CA2194397A1 - (-)-(3r)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy} butyric acid as cellular adhesion inhibitor - Google Patents
(-)-(3r)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy} butyric acid as cellular adhesion inhibitorInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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Abstract
The novel optically active compound (-)-(3R)-3-methyl-4-{4-¢4-(4-pyridyl)-piperazin-1-yl!phenoxy}butyric acid, and pharmaceutically-acceptable salts, esters, amides or solvates thereof. Processes for the preparation of the compound, pharmaceutical compositions containing the compound and its use to inhibit cellular adhesion, for example platelet aggregation.
Description
W096/38416 2 ! q 4 S 9 7 PCT/GB96/01260 (-)-(3R)-3-METHYL-4-(4-(4-(4-PYRIDYL)PIPERAZIN-l-YL)PHENOXY) BUTYRIC ACID AS
CELLULAR ADHESION INHIBITOR
The present invention relates to the novel optically active compound (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)pipeld~in-1-yl]phenoxy)butyric acid, [hereinafter (-)-(3R)] and pharm~ceutir~lly-acceptable salts, esters, amides or solvates thereof. The invention also relates to processes for the preparation of the optically active compound, ph~rm~ceutir~l compositions cont~ining it and its use to inhibit cellular adhesion, for example platelet aggregation.
Organic compounds can exist in optically active forms. Such compounds possess the l,lop~lly of being able to rotate the plane of plane-polarised light in either a d~llul~t~ry [prefix (+)] or laevorotary [prefix (-)] manner. Typically an optically active compound possecses an asymmetric or chiral atom such as a tetrahedral carbon atom which is bonded to four different atoms or groups. The four dirr~ t atoms or groups can be arranged around the asyl~ ic carbon atom in two ways to give two chiral cGlllpoullds which are-structurally related as mirror images of one another. Such conlpounds are termed sl~r~oisolllel~ or enantiomers. Enantiomers have ide-ntic~l physical and çhem~ plu~)ellies except that they rotate the plane of plane-pol~riced light by an equal amount but in û~posile directions. A racemic lllixlule is a mixture of equal ~llounts of a pair of enantiomers. Such a mixture does not cause rotation of the plane of plane-polarised light.
The stereochemical purity of an organic colllpound can be of illl~l~lce in the fields of ph~rm~reu~ical chernistry and ph~rm~rology. Many llla~;folllolecules such as the enzymes and receptors within warm-blooded animals which are involved in the m~inten~nre of life are built up from chiral building blocks such as the chiral amino acids. The individual enantiomers which together make up a racemic mixture of a ph~ rologically- active compound may interact to differing extents with a chiral macromolecule such as an enzyme or receptor. The individual enantiomers may therefore possess different potencies as enzyme inhibitors or receptor antagonists. In addition the rate and extent of the absorption, distribution, metabolism and excretion observed when one enantiomer is dosed to a warrn-blooded animal may differ from that observed when the mirror image form is so dosed, i.e. the enantiomers may possess different pharmacokinetic pn~pcllies.
wo 96/38416 2 1 9 4 3 9 7 PCT/GB96/01260 Furthermore the stereoçhPmi~l purity of an organic colllpoulld may also be of importance to the nature and extent of the side effects which may be obtained when a pharmacologically-active compound is dosed. Thus one enantiomer may be a useful compound whereas the other enantiomer may give rise to deleterious side effects or toxicity. It has, for exarnple, been suggested that one of the enantiomers of thalidomide was a safe and effective sedative whereas the other enantiomer controlled the racernic mixture's teratogenic side effect.
The optically active c~ poulld of the present invention is an optical isomer of the racemic mixture (3RS)-3-methyl-4-{4-[4-(4-pyridyl)L,ipe,~ill-1-yl]-phenoxy~butyric acid [hereinafter the (3RS)-racemic mixture] which is disclosed, as the trifluoroacetic acid salt, in Fy~mple 132 of Tntern~tional Patent Application No. WO 94/22834 and Example 203 of Tnt~rn~tional Patent Application No. WO 94/22835. It is disclosed therein that such compounds are useful in the tre~tm~nt of a variety of ~ice~ces involving cell adhesion such as the formation of blood Llll~lllbi following platelet aggregation. Blood thrombi can lead to flice~cec such as thrombosis, stroke, ~olllbo~ic events accol"p~,ying unstable angina, myocardial infarction, atherosclerosis, lhlo~b~.l,bolism and reocclusion during or after thrombolytic therapy.
