQde lndustrial, a Agência Nacionai de Vigilância Sarüária (ANVISA). o Minisiério do Desenvolvimento, lridúsfria e Cornércb Exterior e suas delegacias e Ministério da AgricUltUrq, Pecuária e Abasiecirnento; podencb para tanto assinar qUaisqUer documentos, requetimentos, petições. enfim, represenfar a ódorgante com cs poderes e para ds fins alUdidQs nas procwações a ela conteridas por seus clientes e qUe insfruam processos de seus interesses em hàmite naquele árgào federal. para os devidos fins, qs poderes ora conSeridos permanecerão em vigor cTé 31.12.2012. Cerfifico qUe as cÜstcjs clevidcs peio p(esenie ato foram recolhidas go cartôrio. de acordo com a pQrfana 84/2010 da Coxegedoria Geral de Justiça do Rio de janeiro, da seqUinte formq: cusÍCis R$ ] 1,28 jiab 7. obs. 2", letra a); comunicação .ao 'distribuidor R$ . 4,91 (tab 7. obs 14¶: infçxmática R$ 6,40 (tab 1,9), microhlmagern R$ 1.27 (tab 1,7): gravação eklrõnlca R$ 3;20 (iab. J,l0); MÚ'tUa, Acoteij e Anoreq R$ 9,63; Recdhido o acréscimo de 20% insÍifUÍdo peb lei 3217/99, no vcdor de R$ 6,01 0 devicio ao FETJ, o acréscimo de 5% instltuído pela Lei 4664/2005. río valor de R$: 1,50 devido ao FUNDPFRJ e o acréscimo de 5% institUído pela Lei Complementar n.° 111/2006, 'no valor de R$: 1,50 devido ao FUNPERj; distribUição R$ 24.66 (Lèi n-" - 5.358/2008). Assim o disse, do qUe doU kS, me ijediU qUe lhe laVrasse nesias Notas cj presente instmmenio, qUe lhe [j, aceita e assina dispensando testemunhas, conforme Prov. 92/84 da Corregedoria justiça desfe Esiacjo do Rio de Janeiro. EU:JÇEj: ¶ARDO DA SILVA DIMÍZ, MaÊricuY '94/4921, SUbstitUto, lavrei, li e colho a 9s5T!ah"a- Á eu 'S) UfZ FÉRNÃNDO CARV LHO DE FARLA.- Tabelião. mat 06/177YiPERj. a e/ õceK¢ r q sUbscrcLvcL (ass) DA'i/llj MERRYLEES. Trasladada e cenigcadQ nesZa Çafa. EÜtF/ digitei 6\ a wbscre¶ e assino.

( "T""~ \S· OF|ClO DE NOTAS Rlc"6d0 da silva omi" AvÉ}:i=" ")sj'))))) , ill!l[Ili|ÍÍIi:ilr' 0 ARi3 de ja.n9\roj

(12) INTERNATIONAL APPLÍCATION PUBLISHED UNDER THE PATENI' C()OPERAT[ON TREATY (PCT) (19) Wodd Intellectua! Property Organization 4 |||]|ll|à|l|||||||||||f||li|||||Ú||Ú|||||||||||i||||M||||h|||I:])l|lI|||h|||||N| Intemational Bureau P (10) h]tematioDal Publication Number (4J) Iàernation al 'Publication Date 30 June 2011 (30.06.201Ã) PCT' WO 2011/077158 Al (51) International Patent Cla&sincatk)n: AO, AT, AU, AZ, BA, BB, BG, BEL BR, BW, BY, BZ-, A61K3//192 (2006.01) A6lP 7/02 (2006.Ql) CA, CH, CL, CN, CO, CR, CU, CL DE, DK, DNL DO, A61K31/21 (2006.01) DZ, EC, EE, EG, ES, ÊI, GB, GD, GE, GK GM, GT, HN, HR, HU, ID. IL. IN. IS, JP, KE, KG, KM, KN", KP, (21) Mernatiouàl Applieation Number: KR, KZ, LR LC. LKJ LR. LS, LT, LU, LY, MA. MD. PCT/GB2ÚlO/052l94 Me, MG, MK, MN, MW, MX, MY, MZ, NA, N'G, NT, (22) hIterÁjatjUna] Filing Date: NO, NZ, OHL PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 22 Deoember 2010 (22-12,2QlO) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT,TZ, Ua. UG, US, UZ, VC, VN, ZA, ZM, ZW. @5) Filing Language: English Doigmted States (unless ot/íerwise indicated. for evay (26) Pubheation Language' English (84) kind ofregional pmecüon avai/ab/e): ARIPO (BW, GH, (30) Èciority Data: GM, KE, LR, LS, MW, MZ, NA SD, SL, SZ, TZ, UG, Q922510,3 23 Decentber 2009 (23.12.2009) GB ZM, ZW), Eurasiaü (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL,'AT, BE, BG. CIL CY, CZ, DE, DK, (71) Applieànt (for a// desi2Tnaled S/a/es excepl US): HAO- 0' MAMED'L'CA LKMITED [GB/GB'j; 1 Brewery Howe, Broo.k SXect, WNerihoe, Coj.dzester, Essex CO7 9DS EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS. rr, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL SK, SK TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (GB). GW, ML, MR, NF, SN, TD, TG)- (72) Inventors; and Declarations imder Rule 4.17: (75) IIÀven(0rs/App)icânt$ Q'or US only): HODGE& Stephen QfiAj¥nto?"s/7P (Ruk 4.I7(í';)) [GB/GB ]; do Haonm Medica Linúied, l Breweiy Housc, Brook Sireeí. Wivenhoe, CoIdíester, Es$cx CO7 9DS Pubjkhed: (GB)- SOPER, Robin [GB/GB]; c/Cj Haoma Medica Lini- wi/h l"nlernaIio1talsea/'c/? rapon (Àrl. 21 (3)) .— Íted, 1 Breway House, Brook Street, Wivenho@ Cokh- — esler,Essex CO7 9DS (GB). before the expiratiQn of /he (ime limit for améxding the cLaims and lo be repub/ished in the evenl QÍ recetp/ Q/ (74) Agents: KIN7'A1RD, Jaines et al.· 90 Hi8h Holbom, amendmems (Ruk 48.2(h)) Wdoz Greater London WCJV 6n (GB). — (81) De$ít'n8ted States (un/ess oíherwise indicated, for eveiy knd qf national prQ/ecliU?I avai/ub/e): AE, AG, AL, AM, m — 0 — (54) Title: ANTICOAGULANT COMPOUNDS AND THI'IR USE — FNuW5 Nm lncorpômtion "' "">\ of¶'CO, mm \ CY o — M {DPlW} mn? ^R' — 0~ U Fk (I ~ \"~ r N — ¶ ~ < .m, 0 . 1® = HO 4·» W í: çrj BB CpncBntrat|Dn {µ M] e lnNMônd Cm Ln ~uNú0(Vl|l: N tm pm Qt mwa %Àwmn tn ~ Ki hmqu~ (íf f) r- aa tncorpm+ ge GQZ 1d çdpm) r- BB híhibátíQn de La çarbQxy1a$ç gamme pat du Aulrwtc dc sodbum (Vlll) çn présmcc de vltamino m µm = K$ lTya0qUlwne TM) HWr0qlljnon0 Kj çn'a) ~ m (57) Abstr3¢t: According to the inveniion there is provided a compound cjf fòímula (1): wherehi R', R', R"' and n have meanhigs ~ = given Ül the description, or a phamíaceuticdly acceptabk soivate, salt or prodrrig th«eof for use as an anticoagulaüt. n

O b

WO 2011/077158 PÇT/GB201W052194

ANTICOAGULANT COMPOUNDS AND THEIR USE The present invention relates to anticoagulant compounds and uses thereof.

Anticoagulants are given to stop inappropriate bbod cbtting, arid disorders resulting therefrom, and may be used inter alia in prevention of deep vein thmmbosis, pulmonary 5 embolism, rnyocardial infarctions and strokes, rnairitaining mechanical heart valve function fotlowing mechanical, xeno-, homo- or autologous heart valve replacement and prevention of dot fbrmation duririg surgery.

Warfarin and heparin are cmmonly used anticQagLI|ants with bleeding being the most 0 óommon complication of their therapeutic use.

'lt has now surprisingly been found that certain naphthoquinone compounds are able to act as anticoagulants. Thus, the present invention relates to an aiternative antmagU|ant.

