CA2242598A1 - Quinolones and their therapeutic use - Google Patents

Abstract

A compound of formula (I), wherein R1 represents a bicyclic structure in which a cycloalkyl or heterocyclo ring is bound to NH and is fused to a second ring selected from aryl or heteroaryl, and in which either or each ring is optionally substituted by one or more substituents chosen from halo, C1-6 alkoxy, hydroxy, CN, CO2H (or C1-6 alkyl esters or C1-6 alkyl amides thereof), C1-6 alkyl, NR6R7 and SO2NR6R7; R3, R4 and R5 are the same or different and represent H, halo, C1-6 alkoxy, hydroxy, CN, CO2H (or C1-6 alkyl esters or C16 alkyl amides thereof), NR6R7, SO2NR6R7 or C1-6 alkyl in which alkyl is optionally substituted with halo, C1-6 alkoxy, hydroxy, CN, CO2H (or C1-6 alkyl esters or C1-6 alkyl amides thereof), NR6R7 or SO2NR6R7, or any adjacent two substituents R3-R5 are joined to form an optionally substituted carbocyclic aromatic, heteroaromatic, saturated carbocyclic or heterocyclic ring; R6 and R7 are the same or different and represent H, C1-6 alkyl, cycloalkyl, C1-6 alkylcarbonyl, arylcarbonyl, C1-6 alkoxycarbonyl, arylsulphonyl or C1-6 alkylsulphonyl, or NR6R7 is a 5 or 6-membered ring such as pyrrolidine, piperidine, morpholine or piperazine; X represents a linking group selected from -(CR9R10)2-3-, -Y-(CR9R10)2-, -(CR9R10)2-Y-, -CR9R10-Y-CR9R10- and -Y-CR9R10-Z-, Y and Z being independently NR11, O or S(O)0-2, provided that Y and Z are not both S(O)0-2; Q represents O or S; and each R9, each R10 and R11 are the same or different and are H or C1-6 alkyl; or a pharmaceutically-acceptable salt, solvate or hydrate thereof.

Description

OUINOLONES AND THEIR THERAPEUTIC USE
Field of the Invention The present invention relates to novel qllinolone derivatives and pharm~ceutir~lly-acceptable salts thereof, processes for their production, and their 5 formulation and use as pharm~ce~lticals.
Back~round of the Invention Qllin~cne and quinolizine compounds are known mainly as ~ntib~erial agents (JP-A-05025162; US-A-5037834; EP-A-0420069; JP-A-02040379; EP-A-0343560;
DE-A-3816119; EP-A-0304158; FR-A-2644784; WO-A-9410163; DE-A-3641312) or 10 antiviral agents (US-A-4959363), but also as inhibitors of 5-lipoxygenase (JP-A-02124871), cardiotonics and vasodilators (JP-A-01061461~ and 5-HT3 antagonists for the tre~tm~nt of peripheral disorders associated with pain (WO-A-9501793; GB-A-2236751).
GB-A-2236751 describes quinolone-3-carbox~mides as 5-HT3 antagonists, for 15 use in the trç~tn~-nt of neuro-psychiatric disorders. US-A~001243 dicrlosec bPn7oqllinoline-2-carboxylic acids and esters as anti-microbial agents. GB-A-1433151 ~licclo~c N-tetra7-olyl-~n7~r~llinnli7in~-2-carboy~mi~iec~ as agents that may be useful in the tre~tm~ont of allergies incl~lrlin~ asthrna.
phospho~liest~rases (PDE) and Tumour Necrosis Factor (TNF), their modes of 20 action and the therapeutic utilities of inhibitors thereof, are described in WO-A-9704?75 and WO-A-9704779, the co,lLt;"L~ of which are incolyolaLed herein by reference. The same do~ "~ ie- lose quinolones having utility as PDE and TNF inhibitors.
Summary of the invention This invention relates to compounds and their utility to treat disease states, for 25 ~ ple disease states ~e~or~te~ with proteins that mediate cellular activity, for ~y~mrle by inhil iLhig tumour necrosis factor and/or by inhibiting phosphodiesLt;l~se IVAccording to the invention~ novel compounds are of formula (I):