According to the present invention, there is provided a compound of formula (i):

O .>?' (R'),, : ~ ! ,,, 0

O (I) 'wherein: R' represents hydrogen, halogen, cyano, trifluóromethyl, rtitro, -OR', SR", SOR', -SO;,R", -SO,NR"R', -NR'R', -NR'COR', -NR"CO,Rb, €OR', -CO,R', -CONR'R', or a hydrocarbon 1 group comprising a straight chain, branched or cyclic group each contâining up to 18 carbon . .

atoms, or a heterocyclic group oontain ing up to 18 carbon atoms and at least one heteroatom; R2 represents, independently at each occurrence, hydrogen or, more particularly, haíogen, 5 cyano, trifluoromethyl, nitro, OR", SR', SOR', -SO,R', SO?NR"R', NR'R', NR"COR', -NR"CO,R' -COR', -CO2R', -CONR"R', or a hydrocarbon group comprising a straight chain, branched or cydic group each containing up to 18 carbon atoms, or a heterocyclic group containing up to 18 carbon atoms and at least one heteroatom (e.g. R1 or R2 represents hydrogen, halogen, cyano, trifluoromethyl, nitro, -OR", SR", SOR', 10 -SO2R', -SO2NR"Rb, -NR"R', -NR'COR', -NR"CO,R', -COR", -CO2R', -CONR"Rb, or a " '" 0 hydrocarbon group comprising a straight chain, branched or cyclic group each containing up to 18 carbon atoms, or a heterocyclic group containing up tcj 18 carbon atoms and at least one heteroatom): 15 R' represents a hydrocarbon group comprising a straight chained, branched or cydic group each containing up to 18 carbon atoms, and being substituted by at least one moiety induding a -CO2R" substituent; wherein R' and R" independently represent, at each occurrence, hydrogen, or a hydrocarbon 20 group comprising a straight chained, branched or cyclic group each containing up to 18 carbon atoms, or a"heterocyclic gtoup containing up to 18 carbon atoms and at least one 0 heteroatom (e.g. wherein R" and R' independently represent hydrogen, or a hydrocarbon group comprising a straight chained, branched or cyclic group each coritaining up tcj 18 carbon 25 atoms, or a heterocyciic group containing up to 18 carbon atoms and at least one heteroatom ); n is 0 or, more particularly, 1, 2, 3 or 4: 30 or a pharmaceutically acceptable solvate or, more particularly, sait or prodrug thereof; 2 for use as an arttiooaguiant.

Ih an aspect of the present inventbn, the compound of formula (1) is not vitamin K3.

5 Another aspect çyf the present invention provides phamaceutical compositions cornprising a compound of formula (I) with a pharmaceutically acceptable carrier- ln a further aspect the .

invention relaÊes to a pharmaceutical composition comprising a compound of fmmula (I) and a pharmaceutically acceptable carrier, diluent or excipient therefor, for use as an anticoagulant.

The invention also reiates to use of a compound of formula j, or pharmaceuÉical composition - .

comprising a compound of formula I,. in Lhe manufacture Qí a medicamerit for use as an 0 anticoagulant.

The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingred ient(s) (pharmaceuticdly acceptable excipients) that make up the carrier, as well as arIy product which resuits, directly or indirectly, fmm combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of lhe ingredients, or from other types cjf reactions or interactions of one or more of the ingredients, Accordingly, the pharmaceutical compositions of the present inventiori encompass any cornposition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically accepÉable excipients. Suitable pharmaceulical compositons may be found in, for example, Remington 0 The Science and Practice of Pharmagy, 19th ed., Mack 'Printing Company, Easton, Pennsylvariia (1995), For parenteral administration, a parenterally acceptable aqueous solution may be empbyed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions wiü be well known to the skilled person, with numerous methods being described in the Iiterature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science (1990) 249, 1527.

3

Reference to the compound of formula (I) herein is taken to include reference to all pharmaceutically acceptable solvates or, more particularly, salts, prodrugs or tautomers, unless otherwise apparent from the context. Accordingly in its broadest asped the present invention relates to compounds of formula (l) or a pharmaceuticalty acceptable solvate or, 5 more particularly, salt, pmdrug or tautomer thereof, for use as anticoaguknts, and in the manufacture of medicaments for use as an anticoaguíant.

The terrn "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases inciuding inorganic bases and organic bases (for example, given 10 the presence of substituent -CO2R' present iri R3), or salts prepared from pharmaceutically 0 acceptable non-toxic acids includíng iriorganic acids and organic acids (for example, in the case where a basic substituent is present in any of R1 or R2), Salts derived from inorganic bases include afuminum, ammonium, calcium, copper, ferric, 15 ferrous, lithium, magnesium, potassium, sodium, zinc, arid the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, seoondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamirie, 2-dielhylaminoethanol, 2-dimethylamlnoethanol, · 20 ethanolamine, ethylenediamine, N-ethylmorphotine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, [ysine, morpholine, piperazine, piperidine, polyamine 0 resins, procaine, pu rines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like.

25 Salts derived from acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fu maric, glutamic, hyd robrom ic, hydrochbric, isethionic, lactic, maleic, mandelic, methanesuifonic, nitric, pamoic, pantotheníc, phosphoric, succinic, sulfú ric, tartaric, p-toluenesuifonic acid, and the like.

4

WO 2011/077158 As mentioned above, also encompassed by formula I are any sdvates of the compounds and their salts. Preferred solvates are solvates formed by the ineorporation into the solid state structure (e.g. crysÉal structure) of the compounds of Éhe inventlon of molecules of a non-toxic pharrnaceutically acceptable soIvenÉ (referred to below as the scÀvating solvent). Examples cjf 5 such solvents include water, alcohals (such as ethano.l, isopropanol and butanol) and ditnethylsulphoxide. Solvates can be prepared by recrystallising the cornpounds d the invention with a solvent or mixture of solvents containing fhe solvating solvent. Whether or not a solvate has beeri formed in any given instance can be determiried by subjecting ctystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray .

ctystallography. 0 The sdvates can be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to rnake and characterise them, see Bryn et al., So//d-Sta/e Chemistry of Drugs, Second Edition, published by SSCl, lnc of West l-afayette, IN, USA, 1999, ISBN 0-967-06710-3.

The present invention also includes within its scDpe the use of prodrugs cjf the compounds of formula (I). lri general, such prodrugs are functional derivatives of the compounds of formuk 0 (1) which are readily convertible in vivo into the required compound. ConvenLiorial pmcedures for the selection and preparation of suitable prodrug derivatives are well known in the art.

The terrn "prcxirug" of a relevant oompound of formula I includes any compounc! that, following administration (e.g. orâ or parenteral admirústration), is metabolised ln vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g.

withln a dosing iriterval of between 6 and 24 hwrs (i.e, once to four times daily))- 5

: 0

I l e i WO 2011/077158 -· - PCT/GB2010/052194 + P*rúgs of compounds of formula I may be.prepared by modifying functiÓnal gmups 'pre'sent . & onithe cõmpound in such a way that the modifications are deaved, in vivo when such prodrug ls 'administered . tó a .mamma|jan subject. The modifications' typically " are achieved by' ..' synthesizing the pàrent compound with a prodrug substituent. Prodrugs include compoünds -. .. . ...

5 of formula I wherein. a hydroxyl, amino, sulfhydryl, carboxyl 9r carbohyl group in a comppund " .' of formula l jf ,,bonded to any group that may be cleavecl "in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl Qr carbonyl groupt respectively- ' Exàmp[ès jof prodrugs .include, but are not ,limited to, esters and carbamates of hydroxyl " 10 functional' gToL!ps, esters' groups of carboxyl functlonal groups, N acyl derivatives arid N-. .' 0 Mannich bases. General information on prodrugs, may be found e.g. in Bundegaard, H, 'Design of Prodrugs" p. 1-92, Elsevier, New York"Oxford (1985). " " " " lri one' aspect the prodrug is not vitamin K. Unless otherwise stated, the term "vitamin K" as 15 used her?in retates to vitamin K1 and vitamin K2 collectively and not to man-made anabgues of vitamin K. .

CD!npDunds of formula I may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double' bond.' ·All such isomers and 20 mixtures thereof are included within the scope of the invention.

0 Compounds of formula I may exist as regiQisomers and may also exhibit tautomerism All .· , ' tautomeric form and mixtures thereof are included within the scope of the invention. .