W O 97~0999 PCT/GB97/00491 R ~ ) ~/~ 1 X/ (I) wherein R~ .c;~,ll~ a bicyclic structure (e.g. indanyl) in which a cycloalkyl orheterocyclo ring is bound to NH and is fused to a second ring sPIected from aryl or heteroaryl, in which either or each ring is optionally s~h~ .le~ by one or more s~ ; chosen from halo, Cl.6 alkoxy, hydroxy, CN, C02H (or Cl.6 alkyl esters or Cl 6 alkyl amides thereof), C, 6 a~kyl, NR6R' and SO2NR6R~;
R3, R~ and Rs are the same or d~ IL and ,~ ,res ,L H, halo, Cl.6 alkoxy, 1~ hydroxy, CN, CO2H (or Cl 6 alkyl esters or C1.6 alkyl amides thereof), NR6R', SO2NR6R7 or Cl.6 alkyl in which alkyl is optionally substih~ted with halo, Cl~ alkoxy, hyd~u~y, CN, CO2H (or Cl 6 allyl esters or Cl 6 alkyl amides thereof), NR61~7 or SO2NR6R', or any Pf~nt two ~ellbstit~ nte R3-R5 are joined to form an optionally s~,l,sl ;1 ~lcd carbocyclic aromatic, h~lel ~aru",alic, s~L~ Led carbocyclic or heterocyclic ring;
R6 and R' are the same or di~c~ and ,ep,es_.,L H, Cl.6 alkyl, cycloallcyl, Cl.6 alkyl~l,.,l.yl, aryl~l u..yl, C~ 6 alkux~,a.l~onyl, arylculphonyl or Cl.6 alkyic llpho,.~l or NR6R7 is a 5 or 6-membered ring such as pyrrolidine, piperidine, morpholine or e;
X r~ 3e.lls a linking group selecteci from -(CR9RI~)23-, -Y-(CR9RI~)2-, -(CR9R'~)2-Y-, -CR9RI0-Y-CR9Rl0- and -Y-CR9RI0-Z-, Y and Z being in~e~ y NRII, O or S(0)0 2, provided that Y and Z are not both S(0)0 2;
Q .~,~.escillts O or S;
each R9, each Rl~ and Rll are the same or di~.e-,L and are H or Cl 6 alkyl;
and pharrn~ce~ltir~lly-acceptable salts, solvates and hydrates thereo~
Combin~tionc of sub~ .fn~c and/or variables are only permicsible if such coll,binalions result in stable compounds.

Description of the Invention Suitable phal...A~ ic~11y-ArceptAhle salts are pharm,.f~eufir~11y-~ccept~hle base salts and pharm~ceuticAlly-acceptable acid addition salts. Certain of the compounds of forrnula (I) which contain an acidic group form base salts. Suitable pharmArie~1ti~z~11y-5 acceptable base salts include metal salts, such as alkali metal salts for example sodiumsalts, or organic amine salts such as that provided with ethylene~liA...;..r Certain of the compounds of formula (I) which contain an arnino group form acid ~AAiti~n salts. .c~ acid addition salts include pha~ f e-lti~ y-acce~Jlal)le U~Olgalllc salts such as the s~1ph~t~, nitrate, phosphate, borate, hydrochloride and hydrobromide 10 and ph~...Ac~ 11y-~ceplA~le organic acid addition salts such as acetate, tartrate, m~ te, citrate, s~cnin~te, b~n7o~te ascorbate, ,l~ ne~l~lrhate~ a-k~tog1ut,.rate, a-gly~,c,pho.,~ e and glucose-l-ph~ e The phal ...~ tic~11y-acceptable salts of the compounds offorrnula (1) are p-ep~ed using conventional procedures.
It uill be a~l~;aLd by those skilled in the art that some compounds of formula 15 (I) can exist in more than one t~tometric form. This invention extends to all IA~IIO.~ - ic forms.
It will be a~plG~,;at~d that some of the compounds according to the invention can contain one or more asyllllllGllically-substituted carbon and/or sulphur atoms. The ~.~..ce of one or more of these a~y~u~t;ll ic centers in a compound of forrnula (I) can 20 give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, inr~ ing enantiomers, and diastereoisomers and nu~Lul~s, in-~7~-~ing racemic mixtures, thereo~
When used herein the term alkyl whether used alone or when used as part of anothergroup inrl-1dP!s straight and b-~cl-ed chain alkyi groups. CycloaLkyl inClu~es a 2~ non-~,l..aLic cyclic or multicyclic ring system of about 3 to lO carbon atoms. The cyciic alkyl may optionally be partially unsaturated. Alkoxy means an alkyl-O- group in which ~ the alkyl group is as previously described. Alkyl amide in~1udes both mono~1kyl and dialkyl amides, in which the alkyl groups (previously defined) may be the sarne or di~rerenl. Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as30 previously d~-ibed. Aryl ;..~ f C carbocyclic radicals co.~ about 6 to lO carbon atoms. Heteroaryl means an about 5 to about lO-membered aromatic monocyclic or multicyclic ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
Heterocyclo means an about S to about 10-membered saturated or partially saturated monocyclic or multicyclic ring system in which one or more of the atoms in the ring S system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur. Aryl~a l,.,.,~l means an aryl-CO- group. Arylsulphonyl means an aryl-SO2-group. AL~cyl~ .h~ rl means an alkyl-SO2- group. ALIcoxycarbonyl means an alkoxy-CO-group. When any h,vo of R3, R~ and R5 are joined tog.=th~r, an ~ plc is methylenedioxy (OCH20). Halo means fluorine, chlorine, bromine or iodine.
The compounds of formula (I) are preferably in pharmi~cel-~ically-~cG~pl~ble form. 13y ph~...~Ge~ ly-acceptable form is meant, infer alia, a pharm~re~lti~ ~ily_ r ~ 2~ ~ L !~ level of purity excluding normal ph~ ~--~ ~tic~l additives such as diluents and carriers, and in.~l~1ding no material con~idered toxic at normal dosage levels. A
pharm~çe~lti~lly-acceptable level of purity will generally be at least 5û% -~c~ ng 1~ norrnal pharm~çellti~ additives, p,ere,~bly 75%, more p,~_rt,~ly 90% and still more preferably 95%.
Compounds of the invention can be used in the prevention or l~r ~ 1 of "TNF-".P~ l disease or disease states", i.e. any and all disease states in which l'NF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be 20 released, such as but not lirnited to IL-l or IL-6. A disease state in which IL-1, for c~, is a mayor component, and whose production or action is exacc,l,aL~,d or secreted in ~ ullsO to INF, would therefore be considered a disease state ..~ç-l;A~e~ by ~F. As TNF-~ (also known as Iymphotoxin) has close structural homology with TN~-a ~also known as ~ ;.,), and since each induces similar biologic responses and binds 25 to the same cellular rece~Lor, both TNF-a and l'NF-~ are considered to be i.lhil,iLe~ by p~ le ofthe present invention and thus are herein ~f~led to collectively as "TNF"
unless specifically int~ic~tecl otherwise.
This invention relates to a method for .~ AiA~ or inhibiting the e.~ylllaLic activity or ca~alytic activity of PDE IV in a I~ a1 in need thereof and for inhibiting the 3û production of TN~ in a m~mm~l in need thereof, which co"~, ises ~lmin;ctering to said s mslmmzll an effective amount of a compound of Forrnula (I) or a pharmz reutirs lly_ S~ccept~le salt thereo~
PDE IV il~llil,ilo.~ are useful in the ll~l ..f~ of a variety of aaergic and ;"n~ ,.."~ lo.y diCL~z~cp-c~ incl~l iing asthma, chronic bronchitis, atopic dL ..l,aLiLis, urticaria, 5 allergic rhinitis, allergic conjunctivitis, vernal corljllnr,tivitis~ ;..n~ ;on of the eye, allergic responses in the eye, eosinophilic grzmlllomzl psoriasis, Bechet's disease, ~"yli~L l-~lu~c,~phyt~ - ~purpuranephritis, joint;..lls~ l;rJn,arthritis,.l~ oi:l arthritis and other arthritic con~iitionc such as rhPl-m~toiL~ spondylitis and osteoa- lLl ilis, septic shock ulcerative colitis, Crohn's disease, reperfilsion injury of the myocardium and 10 brain, chronic glomerulonephritis, endotoxic shock and adult ~ ilaLuly distress a~y~dlu~-e In ~Mition, PDE IV inhibitors are useful in the trPz~tmPnt of rli~hçtes incip ~llc and conriitionc associated with cerebral metabolic inhibition, such as cerebral serlility, senile d~mPntiz~ 7h~imprls disease), memory illlpaulll~ l associated with Pa.hinson's disease, depression and multi-infarct dPm~nti~ PDE IV inhibitors are also 15 useful in conriitiQn-c ameLiorated by neu-oprote.~--l activity, such as cardiac arrest, stroke and i~ .llliLL~,nL clz~uAic~tion~ PDE IV inhibitors may be useful in the llç~
of mllltirle sclerosis, tardive dyat il~ icrll~. ..is and ~lmtin~Qn~s disease.
Additionally, PDE IV u~il,iLol~ could have utility as ~ ,lole~ A special embodiment of the therapeutic metho~s of the present invention is the lleS l -~ of 20 asthma.
The viruses co..l~..p~z te~i for treS~tm~nt herein are those that produce TNF asa result of infection, or those which are sensitive to inhibition, such as by de~ ,~e~
replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HlV-1, H~-2 and HIV-3, ~,ylQ~çgi-iovirus (CMV), 25 influçn7z, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
~ This invention more speçifif z~iiy relates to a method of treating a mstmms i afflicted with a human immtlnofie~fi~ nry virus (~V), which CO~y~ ises Z~ r ~ ing to such ms mmz i an effective TNF-inhibiting amount of a compoulld of Forrnula (I) or a 3û pharmzlcetltirz~lly-acceptable salt thereof The compounds of this invention may be also be used in association with the V~,L~ y LleA~ of 7nim7Al~, other than h~m7~n!;, in need of inhibition of TNF
production. TN~ me~iAted ~licp7~ces for Ll~n~ therapeuticAlly or prophylactically, in animals include disease states such as those noted above, but in particular viral 5 infections. FY~mrlP!s of such viruses include, but are not limited to, feline imm-mod~ficiency virus (FIV) and other retroviral infections such as equine infectiollc A/~7~ Vlrus~ caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
The compounds of this invention are also useful in treating parasite, yeast and fungal ;-.r~ c, where such yeast and fungi are sensitive to upregulation by TNF or will 10 elicit TNF production in vivo. A p-.,re.-ed disease state for l,~,.l.,....l is fungal ~ m~nin~sic Compolm~c ofthe invention may also suppress neurogenic i..~ ;on through elevation of cAMP in sensory neurones. They are, Ll.e-erole, 7~n7~lg~cic, anti-tussive and anti-hyperalgesic in ;..ll~ lo~y dic~o~cps a~oci~ted with irritation and pain.
Compounds ofthe general formula (I) may be pre?an,d by any suitable method known in the art and/or by the following process, which itself fo~ns part of the invention.
In the de~.;~Lion and formulae below the groups Rl, R3, R4, R5, R6, R7, R9, Rl~,Rll, Q, X and Z are as defined above, except where otherwise in~i5~ted It will be appr~;aLed that fLIn~;Liona~ groups, such as amino, hydroxyl or c~uLo~yl groups, present 20 in the various compounds described below, and which it is desired to retain, may need to be in ~)rul~iLed form before any reaction is initi~te~ In such in~t~n~c, removal of the protecting group may be the final step in a particular reaction. Suitable p.c,tecLing groups for such functionalities will be appa"_..L to those skilled in the art. For specific details see "Protective Groups in Organic Synthesis", Wiley Interscience, T W Greene, 25 PGM Wuts. Ihus a process for ~.e~ing compounds of formula (I) in which, say, R~ is CO~I c~ ,lise3 d~i~lul~Li lg (for e ~ le by hydrolysis) a co,l,po~,~d of formula (I) in which R~ is CO2R wherein R lt;~.cse-.Ls a suitable p.ute -li..g group ~e.g. methyl).
A pl~fel l ed embodiment of forrnula (I) COIll~)l ises those compounds whe;ein X
is (CR9RI~)3.
A process for prep~;llg compounds of general formula (I) col"~,ises coupling an acid of forrnula (~I) ' R3 Q O
J ~J OH