25 Compounàs of foimula l mày contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatogmphy or fractbnal crysta|!isation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crysta1lisation or HPLC, techniques. Alternatively the 30 desired optical isomers may be made by reaction of the appropriate optically active starting 6 materia|s under conditions which wiif not cause racemisatbn or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e, a resolution, including a dynamic resolution), for example with a homochiml acid folbwed by separation of the 5 diastereomeric derivatives by convenüonal means such as chromatography, or by reaction with an appmpriate chiral reagent or chirat catalyst all under conditions known Èo the skilled person. All stereojsQn)ers and mixtures thereDf are included within the scope of the invention.

The cornpound of formula (I), or pharmaceuhcal compositions comprising the compound of formula (I), for use mentioned in the above-meijtioned aspects of the invention may be utiúsecl iri a method of medical treatment. Thus, according to further aspeds of the invention, 0 there is provided: (i) the use of a compound formula (Í), or pharmaceutical compositbn comprising a compound of formula (I), for the manufacture of a medicament for use as an antjcoagu|ant; and (ii) a method of treatment or prevenÊion of a disorder or conditbn benefitting from anticoagulant therapy, which method comprises the administration of an effective amount of a compound of formula (I), or a pharmaceutical composition comprising the colnpDurjd of formula (1), to a patient in need of such treatment. .

The term "disorder or coridition' benefitting from anticoagulant therapy" will be uriderstood by those skilled in the art tQ include: thrombosis, and diseases rejated thereto. For example D diseases related b thrombosis include deep vein thrombosis (particularly prevention of deep vein thrombosis ), pulmonary embolism, myocard ial infarclion (e.g, myocardial infarcticm in surgicai procedures requiring anticoagulaÉicm), strokes, and maintaining heart valve t'uncüon for mechanical or transplanted hearts, such as human or, particularly, non-human hearts (e.g- following mechanical, xeno-, hDmo- or autologous hearÉ vaive replaoement and prevenfion of cIot formation during surgery).

7

Thus, in one aspect the compound of formula (I) is used as an anticoagulant to prevent thrõmbasis and diseases reiated to thrombosis. Particular' disorders or conditions that may be mentioned in relation tó the aspects of the invenüon described hereinbefore Ínclude 5 The compounds and compositions of the' invention having anticoagulant activity may be used f'or the prevention or treatment of thrómbosis, and diYases relat!?d thèreto, fór example in preventiôn of deep vein thrombosis, pulmonary embolism, myocardiàl infarctions in surgical .

procedures requiring anficoagulaÚon, strokes, and maintaining heart vaive function for, 10 rnechanical or transplanted hearts: such as human hearts or, particularly as non hurnari · .

0 hearts (e.g. following mechanical, xeno-, homo- or-autdogous heart valve replacement and prevention of clot formaticin during surgery).

Thus, further aspects of the invention relate to the fdlowhg.

15 (a) A compound of formula I, or pharmaceutical composition comprising a compourid of formula (l), as hereinbefore defined, for use in the treatment ot prevention of a condition or disorder selected from thrombosis. deep vein thrombDsis, pulmonary embolism, myocardial infarction in surgical procedures requiring anÉicoagu|ation, 20 strokes, and maintaining heart valve function for mechanical or transplanted hearts (e.g. thrombosis). 0 (b) Use of a compourid of formula I, or pharmaceutical compQsition oomprislng a compound of formula (I), as hereinbefore defined, for the preparatiori of a 25 . medicament for the treatment or prevention of a condition or disorder selected from thrombosis, deep vein thrombosis, pulmonary embolism, myocardial infarction in surgical procedures requiring anticoagufation, strokes, and maintainlng heart valve function for mechanical or transplanfed hearts (e.g. thrombosis).

8

(C) A method of Èreatment or prevention of a disorder or conditbn selected from thmmbosis, deep vein thrumbosis, puímonary embolism, myocardial lnfarcÉion in surgical procedures requiring antiooaguktion, strokes, and mairítaining heart valve function for mechanical or transplanted hearts (e.g. thrombosis), which method 5 comprises the administration of an effectíve amount of a compound of fõrmula (Í), or a pharmaceuticai composition comprising Éhe compound of formuta (1), to a patient in need of such treatment.

For the avoidance of doubt, in the context of the present lnventiôn, the term "treatment" includes references to therapeutic of palliative treatment of patients in need of such heatrnent, as well as to the prophylactic treatment and/or diagnosis of patients which are 0 susceptible to the relevant disease states.

The terms "patient' and "patients" include references to ma mmalian (e.g. human) patients.

The term "eff'ective amount" refers b an amount of a compound, which confers a therapeutic effect on lhe treated patient (e.g. sufficient to treat or pTevent the disease). The eft'ect rnay be objective (i.e, measurable by some test or marker) or subjective (i.e. the subject gives an ind ication of or feels an effect).

The terrn "habgen°' as used herein includes fborine, chbrine, bromine and iodine (e.g.

bromine or, more particulariy, chlorine of fluorine). 0 The term "hydrocarbon" as used herein with reference to any of RÍ R2, R3, R" and R' includes alkyl, alkenyl, alkynyl, cycloalkyl, alkyl, açyl, aryl-alkyi, aryl-alkenyl and aryl-alkynyl- Suitable alkyl groups include straight chalned or branched alkyl grôups containing from 1 to 18 carbon atoms, or more prefeTably 1 to 9 carbon atoms. For example, typical examples can iriclude methyl or eÈhyl, or straight chained 'or branched propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or the like.

9

Suiwble alkenyl groups include straight chained and branched alkenyl groups oorjtaining from . .

2 to 18 carbon atoms, and may include vinyl, allyl or isoprene moieties, 2-, 3- or 4- pentenyl, .

or 2-, 3-, or 4- hexenyl or the like, and isomeric forms thereof. Aikenyl groups as present in 5 Éhe compounds of the invention may include one or more degrees of unsaturaüon.

Suitable alkyny! groups inciude straight chained and branched afkynyl groups containirig from " 2 to 18 carbon atoms. For exampte, typical examples can include ethynyl and propynyf groups.

10 0 Suitable cycloalkyl groups include groups containing from 3 K) 7 carbon atoms, for example cyclopropyl or cyc|ohexyl.

Suitable aryl groups can indude aromatic hydrocarbon systems having one ring or two or 15 three fused rings, such as phenyl or naphthyl. A particuiarly suitable aryl group can be phenyl.

Suitable heterocyclic groups can include ring systems having 5 or 6 ring atoms of which at least one ring atom is oxygen, sulphur or nitrogen. The ring systems can be aromatic or non- 20 aromatic. Examples can include piperazinyl, morpholinyl, pyrrolyl, imidazolyl, thienyl, furanyl or other known heterocyclic ring systems. 0 According to a preferred embodiment of the present invention, R' represents a hydrocarbon group comprising a straight chain, branched or cyclic group each containihg up to"18 carbon 25 atoms. More preferably R' represents an alkyl group including straight chained or branched alkyl groups containing from 1 to 18 carbon atoms, or more preferably 1 to 9 carbon atoms (e.g. 1 to 6 carbon atoms, such as 1 to 5 carbon atoms). lt is particularly preferred that R1 represents methyl.

10

Acconding to a further preferred embodiment of lhe present invention, n represerits 0 or, .

alternatively, n is 4 and R2, at each occurrence, is hydi'ogen (e-g. R2 represents hydrogen and n Ís 4).

5 According to a still further preferred embodiment of the present invention, rè represents a . - ..

hydrocarbon group cxjn)ptising a straight chained ot branched hydrocarbon group containing up to 18 carbon atoms, preferably an appropriate alkyi or afkenyl groUp, substituted by at least one moiety including a -CO2R" substituent. Mare preferably, R' represents C1-9 alkyl or C2-9 alkenyl, which can be straight chained or branched, substitufed by at least one moiety lncludirig a -CO2R" substituent, whereirí R' is substantialiy as hereinbefore defined.

Preferably in the context of R', R" represents hydrogen, or a hydrocarbon group comprising a - 0 straight chained or branched hydrocarbon group containing up to 18 carbon atoms, preferably up Éc) 9 carbon atoms, and even more preferably up to 6 carbon atoms. Preferably R" represents hydrogen or Cjg straight chained or branched alkyl, in particular methyl.