X/ (Il) 10 or an activated derivative thereoft with an amine offormula (m) NH2-~ (III) Amines of formula (m) are Cu~ ,ialiy available or can be readily obtained 15 from colll--,e,~ialiy-avaiiable starting materiais using methods known to those sicilled in the art. Some of the amines of forrnula (m) are conveniently plt:p~ed by reductive ;on of an ~p~-u~-iate carbonyl compound with a suitable amine. This ~min~tion may be carried out under any suitable standard conditions known to those skilied in the art. Active derivatives of acids of formula (II) include, for examplet acid anhydrides and 20 acid halides, such as acid chiorides.
The co~rling reaction may be pt;lrol.ned using standard con~itions for aminationreactions of this type. Thus, the reaction may be achieved in a soivent, for ~ ,ie an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofurant an amide, e.g. a substituted amide such as dimeth~lro-...-...;de~ or a haiogenated hydrocarbon such as dichiorometh~nP, at a low te~ el~LIlre, e.g. -30~C to ~II~ ~t te.llp~ .~L-Ire, such as -20~C to 0~C, optionally in the pl~;sence of a base, e.g. an organic A base such as an amine, e.g. triethylamine or a cyclic amine such as N-methyimorpholine.
The reaction may additionally be pe~ru~lcd in the ~-c;sence of a cor~ ncin~ agent, for example a diirnide such as N,N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as l-hydroxybenzotriazole. Alternatively, the acid may be WO 97/30999 PCT/GB97tOO491 reacted with a chloroformate, for ~Y~mple ethyl chloroformate, prior to reaction with the arnine of formula (m).
Acids of general formula (II) may be ~rel,aued according to the procedure described in EP-A-0373531, DE-A-0683169 or by ~minCI~y and Meltzer, .f. Med.
S Chem., 11:160-164 (1968). This procedure incllldes hydrolysis ofthe cclrle~o~ ,g ester of general forrnula (IV) R3 Q o R~\OR12 (~

1~ where Rl2 ~ s_ ~ls an (ar)allyl group such as methyl, ethyl, benzyl or terf-butyl.
Compounds of formula (I~l) in which Q=S may be derived frorn the corresponding compounds where Q=O using standard conditions for sul~huli~aLion of such comro~-n-1c For ~ - ;....plc suitable conditions comprise reaction with phosphorus p~nt~c~ hide (P4S,o) in an organic solvent such as pyridine at an applopl;ale 20 temperature. The reflux te,l-pt~ re of the solvent is ~l efel I ~,d.
Esters of general formula IV wherein X is -Y'-CR9Rl0-Z', Y' and Z' each being NRII, O or S, e.g. -~CR9R~0-NR"-, may be p.~;~,ared by cyclisation of illle"..cAi~t~s of general formula (V) R3 o O
~ ~ ~, ~ ~ oR12 F Z
~y~ + R9 using procedures evident to those skilled in the art; for example, cyclisation may utilise a tetraalkyl~mmo~ m fluoride such as tetrabutylammonium fluoride as reagent. Y' or Z' as S may subsequpntly be converted to SO or SO2.
Interm~Ai~Ps of general formula (V) may be prepared by forrnylation of a co,.~ nding intermç~ te of general formula ~VI) R3 o O
lOR ~

F ~H

using, for example, formaldehyde.
Compounds of general forrnula (VI) may be prepared from the corresponding pl o~ ,Led compounds of general forrnula ~VII) ~ r ' 12 2~ F PZ' (~/II) wht.ein P is any suitable protec~ing group, e.g. Boc, by deprotection using methorl5 evident to those skilled in the art, such as reaction ~,vith base.
The rl ~-noli~le nucleus in the above compounds may be generated by reaction of 30 an ester of forrnula (VIII~

R3 o o R r ' R F--OEt F ( /111 with an amine of general formula (IX) H2N-ZP (I~

Intermediates of general formula (VIII) may be made from benzoic acids of general formula (X) R4~,~, COOH
l ll R5~--F (~) 25 using methodology analogous to that reported previously (J. Med. Chem. 34:1142 (1991)).
When X is -CR9Rl0-~-CR9Rl0-, esters of general formula (rV) may be pl ~ ,d from the co..~,~p~nding interm~ te of general formula (Xl) R3 o o 1:: J
H H (>~I) by reaction with a formate derivative of general formula (X~) R9R'0C(oRI2)~ (XII) Compounds of general formula (Xl) may be p~ ~ed by hydrolysis of the col,e:,ponding interm~ tes (xm ~/ OR~;

25 wherein R.13 ,eprese-l~s a protected form of Y'H such as OAc, SAc or NRI'Boc.The q~inolin~ nucleus in the compounds (IV) and (Xl~) may be generated by cyclisation of an ester of formula (XlV) or (XV) R ~ C(COOR )2 ~ (COOR )2 Q~l\/) (X\~) using methodology analogous to that described by ~min~l~y and Meltzer, supra.
Suitable con~lifinnc include, for ~ r ~, heating to reflux in diphenyl ether or a eutectic mixture of diphenyl ether and biphenyl.
1~ Compounds of formula (XtV) or (XV) may be ~ arcd by the reaction of an aniline of general formula (XVI) or (XV~) ~'X/ ~R13 ~VI) ~VII) with a diallyl alkoxyethyli~linpm~lonate of the formula (X~III) (Rl2ooc)2c=cH-oRl4 (XVIII) wherein Rl4 is a lower alkyl group such as methyl or ethyl. This reaction may be carried out under suitable standard con~itionc known to those skilled in the art, for PY~mple those described by ~minCIry and Meltzer, supra. For example, the reaction may becarried out at elevated te"~pe~aLu~e~ ~or example 80-150~C, in an inert solvent (such as 5 xylene) or, p, ~re, ably, in the ~s~nce of solvent.
Inte,..~ iA~ec of formulae (I~), (X), (~), (XVI), (XVII) and (XVm) are commercially available or can be readily obtained from co~ nel eially available starting materials using mPSht)rl~ known to those skilled in the art.
Compounds of formula (I) may also be prepared by il~Lercoll~ersion of other 10 compounds offormula (I). I hus, for example, a compound of formula (I) wherein R4 is Cl 6 alkoxy may be ple~al~d by applo~liate alkylation of a compound of forrnula (~
wl._. e,ll R~ is a l,ydr~ group.
Any rnixtures of final products or i"~ es obtained can be sep~ aled on the basis ofthe physico-çhPm~ differences ofthe con~titllentsJ in known manner, into the -15 pure final products or illlelll~ t~c~ for example by chromatography, dictill~tio~, fractional cryst~lli7~tiQn~ or by formation of a salt if ap~, up, iaLe or possible under the c~ r~C It will be a~ ~;aled that where a particular stereoisomer of forrnula (I) is required, this may be obtained by conv~ntion~l resolution techniques such as high - p~.ru~u~lce liquid .. hl u,,,a~ography. Where desired, however, a~" u~, ;a~e hornochiral 20 star~ing ~,.a~e,i~ls may be used in the reaction seq-len~e to yield a particular ste~eoiso, of formula (I).
A compound of formula ~[) or where apl), op~ iaLe a pharm~ceutically-acceptable salt thereof and/or a pharm~ceutic~lly-acceptable solvate thereof, may be ~minicpred per se or, p,~ft,.~ly, as a pharm~.e~ltic~l composition also co,,,~ ulg a 2~ pharm~rellti~lly-acceptable carrier.
Accordingly, the present invention provides a pharm~ea-tic~l composition comprising a compound of formula (I) or where appropriate a pharm~ce~ltir,:-lly-acceptable salt thereof and/or a pharrn~re~tic~lly-~cc~rt~ble solvate thereof, and a pharm~ce~lti~lly-acceptable car.-ier.
The active compound may be form.ulated for ~.l.. ;.,:~l a.ion by any suitable route, the preferred route depending upon the disorder for which tre~tm-~nt is required, and is preferably in unit dosage form or in a form that a human patient may ~ . to himselfin a single dosage. AdV~nt~gf-~ollcly~ the composition is suitable for oral, reetal?
topieal, p~Gl.~ ion or through the respiratory tract. P~,pa.~lions may be ~esi~ned to give slow release of the active in~l edicl-L.
S The term ~c~Le ~I as used herein inrludf ~ ~ lhcut~neous injeetions, i~ veno~ls, intr~m ~ ~Lc --al injeetion or infusion terhniqlles In addition to the Lr~l~.. l of warrn-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, ete, the compounds ofthe invention are effective in the trÇ~tm-~nt of hllm~nc The compositions of the invention may be in the form of tablets, cAr.;,.~lrc sachets, vials, powders, granules, lozenges, suppositories, lccon~f;l~ l le powders, or liquid l~rcp~aLions such as oral or sterile parenteral solutions or s--cr- ncions Topical formulations are also envisaged where app, Opl iale In order to obtain ~ of ~ tion it is pl crt:~ l ed that a composition of the invention is in the form of a unit dose Unit dose pl~c~ .lAlion forms for oral a~ l dliOl~ may be tablets and r~rSlllpc and may contain eonventional c ~ sueh as binding agents, for ~ ~~ ..ple syrup, acacia, gelatin, sorbitol, tr~g~ nth, or polyvinylpyrrolidone; fillers for: ~-le lactose, sugar, maize-stareh, ealcium pho:,ph,-sorbitol orglyeine; ~ g lubricants, for example m~gn.ocillm :i~ea-~,Le; ~ ;"",~
for example starch, polyvinylpyrrolidone, sodium starch glycolate or rnicrocrystalline 20 r~llnlose, orph~l~ ll;r~lly-~ t~llle wetting agents such as sodium lauryl s~lrh~tP~
Solid oral compositions may be p.c~,a.cd by conventio~ meth~ of b'e " l~"
filling, ~ ' ' g or the like. ~2 Te~t~A blending operations may be used to di~L. il~LIle the active agent thro~Phout those c~....l.o~;lio--c employing large ~lu~ntiti~ offillers.
Such operations are of course conventional in the art. The tablets may be coated25 accc"dillg to methods well Icnown in normal phan~ceutir~l practice, in particular with an enteric co~tin~
Oral liquid p~ Lions may be in the form of, for example, emulsions, syrups or elixirs, or may be ,c ~ csc--~ed as a dry product for reconstitution with water or other suitable vehicle before use~ Such liquid preparations may contain conv.,..Lio.~al additives 30 such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelati~
hydroxyethylcçll--lose, carboxymethylcellulose, ~lllminillm stearate gel, hydrogenated edible fats; emulsi~3ring agents, for PY~mple lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl aicohol;
J preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, as 5 desired, conventional flavouring or colouring agents.
Co,.-l,o~ilions may also suitably be prese ~Led for ~ dlion to the ~e~p;lalo~y tract as a snuff or an aerosol or sol~1tion for a tleb~ Pr, or as a microfine powder for ",~nm,.~ n, alone or in co...l.:n ~ with an inert carrier such as lactose. In such a case the particles of active compound suitably have ~i~metPrS of less than 50 ~,lm, such as 10 from 0.1 to S0 !lm, ~Jrèrel~ly less than 10 ~lm, for example from 1 to 10 ~m, 1 to 5 llm or from 2 to 5 ~,lm. Where app-op-iate, small amounts of other anti-~ethm~tire and ...... l~n.I~ o~, for ~ le syl~yalho~n;~ ;c amines such as isop",naline, iSG~.. ha~ine, e~ll.u~ l, phenylepLil-e and ~l~he.l~ e; corticosLe-oids such as pr~ solone and adrenal stim~ nte such as ACTH may be inrl--d~A
For p~llLc~ A~ lion, fluid unit dosage forms are plepa.~,d ~tili7ing the con.pou.~d and a sterile vehicle, and, dep~nAing on the conr,e-~ Lion used, can be either "..~ Aed or dissolved in the vehicle. In ~ ~;ng solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ~mpo--le and sealing.
Ad~ ,uly, adjuvants such as local ~ I;r, a preservative and buffering agents can be dissolved in the vehicle. To ~nh:~nce the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Pa~enLel~l ~IS~ onS are Pl~ ~al~ in s~bst~nti~lly the same manner, except that the co--.pou..d is suspended in the vehicle instead of being dissolved, and ,Lel;lic~l;on cannot be25 accomplished by filtration. The compound can be sterilised by exposure to a suitable ~n .~ g agent, before sU.,I~,nd~ll~, in the sterile vehicle. Adv~nt~geo-lsly, a s-.. r~
or wetting agent is inr,l~ eA in the composition to f~rilit~te uniform distribution ofthe compound.
The compositions may contain from 0.1% to 99% by weight, plerelably ~om 10-30 60% by weight, of the active material, depending on the method of ~,..;. ,;~l ~ ;iLio--.