Preferably R' can be represented by the following formula (Il) ' l CR'Rd ] [ R"R"C- - - -CR'R" ] ! CR"Rd] CO2R' q r . 8 (ll) where the unaüached bond represents the point ôf attachrnent of the structural fmgment af formula (ll) to the restof the compc>und of Formula (I): 0 R" is as hereinbekre defined; R', R' and R" are independently selected from hydrogen or C,-6 alkyl (which can be straight chained or branched); qis1,2,3or4; 11

. . . P P . Ç .

WO 2011/0'77158 ' . PCT/GB20I0/0521')4 r and s are independênt|y selected 'hom. Q, 1, 2, 3 or 4; .. + · - . P: . .

- -:-- -- representsi a single or double bond, and when íhis is a dóuble bond R" is hot prèsent " in above formula (ll). . -. . ' 5 Preferably formula (ll) represents a C4s straight chained or branched alkyl group, or" a C4a " ' straight chained' or branched alkenyl groujj substituted by CO2R",'wherein kreferab|y R" ." '" represents hydrogen or C,-,, straight chainéd or .branched alkyl, in particular methyí (e g. R" when attached to R' represents H or CH3). ' 10 0 Especially preferred groups represent by formula (ll) include: - ·· -(CH2)7CO2H; -CH2CH=C(CH3)(CH2)2CO2H: and 15 -CH,CH=C(CH3)CO,H.

Specifically, the present invention provides one of more of the following compounds: (i) 2,3-dimethoxy-1 ,4-naphthoquinone (XVI); (ii) menadione (lll); , b 20 (íii) KCAT-5C-Me (XlX): 0 . (iv) NaQuinate-Me (Vll); " . ' . ., (V) (4E)-6q1,4-dihydro-2-mdhy|-1,4-dioxonaphma|en-3-ylµ-methylhexA-enoic· acid - N!ll); ' (vi) (2E)4-(1,4-dihydro-2-methy|-1,4Aioxonapl)tha|en-3-ylµ2-|Tethy|but-2-enoic acid 25 (XlV); and (vii) 8-(1 AAihydro-2-methyl-1,4-dioxonaphtha|en-3-yl)octanoic acid (XV), for use as an anticoagulant.

12

For the avoidance of doubt, if Êhere is a cxmflict between the given chemical name and the e ehemical stmcture, the chemical sÉructure predominates- Especially preferred is (4E)-6-(1,4-dihydro-2-nlethy|-1,4-dioxQnaphtha|en-3-ylP4«ethyIhexA- 5 enoic acid (Vlll) for use in therapy according to the Present inventbn substantially as hereinbefore described.

The present invention also provides novel compounds fior use in therapy according to the present invention substantially as hereinbefore described, Specifically, these novel compounds are (2E)+(1,4Aihydro-2-methyl-1,4--dioxona|7htm1en-3-yl)-2-mmhy|but-2-enoic acid (XlV) and 8-(1 A-dihydro-2-methy|m,4-dioxor1aph[halen-3-y|Ntanoic acid (XV)-- 0 ln a particular embodiment, the compound of formula (í) is not menadjDne, The invention also relales to use of a compound of formula I, or pharmaceutical composition cDmprising a compQund of formula l, in the manufacture of a medicameM for use as an anticoag ularit.

The irivention also relates to use of the compound of formula (I), or pharmaceutical compositions comprising the compound of forrnula (I), iri the preparatbn of a medicament for prevention of thrombosis, or diseases caused thereby, in a patient who is to underlake a surgical pmced ure. Thus the invention also relates to a compound of formula (!), or 0 pharmaceuÉical compositions comprising the compound of formula (i), for use in the prevention of thrombosis, or diseases caused thereby, in a patient who is to undertake a surgical procedure and to a method of preventing thrombosis, ôr diseases caused Íhereby, ln a patient who is to undertake a suFgica| procedwe by administraüon of an effective amount of the compound of formula (I), or pharmaceutical compositions comprising the compound of formula (I), to the patient (e.g- in advance çjf swgery or after surgery).

13 ln one aspect the use of the compouncl of Éhe invention may be asj part of a combined therapy abng with another therapeutic agent- The invention also relates to a combination of a compound of fohnula (Í) with a coagulant, 5 such as vitamin K. ln one aspect the compound of formula (i) is to mòdulate the coagulation effect of the coagulant (e.g. the compound of formula (I) modulates the. coagulation effect of the coagulant). ln another aspect, the coagulant is provided to mQdulate,.the anticoagulation .

effect of the compound of formula (1).

10 0 The invention also relates to use of vitamin K in preparation of a medicament for reversal of ·- ·', - · -'- -·-, '- the anticoagulant effects of the compound of formula (I). " "" "" .

ln anoÉher aspect of the present invention Éhere is provided a method for the treatment or 15 prevention of diseases caused by blood coagulation, whích oomprises administering to a patient in need of treatment a therapeutically effective amount of a compound or compos ition of the invention (e-g. a compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I)). Thus, Éhere is also provided a compound of formula (I), or a . , pharmaceutical composition mmprísing the compound of formula Q), for use in the treatment 20 or prevention of diseases caused by blood coagulation and the use of a compound of formula (1), or a pharmaceutica) composltion comprising the compound of formula '(1), for "the " 0 preparation of a medicament far the treatment or prevention of diseases cau'sèd by blood coagulation.

25 ln another aspect of the present invention there is provided a methnd kr the management of the blood cIotting capability of a patient, the method comprising administering to a paüent iri need of treatment a therapeutically effective amount of a compound or composition of the Ínvention (e.g. a compound of formula (l) or a pharmaceutical composition comprising the compound of formula (I)), to exert an anticoaguiant effect, then administration of a coagulant 30 to modulate or reverse the anticoagulant ehect- Thus, there is also provided a oompound of 14

Íiarmula (l), or a pharmaceuticd composiÉion comprising the compound of formula (i), for use in a method for the management of the bbôd clotting capability of a patient, the mBthDd comprising administering to a pafient in need of treatment a therapeutically effective amount of a compound or composition of the invention (e.g. a compound of formula. (j) or a . - ----·- · .- . - .

5 pharmaceutical oomposition comprising the compou nd of formula (I)), - to exert. an - .. - anticoagulant effect, then administration of a coagulant to modulate. or reverse the -- - anticoagulant effect and the use of a compound of formufa (I), or a pharmaceutical composition comprising the compound of fbrmula (I), for the preparation of a medicament for use in a method for lhe management of the blood clotting capability of a patient, the method comprising administering to a patient in need of treatmenl. a therapeutically effective amount - .- of a compourid or composition of the inverjtion (e.g. a compound of forrnula (I) or a ·. 0 pharmaceutical composilion comprising Éhe compoIjnd of forrnula (I)), to exett an anticoagulant eftect, then administration of a coagulant to modulate or reverse the anticoagulanl effect.

By way of example, a patie.nt who needs to undergo surgery and who is on an antiooagulant needs to be treated with a coagulant to prevent excessive bleeding fdlowing surçery. The use of Éhe compound of formula (I), and pharmaceutical compositions oomprising the compound of fomula (I), as anticoagulants allows for ehicient and quick reversal of anticoagulant effect by the use of vitarnin K (e.g. vitamin K, or K2) and 1Ês rapid elimination .

from the body. ln other words, the use cjf a compound of formula (I), and pharmaceutical compositions comprising a compound of formula (l), as an anticoagulant enables one to 0 quicícly and emcier)tly reverse the arúicoagulant ehect by: (a) adding vitariiin K (e-g- vitamin K1 or K2): and/or (b) stopping adminisíration of the compound of formula (I), as the compound of formula (I) is rapídly eliminated hwn the body.

In çontrast, reversal of the effect of warfarin, another anticoagulant, is more time consuming and takes bngerto achieve, as warfarin has a relaüvely long bidogical half-life (2.5.days)- 15

Thus in one aspect the invention, .relates to a treatment fegime comprising treatment of a patierit with the compound ôf formula (j), or pharmaceutical compositions comprising ihe ." " compound of formula (I), then treatment cjf the same patient with vitamin, K, or other coaguknt, following surgery, to allow for biood clotting to occur. Optionally the patient can be 5 treated with the compound of formula (í), or pharmaceutical cõmpositions comprising the · compound of formula (i), after Èhe surgery has been comi!)|eted. The invention relates to use of the compound of formula (I), or pharmaceutical compositions comprising the compound of formula (1), in such a regime, and in the preparation of a medicament for use in such a ' regime- 10 0 ln one aspect the invention relates to a combination of a compound of formula I with another - -- - active component, for example another antícoagulant.