Compounds of forrnula (I), or if appropriate a pharn~re~ltically-acceptable saltthereofand/or a pharn ~ro~ ~tic~lly-~ccept~ble solvate thereof, may also be ~lminictered as a topical rO~ alion in coll-l~inalion with conventional topical excipients.
Topical form~ tionc may be presented as, for inct~nce, Oi~ , creams or 5 lotions, i~ .~"~ d dl- jsi"~,s, gels, gel sticks, spray and aerosols, and may contain a~pl-op. i~Le ~ o..~ l ;ol-~l additives such as preservatives, solvents to assist drug penetration and rmollifntc in oi..l~ and creams The formulations may contain pitl;l,le convention~l carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions Suitable cream, lotion, gel, stick, o;"l",r l~, spray or aerosol form~ tione that may be used for compounds of formula (I) or if a,v~.o~.ia~e a pharm~ce~ltir~lly-t~ salt thereo~, are comr~..Liollal form-ll~tionc well known in the art, for e,L p!~, as d~.il,ed in ~landa,.l text books such as Ha~s Cocm~tieo~egy published by Leonard Hill Books, R~ ol-'s Pharm~- e~lti~ Srj- nc~ c and the British and US
15 ph~rm~copoeias~
Suitably, the compound of formula (I), or if app-u~-iaLe a pharm~re~-tir~lly-acceptable salt thereo~, will co...~ e from about û.5 to 20% by weight of the form~ tion, ~l~f~,.ably from about l to lO%, for f~f~mrle 2 to 5%.
The dose of the compound used in the Llf,~ l of the hl~vc-llion may be 20 fi~ t~ ~ .. ~ ~r~ by the skilled man, and will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and the relative efficacy of the co--l~ow-d.
However, as a general guide suitable unit doses may be 0 1 to lO00 mg, such as 0.5 to 200, 0.5 to lO0 or 0.5 to 10 mg, for ~ . ~o o.5, l, 2, 3, 4 or 5 mg; and such unit doses may be ~ ed more than once a day, for f~y~mple 2, 3, 4, 5 or 6 times â day, but 25 ~.~,Ç~,~Iy 1 or 2 times per day, so that the total daily dosage for a 70 kg adult is in the range of about 0 l to 1000 mg, that is in the range of about 0 00 l to 20 mglkg/day, such as 0 007 to 3, 0.007 to 1 4, 0 007 to 0.14 or 0.01 to 0.5 mg/lcglday, for ~~Y~mple 0.0l, 0 02, 0.04, 0.05, 0.06, 0 08, 0.1 or 0 2 mglkglday, and such therapy may extend for a number of weeks or month~