The compoLlnds may be used together as a combined preparation for simultaneous, separate 15 or sequential use.

ln accordance with the invention, compounds of formula (I) may be administered abne (i.e. as a monofherapy, such as a monotherapy for the preventicm or treatment of thrombosis etc), In alternative embodiments of the invention, however, compourids of formula (I), may be 20 administered in combination with another therapeutic agent (e.g. another therapeutic agent for the prevenfion or treatment of thrombosis or, alternatively, with a coagúlantjcompound 0 ' (e.g. vitamin K)).

Thus further aspects of the invention relate to a combination product comprising: 25 (A) a compound of formula (I), as hereinbefore defined, and (B) another therapeutic agent (e.g. a coagulant (e.g. vitamin K) or an anticoagulant), wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-accspta ble adjuvant, diluent or carrier, 30 16

When used herein, the term "another therapeutic agent" includes references hj one or more m (e.g- one) therapeuÊic agents (e.g. one therapeutic agent) selected from çQagulants and/or anticoagu lants.

5 Partlcu[ar other therapeutic agents that may be mentkmed include, for example, the · coagulants vitamin K., and vitamin K2 and the anticoagu|anL warktm.

When used herein, Èhe term "administered sequehtiá//y. simu//aneous/y or mnw/77itant/f indudes references Éo: administration of separate pharmaceutical formulations (one containing the compound of 'formula [ and one or more others containing the one or more other therapeutic 0 agents); and ad ministration of a single pharmaceutical forrnulation containing the compound of formula I and the oLher therapeutic agent(s).

The combination product descríbed above provides for the administiation of component (A) in conju nction with component (B), and may thus be presented either as separate formulations, wherein at least one of those formu|ations comprises component (A) and at least one wmprises component (B), or may be presented (Í.e-formulated) as a combined preparatiori (i-e. presented as a singie formulation including component (A) and component (B)).

0 Thus, there is further provided: (I) a pharmaceutical formulation including a coú)poünd of formula I, as hereinbefore defined and another therapeutic agent, in admíxture with a pharmaceuticaily- acoeptable adjUvarlt, diluent or carrier (which formulatiart is hereinafter referred to as a "combíned preparation"): and (ll) a kit of parts comprising components: 17

"4 (i) · a pharmaceutical formulation in,duding a comp.oynd of formula l, as hereinbefore . . ...- .adjuvant,,diluent or carrier; , . ,.... . . -

H defined., in "adm'ix,ture with a pharmaceutÍehy-acceptable.

and . --· . ,. " . , . . . " (ii) a pharmaceútical tormuIation induding anõther" therapeutic agertt,-in' admixturé . --" 5 with a pharmaceutically-accepjabk adjuvant, diluent or carrier, -," ", '" ,. . - -.which ,components (i) and (ii) are each provided in a form that is suitable for ' '' ad)ninistratiDn in conjunitiQri With.the other. . ' "-, Component (i) of the kit of parts is thus component (A) in -admixture with'a pharmaceutically- 1O acceptabfe adjuvant, diluent or carrier. ' Similarly, compo'nent (ii) is comporient (B) in -'- 0 admixture with a 'pharmaceutiçally-acceptable ad juvant, diluent or caçrier..

ln one aspect ihe invention relates to a method of preparing a combined medicine, the method comprising combining a coagulant, for example vitamin K, with the compound of 15 formula (I).

Optionally the mmbined medicine may then be combined with any pharmaceutically acceptable excipient, diluent or carrier to form a pharmaceutical compo'sition 20 Optionaiiy the combined medicine or pharmaceutical composition may be formulated into a tablet for oral delivery, 0 The magnitude of prophylactic or therapeutic dose, of a compound of formuiá (1) will, of course, vary with the naturé and the severity of' the condition to be treated and with the 25 particular compound of formula I and . its route of administration, It will also vary according to a variety of factors induding the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. ln general, the daily dose is from about 0.001 mg to about 1000 mg (e.g. 0.001 mg to about 100 mg) per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg.

30 On the other hand, it may be necessary to use dosages outside these limits in some cases. ln 18 any event, the medical practitioner, Dr other skille.d person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.

The amount of active irtgredient that may be combined with the carrier materiais to produce a 5 single dosage form wili vary depending upon the host treated and the particular mode of administration. For example, a brmulation intended for the oral administration of humaris may contaüi from 0.05 mg to 5 g of active agent ccjmpounded with an appropriate and oonvenient amount of carrier material which may vary from about 5 to about 99.95 percent of the tiofal composition. Dosage un it forms wil! generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, lypically 0.5 mg,.1 rng, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, - 100 mg, 200 mg, or 400 mg. 0- Preferred doses are of compound of formula (1) are a dose of greater than 40mg daiiy, more preferably at least 45 mg daily.

The total daily dose may be delivered in one or more separate doses over the course of the day, alone or in combinaticm with other therapies, Compounds d formula (I) may be adminístered by any suitable means, for cxample orally, by inhalation spray, topically, parenterally or rectally in dQsag0 unit formulations contairring conventional non-toxic pharmaceutically acceptab|e carriers, adjuvants and vehicles. The term "parenteral" as used herein includes gubcuÉaneous injections, iritravenous, 0 inlramuscu lar, Íntrastemal in jection or infusion techniques.

The pharmaceutical oomposhions containing the active ingredient may be in a form suitable for oral use, fbr example, as tablets, bzenges, aqueous gjf oily susper)siQns, dispersible powders or granules, emulsbns, hard or soft capsules, or syrups or elixirs. Compositions intended for oraj use may be prepared acwrding to any method knowri Éo the art for the mariufacture of pharmaceutical compositions and such compositions may contain one or more agerits selected ftom the group consisting of sweetening agents, flavouring agents, 19 colouring agents and preserving agents in order to provide pharmaceuticdly e]egant and .

palatable preparations, Tablets cohtain the active lngredient in .admixture with non-toxic . .

pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. ' These excipients may be for example, inert 'diluents, such as calcium carbonate, sodium · .

5 carbonate, lactose, calcium phosphate or sodium phosphate; granulating and 'disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gefatin or , acacia, and lubricatíng agents, for example, magnesiuni stearate, stearic acid Qr.talc. , The tablets may be uncoated or they may- be coated by known--techniques to delay '- ' ' "' , 10 disintegration and absorptiori in the gastrointestinal tract and thereby provide a sustained 0 action over a longer period. For example, a time ·delay material 'such as glyceryi .

monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for controlled release.

15 Formulations for oral use may also be presented as hard gelatin capsules wherein Éhe active ingredient is mixed with an inert solid diluent, for example, calcium carbQnate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propyiene glycol, PEGS and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

20 For example, a solid oral' composition such as a tablet or capsule may contain from 1 to 99 °/, ' "' ..

0 (W/W) active ingredient; from 0 to 99% (w/w) diluent or filler; kom 0 to 20°/a (W/W) of a - disintegranÉ; fíom 0 to 5°/, (w/W) of a lubricant: from 0 to 5°/, (W/'M) of a How aid; from 0 to 50% (W/W) of a granulating agent or binder; hom 0 to 5% (W/w) of an antioxidant; and from 0 to 5% 25 (W/W) of a pigment. A controlled release tablet may in addition contain from 0 to 90 '/j (W/W) ôf a release-c.ontrolling polymer.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example 30 sodium carboxymethyicellulose, methylcellulose, hydroxypropyl methylcellulose, sodium 20 aiginate, po|yvjny|pyTro]idone, gum bagacanth and gum acacia; dispersing or wetting agents may be a naturallynccurring phosphâtide, for example lecithin. The aqueous suspensions may also contain one or more preservatives, one or more coiouring agents, one or more flayouring agents, and one or more sweetening agents 5 A parenteral formulatic'n (such as a solution or suspension. for injection or a soIution fior infusion) may conÉain from 1 to 50 '/) (W/W) active Íngredient; and frQm 5O°/, (wM) to 99°'6 (w/W) of a liquid or semiscdid carrier dt vehicle (e.g- a solvent such as water); and 0-20% (W/w) of one or more other excipients such as buftering agents, antioxidants, suspension stabilisers, tonicity ad justing agerüs arid preservatives.

0 Oily suspensions may be formulated by suspmding tbe active ingredient in a vegetabê oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mirieral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, br example beeswax, hard paraffin or cetyl akohol. Sweetening agents and flavouring agents may be added Éc) provide a patatable oral preparation. ThèSe .compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid, vitamin E or some such equivalent agent.

Dispersible pcmders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredíent in admixture with a dispersing or wetting agent, suspending agent and one oi" mcwe preservaÉives. Suitable dispersing or wetting agents and suspemfing agents are exemplified by those already mentioned above- Addiüonai excipients, 0 for example sweetening, fjavouring and colouring agents, may also be present- The ph'armaceutical compositions of the invention may also be in the Form of an oil-iri-water emulsion. The oily phase may be a vegetable oil, for example ojive oil ct amchis oii, or a mineral oil, for example liquid paraffin or mixtur'es of these- Suitable emulsifying agerits may be naturally-occurring phosphatides, fbr example soy bean, Iecithin, and esters or partial esters derived from fatty acids and hexitd anhydrides, for example sorb itart monooleate, and coridensation products of the said partial esters with ethylene oxide, for example 21

'WO 2011/077158 PCT/GB20l0/052194 -' pdyoxyethylene sorbitan monooleate. The emulsbns may ajso contain svyeetening and ,- flavouring agents.

Syrups and elixirs may be formulated.-with sweetening agents, for- example glycerd, ." 5 propylene glycol, sorbitol or sucrose. ' Such formulations may also contaln a preservative, and flavouring and colo'uring agents- The pharmaceutical compositions may be in the form of a .

sterile injectable aqueous or oleagenous suspension'., This suspension niay.' be formulated .

according to the known art using suitable djspe}rsing or wetting agents ,and súspending agents. The sterile injectable preparation may also be a sterile ínjectable solution .or .

10 suspension in a non-toxic parenf:erally-acceptabte diluent or soIvent, tbr exainple as a solution · - -·· 0 in 1,3-butane diol. Among the acceptable vehicles and solvents Éhat may be empbyed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, . .

propylene glycoi or polyethylene glycols may also be used. ln addition, sterile, fixed oils are conventionally empbyed as a solvent or suspending medium. For this purpose any bland 15 fixed oil may be employed including synthetic mcmo- or di-glycerides. ln addition, fatty acids such as oleic acid find use in the preparation of in jectables.

Compounds of formula (I) may also be aãministered Ín the form of suppositories for rectal administratbn of the drug. These oompositions can be .prepared by mixing the drug with a .

20 suitable noírirritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and wiíl therefore melt in the rectum to release the drug. Such materials are. " 0 cocoa butter and poIyethylene glycols.

For topical use, creams, ointments, gels, solutions 'or suspensions, etc., containing the ' 25 compound of formula (I) are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

22

List of Figures The invention will now be descíibed, by way of example only, with reference ta lhe - accompanying figares, in which: Fígure 1 is an example of a syntheÉic pathway for a compound VIll (also called 5 NaQuinate herein); Figure 2A is an example of a synthetic pathway for a compound V used in the pathway shown in Figure 1; Figure 2B is an example of a syr|Éhetjc pathway for a compound V used in the pathway shown in Figure 1; Figure 3 shows the lnhibiEion Qf y'mrboxylase by KCAT-5C (XJV) in the preserice of 220µM vitamin K, hydrcxjuinone (n=1); 0 Figure 4 shows the inhibition of 7-carbE)xy|ase by KCAT-5C-Me (XlX) in the prese[1ce '' of 220µM vitamin K, hydroqujnone (ri=1); Figure 5 shows the inhibition of 7-carboxyíase by NaQuinate {VIll) in the presence of 220µM vitamin K, hydroquinone (n=1); " Flgure 6 shaws the inhibition of j'-carboxylase bY NaQüiríatè-Mè (Vll) in the presence of 220µM vKamin K, hydmquimne (n=1); Figure 7 shows the inhibition of Tcarbc)xylase by QCAT-Me (XVIll) in the presence of 220µ-M vitamin K, hydroquinone (n=1); Figure 8 shows the inhibition of Y-càrboxylase by DMK (XVl) in the presence of 220µM vitamin K1 hydroqujnQne (n=1); and 0 Figure 9 shows the hhibiticm of 7-carboxylase by Vitamin K3 (lll) in the presence of 220µM vitajT]in K, hydroqL|ino|]e (n=1).

A compound according to the present invention may be synthesised by any suitabk method.

A suitable method is disclosed bebw with reference to Ruttimann et al "Chimica" (1986) 40 (9) 290-306, and Gerorkzan et al "Chem. Hetroçyclic Compd" (Engl. Trans.) (1989) 2, 269 am Figure 8 and 9. ln addition, compounds of Éhe invention may be made by anabgy to the methods disdosed in GB 2,314,773 aríd incorporated herein by reference. As will be 23 appreciated, the cpmpounds of the current invention may be prepared by analogy to the j .- methods disclosed in the aKàveâentioned ref,erences or may be bought cmÍmerciaHy (where ".

indicated).

5 As shown in Figure 1 herein, the starting material menadione (Aldrich Chemical Company, Ill) -,- was employed and reacted with cydopentadiene at 25°C to generate the fused derivative ' ' thereof (lV). TTeàrriènt" Yvith base, O"K" (e.g, potassium "teÁ-butoxidej and subsequent treatment witri methyl 4.-methg|-6-brom+hex-4-eneoate (V), introduced the 3-substituent' Ni). " - '. " ' " The intermediate was further reacted by application of heat in the range of 70°C to 11O°C ,.

10 causing the eliminatio.n of cyclopentadiene with Éhe 'resultant isolation of the prodUct methyl · - 0 ester NaQuinate (VIl)- The characterisation of Èhis compound is given. by Ruttimann et al as hereinbefore referred, which is incorporded herein by reference.

The compound (Vll) is gonverted to the corresponding carboxyíic acid by means of base 15 hydrolysis, for exarnple using KOH, and subsequent acid treatment for example using H3O" (e.g. aqueous hydrochloric acid), or equivalent, in kr)own manner, thereby generating NaQuinate (Vlll). The characterisation of this compound is given by Ruttimann et al as hereinbelbre referred- 20 The preparation of intermediate (V) used above is carried out as shown in Figure 2A. Prenyl bromide (Aldrich Chemical Company) (lX wherein L = Br) was converted to the epoxide using . 0 mCPBA, which was subsequently heated to derive the intermediate (X) wherein L = Br.

Treatment with Ac2O-DMAP generated the ester (Xll) wherein L = Br, which was then subject to Claisen (e.g. lrdand€laisen) rearrangement using standard reagents such as LDA and 25 TMSCI (referred to"in figure '2A as TMSU). The rearranged product thereof (Xlll) whereiri L = Br was converted to the methyl ester (V) by reaction with CH2N2 fior use in the preparation of NaQuinate as hereinbefore defined. The characterisation thereof is provided by Gerorkzan et al as hereinbefore referred, which disclosure is incorporated herein by reference.

24

Altematively, a more particular preparation of intermediate N) used above is mrried out as shown in Figure 2B. Prenyl alcohd (17) was protected with tert-bufy|djmethyÍsi|y|ch|oride (TBDMSCI) to form TBDMS ether 18. Reaction of 18 with meta-chioroperoxybenzoic acid brmed epoxide 19, which underwent subsequent rearrangement to form alcohd 20 under 5 high temperatwe reflux. Reaction of 20 with tr(methy|orthoacetate ln the presence of propionic acid produced ester 21, which was deproted.ed to provide free alcohol 22 (using tetFabL|ty|amrnonium fluoride). Subsequent functional group interconversiori of 22 to the brornide 23 (also referred to herein as compound (V)) was achieved using carbon tetrabromide and tripheny|phosphine.

Equivalerit methods may be used to make other cxjmpQUnds within the scope o'f the present 0 irtvention.

Determining Bidogical Activity: The various compounds of formula t can be tested using any of the following assays to determine their activity as ariticoagulants: activated partial thromboplastin time (aPTT) test, prothrombin time (PT) test, and derivatiorI5 of PT prothrombin ratio (PR) and international nationalized ratio (INR), fibrinogen testing (often by the Clauss method), platelet ccmnt, platelet furiction testing (often by PFA-IOO), TCT, and b]eedinq time.