When used herein the term ''~h~A~ r~tir~lly-accc~)lablet~ ro~ Acses l,-aLcliaAs suitable for both human and ~,elc.in~A,~y use. No toxicological effects have been ~ost~hli~hec~ for compounds of formula ~I) in the above-m~ntif n~d dosage ranges.
,,, The following Example illustrates the invention.
5 FS~I~A .~ 9-fluoro-6.7-dihydro-5-methyl-N-[1-amino-5.6-~1imetht~xyindan oxo-lHSH-benzo-riJ~quinolizine-2-carbox~mi(le Flumequine (0.46 g) and dichlorome~h~ne (16.3 ml) were co",bincd under l~oge-~ and cooled to 0~C. Tli.,lhrldl.~ e (0.27 m~) was then added dropwise, followed by ;sop,u~c,,~ lo-ofol--~ ~e ~0.21 ml) and the whole stirred for 60 mimlfes 1-Amino-10 5,6~ yindane (0.37 g) (~,c~JaAcd by the procedure of EP-A-0051391) was then added and the reaction stirred for 20 h, conr,en~rated onto silica and purified by flash column CIAIOI~IaIO~a~h~ to give the title compound (0.22 g) as an oAff-white solid.
TLC Rf = 0.1 (EtOAc) m.p. = 226-227~C
-15 Assav Methods PDE IV Inhibition Assav The methods used to confirm the phosphodiesterase IV i~ o, y activity of compounds of forrnula (I) are ;,l~AAddA d assay procedures, as disclosed by Srhillin~ et a~, An. Biochem. 216:1~4 (1994), Thompsor and Strada, Adv. Cycl. Nucl. Res. 8:119 20 (1979), and Gristwood and Owen, Br. J. Pl~d,."acol. 87:91P (1985). Compounds of formula (r) have exhibited activity at levels co~ ..l with those believed to be useful in ~ AIiA~g phospho-tiesterase IV related disease states in those assays.
TNF Inhibition Assa~r The ability of the compounds of formuAa (I) to inAhibit TN~i production iA"A human 25 monocytes is measured as follows. Peripheral blood monon~ r cells are ~l~,?art,d from freshly taken blood or "Buffy coats" by standard procedures. Cells are plated out in RPMI + 1% foetal calf senAm in the presence and absence of inllibitors. LPS (100 ngtml~ is added and cultures are inr,ub~te~ for 22 h at 37~C in an atmosphere of 95%
air/~% COt. Su~clllaL~lLS are tested for TNFa by ELISA using co"~,.c.cially avaiiable 30 kAts.

Skin Eosinophilia Model In ~w activity in a skin eosinophilia model is dtlellnilled by using the m~tht~cdescribed by Hellewell et al Br. J. Pharmacol. 111:811 (1994) and Br. J. pl"~ ,ol 110:416 (1993). Activity in a lung model is measured using the procedures desclil,ed S by Kallos and Kallos Int. Archs. Allergy Appl. Tmml -nnl 73 :77 (1984~ and Sanjar et al Br. J. Pl~.,.acol. 99:679 (1990).
The following abbreviations have been used:
TNF tumour ne ,l~iS factor LPS lipopolysacchande (endotoxin) 10 ELISA enzyme linked imml-nosorbent assay ~ertain general description, and description relating to the pl.,~ ion of intt~C, may be found in a copelldi ng Application, for the same ~ , having the same f~ing date.