The prothrombln time is most commonly measured using blood plasma. Blood is drawn into a 0 test tube containing liquid citrate, which acts as an anticoagulant by binding the calcium in a sample. The blood is mixed, then centrifuged to separate bbod cells from p|asrna. The plasma is analyzed on ari automated instrument at 37"C, which takes a sample of the plasma.

An excess of calcium is added (thereby reversing the effects of citrate), which eriables the blood to cIot again. Tissue factor (also known as factor lll) is added, and the time the sample takes to CIOt is measured optically. The prothrombin time is the time il takes pÊasma to cbt after addition of tissue fàctor (obtained from animals). This measures the quajity of the extrinsic pathway (as well as the common pathway) of coagulation.

25

The INR was devised to standardize the results. TFÍe INR is the ratio of a patient°s piothrombin time to a "norrhal (control) sample, raised to the power' of the lSl value for the analytical sy;tem used. Each manufacturer assigns an lSl value (lnternational Sensitivity -" - 5 Index) for any tissue factor they manufacture. The lSl value indicates how a particular batch of tissue factor compares to an internationally standard ized sample. The normal range for a healthy person is 0 9M.3, ánd for people' on warfarin therapy, 2.0-3.0:" although the targèt' INR may be higher in particular situations, such as for those with a mechanical heart vaive.

10 The teaching of all references in -the present application, including patent applications and 0 granted patents, are herein fuily inoorporated by reference. Any patent appiication to which this application claims priority is incorporated by reference herein in its entirety in the manner - - described hereín for publícations and references.

15 For the avoidance of doubt the terms 'comprising', 'comprise' and 'comprises' herein is intended by the inventors tcj be optionally substitutable with the terms 'consisting oF, 'consist of', and 'consists cjt, respectively, in every instance. The term "about" (or "around") where used in all numerical values allows for a 5% variation, i,e. a value of about 1.25% would mean from between 1-19°/,-'| .31°/,.

20 lt will be understood that' particular embodiments described herein are shown by way of 0 iílustration and not as limitations of the inverition, The principal features of this invention can be employed in various embodimerits without departing from the scope of the inventlon, Tliose skilled in the art will recognize, Ôr be able tcj ascertain .using no more than routine 25 study, numerous eq'uivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the daims. All publications and patent applications mentioned in the specification are indicative of the levei of skill of those skilled in the art to which this invention pertains. All publications and patent appiications ate herein incorporated by reference êo the same extent as if each individual 26 publication or paterit applicatbn was specifically arid individualjy Êndicated to be irimrporated by reference.

The Llse of the word "a" or "an" when used in conjunction with the term "comprising" in the , 5 claims and/or the specification may mean "one," but it is also corisistent with Éhe meaning of 'bne or more," "aÉ least cne," and "one or more than one." The use of the term "or" in the claims is used to mean "and/or" unless explicitfy .Índicated to refer to alternatives only or the alternatives are mutually exclusive, although the disdosure supports a definition that refers to only aiternatives and "and/or." Throughout fhis application, the term "about" is used to indicate that a value includes the inherent variation of eKor for the measurement, the method being empbyed to determine the value, or ihe variation that exists among the study subjects. 0 The term "or combiriations thereof" as used herein refers to all permutations arid combinatior)s of the listed items preceding the term.

All of the compositions and/or meihods disclosed and cIaimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and rnelhods of this invention have been described in terms of preferred embodiments, it will be apparent to fh2se of skili in .the arl that variations níay be applied to the cDn]positior1s andlor methods and iri the steps or in the sequence ot steps of the method described herein without departing from the concept, spirit and scope of the inventbn. Aü such similar substitutes and tr)Qdifications apparent to those skilled in the art are deemed lo 0 be within the spiriL scope and concept of the invention as defined by the appended cIaims.

Any individual aspect of the invention may be combined with any other aspect, except where apparent fro the context.

The invention will be fúrther described by reference b the fotbwing, non-limiting, examples: Examples 27

WQ 2011/077158 PCT/GB2010/052194 Exámple 1 Observed anticoagulant' adivity Mice were treated with one compound of the present invention (4E)-6-(1 ,'4-dihydro-2- " - 5 methyl-1,4-dioxonaphthalen-3-yl)-4-methylhexA-enoic acid ' (VIll) {also called NaQuinate herein) in the form of a single injection (15µg/mouse/day) administered in iO'/o ethanol in · .. .

saline injections intraBeritoneai(y, 'Control mice received the ciirrier but" not the "NaQuinate r ' active component- 10 NaQuinate treated mice were obseNed to bleed out much more profusely than mice ' · -- . ' 0 that were not treated with NaQuinate, indicatirig, that NaQuinate exerts an anticoagulanf effect- Example 2 NaQuinate inhíbits the vitamin K-dependent enzyme gamma-carboxylation 15 reaction The activity of NaQuinate and related compounds was examined in the vitamin K cycle.

20 0 28

Reductase ¶ " " ~Y' . " " " |",,,:,,,,hA,,o,,,,, Reductase\ OH Carboxylase V F: / .CO:2 O"~O" r "R °' " Prote:"5ÂP,o,,,, 0

O :J>, "= "Y")7"ü" The Vitamin K cycte for Vitamin K, 1- Carboxylase Assay 5 The method of Houben et al (1997) was used [Houben, R. j. et al (1997). "Assay of Vitamin K-Oependent Carboxylase Activity in Hepatic and Extrahepatic Tissues-" Methods in Enzymobqy 282: 358-368]. 0 All the experimental tubes were prepared by Éhe addition of 25µ1 of bovine microsome preparatíon, 5µ1 of 10% 3-[(3-cho[afnidopropy])d imethylammonio]-2-hydroxy-1- 1O propanesulphonic acid (CHÂPS), 25µ1 of saturated ammonium sul'phate solution and 5µ1 of O.IM dithiothreitol (DTT) (Sigma), 25µ.1 of saturated ammonium suiphate (Sigma) sdution and 5µ1 CR 500µM decarboxylated osteocalcin (d-Oc). As the compounds were dissolved iri 10µ1 of DimeÉhy| sulphoxide (DMSO), 10µ1 of DMSO was added Eq the positive and negative contrd tubes. Buúer D (50OmM NaCl and 25mM Tris-HCl (PH 7.5)) was added to each tube to give a uniform volume tjf reactiori mixture (125µ1). The compounds (KCAT-5C (XlV), KCAT-5C-Me 29

Claims (17)

REIVINDICAÇÕES

1. Composto, caracterizado pelo fato de ser para aplicação co- mo um anticoagulante e apresentar a fórmula (I): em que 5 R1 representa hidrogênio, halogênio, ciano, trifluorometil, nitro, -ORa, SRa, SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra, -CONRaRb, ou um grupamento hidrocarboneto compreen- dendo um grupamento de cadeia reta, ramificado ou cíclico cada um conten- do até 18 átomos de carbono, ou um grupamento heterocíclico contendo até 18 átomos de carbono e no mínimo um heteroátomo; R2 representa, de modo independente em cada ocorrência, hi- drogênio, halogênio, ciano, trifluorometil, nitro, -ORa, SRa, SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra, -CONRaRb, ou um grupamento hidrocarboneto compreendendo um grupamento de cadeia reta, ramificado ou cíclico cada um contendo até 18 átomos de carbono, ou um grupamento heterocíclico contendo até 18 átomos de carbono e no mí- nimo um heteroátomo; R3 representa um grupamento hidrocarboneto compreendendo um grupamento de cadeia reta, ramificado ou cíclico cada um contendo até 18 átomos de carbono, e sendo substituído por no mínimo uma porção inclu- indo um substituinte -CO2Ra; em que Ra e Rb de modo independente representam, em cada ocorrência, hidrogênio, ou um grupamento hidrocarboneto compreendendo um grupamento de cadeia reta, ramificado ou cíclico cada um contendo até 18 átomos de carbono, ou um grupamento heterocíclico contendo até 18 átomos de carbono e no mínimo um heteroátomo; e n é 0, 1, 2, 3 ou 4; ou um solvato farmaceuticamente aceitável ou, mais particular- mente, sal ou pró-droga do mesmo. 5

2. Composto de acordo com a reivindicação 1, caracterizado pe- lo fato de que: R1 ou R2 representa hidrogênio, halogênio, ciano, trifluorometil, nitro, -ORa, SRa, SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra, -CONRaRb, ou um grupamento hidrocarboneto compreendendo um grupamento de cadeia reta, ramificado ou cíclico cada um contendo até 18 átomos de carbono, ou um grupamento heterocíclico contendo até 18 átomos de carbono e no mínimo um heteroátomo; R3 representa um grupamento hidrocarboneto compreendendo um grupamento de cadeia reta, ramificado ou cíclico cada um contendo até 18 átomos de carbono, e sendo substituído por no mínimo uma porção inclu- indo um substituinte -CO2Ra; em que Ra e Rb de modo independente representam hidrogênio, ou um grupamento hidrocarboneto compreendendo um grupamento de ca- deia reta, ramificado ou cíclico cada um contendo até 18 átomos de carbono, ou um grupamento heterocíclico contendo até 18 átomos de carbono e no mínimo um heteroátomo; n é 1, 2, 3 ou 4, opcionalmente em que R1 representa um grupamento alquila in- cluindo grupamentos alquilas de cadeia reta ou ramificados contendo de 1 a 9 átomos de carbono.

3. Composto de acordo com a reivindicação 1 ou 2, caracteriza- do pelo fato de que R1 representa um grupamento hidrocarboneto compre- endendo um grupamento de cadeia reta, ramificado ou cíclico cada um con- tendo até 18 átomos de carbono, opcionalmente em que R1 representa meti- la.

4. Composto de acordo a reivindicação 1 ou 3, caracterizado pe- lo fato de que n representa 0.

5. Composto de acordo com a reivindicação 2 ou 3, caracteriza- do pelo fato de que n representa 4 e R2, em cada ocorrência, é hidrogênio.

6. Composto de acordo com qualquer uma das reivindicações 1 a 5, caracterizado pelo fato de que R3 representa um grupamento hidrocar- 5 boneto compreendendo um grupamento hidrocarboneto de cadeia reta ou ramificado contendo até 18 átomos de carbono substituído por no mínimo uma porção incluindo um substituinte -CO2Ra, opcionalmente em que R3 re- presenta C1-9 alquila ou C2-9 alquenila, cujos grupamentos podem ser de cadeia reta ou ramificados, substituído por no mínimo uma porção incluindo um substituinte -CO2Ra, opcionalmente em que Ra da no mínimo uma porção incluindo um substituinte -CO2Ra representa hidrogênio ou um grupamento hidrocarboneto compreendendo um grupamento hidrocarboneto de cadeia reta ou ramificado contendo até 18 átomos de carbono, por exemplo, em que Ra da no mínimo uma porção incluindo um substituinte -CO2Ra representa hidrogênio ou um grupamento hidrocarboneto compreen- dendo uma cadeia reta ou metila.

7. Composto de acordo com a reivindicação 6, caracterizado pe- lo fato de que R3 é representado pela fórmula (II) que se segue: onde a ligação não acoplada representa o ponto de fixação do fragmento estrutural de fórmula (II) ao resto do composto de Fórmula (I); Ra é como definido em qualquer uma das reivindicações 1 a 6; Rc, Rd e Re são selecionados de modo independente entre hi- drogênio ou C1-6 alquila (o qual pode ser de cadeia reta ou ramificado); q é 1, 2, 3 ou 4; r e s são selecionados de modo independente de 0, 1, 2, 3 ou 4; ----------- representa uma ligação única ou dupla, e quando esta é uma ligação dupla Re não está presente na fórmula (II) acima; opcionalmente em que o fragmento estrutural de fórmula (II) é selecionado de:

-(CH2)7CO2H; -CH2CH=C(CH3)(CH2)2CO2H; e -CH2CH=C(CH3)CO2H.

8. Composto de acordo com qualquer uma das reivindicações 1 5 a 7, caracterizado pelo fato de que o composto de fórmula (I) é selecionado da lista compreendendo: (i) 2,3-dimetoxi-1,4-naftoquinona (XVI); (ii) menadiona (III); (iii) KCAT-5C-Me (XIX); (iv) NaQuinato-Me (VII); mais particularmente, (v) ácido (4E)-6-(1,4-diidro-2-metil-1,4-dioxonaftalen-3-il)-4- metilhex-4-enóico (VIII); (vi) ácido (2E)-4-(1,4-diidro-2-metil-1,4-dioxonaftalen-3-il)-2- metilbut-2-enóico (XIV); e (vii) ácido 8-(1,4-diidro-2-metil-1,4-dioxonaftalen-3-il)octanóico (XV), e opcionalmente ácido (4E)-6-(1,4-diidro-2-metil-1,4- dioxonaftalen-3-il)-4-metilhex-4-enóico (VIII).

9. Composição farmacêutica, caracterizada pelo fato de que compreende um composto de fórmula (I), como definido em qualquer uma das reivindicações 1 a 8, e um veículo, diluente ou excipiente farmaceutica- mente aceitável respectivo, para aplicação como um anticoagulante.

10. Composto de fórmula (I) de acordo com qualquer uma das reivindicações 1 a 8, ou composição farmacêutica de acordo com a reivindi- cação 9, caracterizado(a) pelo fato de ser para uso na prevenção de trombo- se, ou doenças causadas desse modo, em um paciente que deve ser sub- metido a um procedimento cirúrgico.

11. Composto de fórmula (I) de acordo com qualquer uma das reivindicações 1 a 8, ou composição farmacêutica de acordo com a reivindi- cação 9, caracterizado(a) pelo fato de ser para aplicação como parte de uma terapia combinada junto com outro agen- te terapêutico; ou para aplicação na modulação do efeito de coagulação de um coagulante; ou para aplicação em um método para o manejo da capacidade de coagulação sanguínea de um paciente, o método compreendendo administrar a um pa- ciente que necessite de tratamento uma quantidade terapeuticamente eficaz 5 do composto ou composição para exercer um efeito anticoagulante, em se- guida administração de um coagulante para modular ou reverter o efeito an- ticoagulante; ou para aplicação em um regime de tratamento compreendendo tratamento de um paciente com o composto composição (I), em seguida tratamento do mesmo paciente com vitamina K, ou coagulante diverso, depois de cirurgia, para permitir que ocorra coagulação sanguínea.

12. Produto de combinação, caracterizado pelo fato de que compreende: (A) um composto de fórmula (I), como definido em qualquer uma das reivindicações 1 a 8, e (B) outro agente terapêutico, em que cada um dos componentes (A) e (B) é formulado em mistura com um adjuvante, diluente ou veículo farmaceuticamente aceitável.

13. Formulação farmacêutica, caracterizada pelo fato de que in- clui um composto de fórmula (I), como definido em qualquer uma das reivin- dicações 1 a 8, e outro agente terapêutico, em mistura com um adjuvante, diluente ou veículo farmaceuticamente aceitável.

14. Kit de partes, caracterizado pelo fato de que compreende componentes: (i) uma formulação farmacêutica incluindo um composto de fór- mula (I), como definido em qualquer uma das reivindicações 1 a 8, em mistu- ra com um adjuvante, diluente ou veículo farmaceuticamente aceitável; e (ii) uma formulação farmacêutica incluindo outro agente terapêu- tico, em mistura com um adjuvante, diluente ou veículo farmaceuticamente aceitável, cujos componentes (i) e (ii) são cada proporcionados em uma forma que é adequada para administração em combinação um com o outro;

opcionalmente em que o outro agente terapêutico é selecionado entre coagulantes e anticoagulantes diversos, opcionalmente sendo a vita- mina K (por exemplo, vitamina K1 ou vitamina K2) ou varfarina; ou compreendendo 5 um composto, como definido em qualquer uma das reivindica- ções 1 a 8, ou composição, como definida na reivindicação 9, e um coagu- lante.

15. Combinação, caracterizada pelo fato de ser de um composto de fórmula (I), como definido em qualquer uma das reivindicações 1 a 8, ou composição, como definida na reivindicação 9, com um coagulante, opcio- nalmente em que o coagulante é vitamina K (por exemplo, vitamina K1 ou vitamina K2).

16. Coagulante, caracterizado pelo fato de ser para aplicação na modulação do efeito de um composto de fórmula (I), como definido em qual- quer uma das reivindicações 1 a 8, ou uma composição farmacêutica como definida na reivindicação 9.

17. Uso do composto para preparo de composição ou qualquer outra concretização da invenção, por exemplo, de produto ou de processo, ou qualquer outra categoria aplicável de reivindicação, desde que sejam en- globados pela matéria inicialmente descrita, revelada ou ilustrada no pedido de patente.