Claims (24)

19

1. A compound of formula (I) R1 represents a bicyclic structure in which a cycloalkyl or heterocyclo ring is bound to NH and is fused to a second ring selected from aryl or heteroaryl, and in which either or each ring is optionally substituted by one or more substituents chosen from halo, C1-6 alkoxy, hydroxy, CN, CO2H (or C1-6 alkyl esters or C1-6 alkyl amides thereof), C1-6 alkyl, NR6R7 and SO2NR6R7;
R3, R4 and R5 are the same or different and represent H,halo, C1-6 alkoxy, hydroxy, CN, CO2H (or C1-6 alkyl esters or C1-6 alkyl amides thereof), NR6R7, SO2NR6R7 or C1-6 alkyl in which alkyl is optionally substituted with halo, C1-6 alkoxy, hydroxy, CN, CO2H (or C1-6 alkyl esters or C1-6 alkyl amides thereof), NR6R7 or SO2NR6R7, or any adjacent two substituents R3-R5 are joined to form an optionally substituted carbocyclic aromatic, heteroaromatic, saturated carbocyclic or heterocyclic ring;
R6 and R7 are the same or different and represent H, C1-6 alkyl, cycloalkyl, C1-6 alkylcarbonyl, arylcarbonyl, C1-6 alkoxycarbonyl, arylsulphonyl or C1-6 alkylsulphonyl, or NR6R7 is a 5 or 6-membered ring such as pyrrolidine, piperidine, morpholine or piperazine;
X represents a linking group selected from -(CR9R10)2-3-, -Y-(CR9Rl10)2-, -(CR9R10)2-Y-, -CR9R10-Y-CR9RI0- and -Y-CR9R10-Z-, Y and Z being independently NR11, O or S(O)0-2, provided that Y and Z are not both S(O)0-2;
Q represents O or S; and each R9, each R10 and R11 are the same or different and are H or C1-6 alkyl;
or a pharmaceutically-acceptable salt, solvate or hydrate thereof.

2. A compound of claim 1, wherein X is -Y-CR9R10-Z-.

3. A compound of claim 1, wherein X is -CR9R10-Y-CR9R10-.

4. A compound of claim 1, wherein X is (CR9R10)q, CR9R10CR9R10NR11, NR11CR9R10CR9R10, CR9R10CR9R10O, OCR9R10CR9R10, CR9R10CR9R10S(O)t or S(O)tR9R10CR9R10, q = 2-3 and t = 0-2.

5. A compound of claim 4, wherein X is (CR9R10)3.

6. A compound of any preceding claim, wherein R1 is optionally-substituted indanyl.

7. A compound of any preceding claim, wherein Q is O.

8. A compound of claim 1, which is 9-fluoro-6,7-dihydro-5-methyl-N-[1-amino-5,6-dimethoxyindanyl]-1-oxo-1H, 5X-benzo-[i,j]quinolizine-2-carboxamide.

9. A compound of any preceding claim, which has one or more chiral centres and is in the form of an enantiomer or diastereomer.

10. A pharmaceutical compasition containing a compound of any preceding claim, as active ingredient, in combination with a suitable excipient.

11. Use of a compound of any of claims 1 to 9, for the manufacture of a medicament for treating a disease state capable of being modulated by inhibiting phosphodiesterase IV.

12. The use of claim 11, wherein the disease state is a pathological condition associated with a function of phosphodiesterase IV, eosinophil accumulation or afunction of the eosinophil.

13. The use of claim 12, wherein the pathological condition is selected from asthma, chronic bronchitis, atopic dermatities, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, rheumatiod arthritis, gouty arthritis and other arthritic conditions, ulcerative colitis, Crohn's disease, multiple sclerosis, adult respiratory distress syndrome, diabetes insipidus, keratosis, atopic eczema, atopic dermatitis, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson's disease, depression, cardiac arrest, stroke and intermittent claudication.

14. The use of claim 12, wherein the pathological condition is selected from chronic bronchitis, allergic rhinitis and adult respiratory distress syndrome.

15. The use of claim 11, wherein the disease state is capable of being modulatedby TNF inhibition.

16. The use of claim 15, wherein the disease state is an inflammatory disease or autoimmune disease.

17. The use of claim 16, wherein the disease state is selected from joint inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, asthma, bone resorption diseases, reperfusion injury, graft vs host reaction, allograft rejection, malaria, myalgias, HIV, AIDS, ARC, cachexia, Crohn's disease, ulcerative colitis, pyresis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease and leukaemia.

18. The use of claim 11 or claim 15, wherein the pathological condition or disease state is asthma.

19. The use of claim 17, wherein the disease state is acute respiratory distresssyndrome, pulmonary inflammatory disease or pulmonary sarcoidosis.

20. The use of claim 17, wherein the disease state is joint inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis or osteoarthritis.

21. The use of claim 15, wherein the disease state is a disease or disorder of the brain, such as brain trauma, ischaemia, Huntingdon's disease or tardive dyskinesia.

22. The use of claim 15, wherein the disease state is a yeast or fungal infection.

23. Use of a compound of any of claims 1 to 9, for the manufacture of a medicament for use in gastroprotection.

24. Use of a compound of any of claims 1 to 9, for the manufacture of a medicament for use as an analgestic, anti-tussive or anti-hyperalgesic in the treatment of neurogenic inflammatory disease associated with irritation and pain.