The anti-platelet agg,~gato~y effect of the compounds is stated to be based on the compounds' ability to inhibit the binding of adhesion molecules such as fibrinogen and von Willebrand Factor to glycGprolein IIb/IIIa (hereinafter GPIIb/IIIa) which is held within the membrane of each platelet. Thereby the n~cess~ry activation and ~lim~ric~tion of, for ex~mple, the platelet-carrying fibrinogen does not occur and processes such as thrombus formation and platelet aggregation are inhibited.
As a possible aid in the search for compounds with an improved therapeutic ratio, it would be desirable to find a compound with increased potency over the compounds disclosed in International Patent Applications Nos. WO 94/22834 and WO 94/22835.It is also known that there are several classes of adhesion molecules such as the integrins, selectins and cadherins. Integrins are found on leucocytes and platelets and selectins are found on leucocytes and endothelial cells. Within each class of adhesion molecules there are many m~mbers. The integrin family includes, for example, GPIIb/IIIa which binds fibrinogen, the integrin av~3 which binds vitronectin and the integrin ~s,B1 2~ 94397 which binds fibronectin. It is believed that the more useful thclal~e~lic platelet aggregation inhibitors will possess selectivity of inhibitory effect between classes of ~rlhecion molecules ~ and between family lllclllbel ~ of each class of adhesion molecules. Thus it would also be desirable to find a colllpoulld which possesses this selectivity or which ~ossesses greater selectivity than known platelet aggregation inhibitors.
Furthermore it is known that there are several classes of GPIIb/IIIa antagonists.
For çx~mrle, monoclonal antibody antagonists to GPIIb/IIIa have been raised. In ~klition, small molecules which inhibit the binding of adhesion molecules to GPIIb/ma are also known, for example from US Patent Nos. 5,039,805 and 5,084,446, from C~n~di~n Patent Application Nos. 2,008,161, 2,037,153 and 2,061,661, and from Alig et al, J. Med Chem., 1992, 35, 4393. Comrnonly the structures of these compounds are based upon the binding regions of the adhesion molecules, for example the amino acid se~lucnr~ RGD (arginyl glycyl as~ ~le) within the structure of fibrinogen. It is believed that such colll~ounds can be used to inhibit platelet aggregation and, for çY~mrle, Ihlo,l~bus fonn~tion for 5llffirient time to allow healing of ~l~m~d tissue without the deleterious sequel~ of over-robust platelet aggl.,~dtion pr~cGsses. It is a theoretical concell, relating to the various classes of GPIIb/IIIa antagonists that the inhibition of platelet agg~gation may lead to a decl~,ase in the rate of blood clotting and hence an in.,lcase in bleeding events and times. Although a small increase in bleeding times may be acceptable, certain çlinir~lly 1~ bleeding events such as intracranial h~.~mnrrh~ge could be life-thre~tening Thus it would be desirable to find a compound with the advantage of the potent GPIIb/IIIa antagonist activity disclosed for the compound of Example 132 of Tntern~tional Patent Application No. WO 94/22834 which did not possess, or which possesced to a lesser degree, the disadvantages of incl~ased bleeding times and/or deleterious clinir~lly relevant bleeding events ~ccoci~ted with the known GPIIb/IIIa antagonists.
According to the present invention there is provided the optically active compound (-)-(3R)-3-methyl-4-~4-[4-(4-pyridyl)~i~eldzin-1-yl]-phenoxy}butyric acid, or a ph~rm~relltic~lly-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
The (-)-(3R) compound possesces subst~nti~lly better potency as a GPIIb/IIIa antagonist than the corresponding (+)-(3S) isomer (greater than 10-fold more potent). The WO 96/38416 2 l 9 4 3 q 7 PCTIGB96/01260 (-)-(3R) co~ )oL~lld also possesses selectivity of inhibitory effect b~l~.,el classes of adhesion molecules and between family lllelll~l~. of those classes. For example, the compound possesses activity against the binding of GPIIb/IIIa to fibrinogen (pICso = 7.65) but not the binding of av~3 to vitronectin (pICso less than 4) or the binding of aS~1 to fibronectin (pICso less than 4).
Accordingly the (-)-(3R) compound is a novel, potent and selective fibrinogen receptor antagonist that substantially reduces the liability or possibility of obtaining adverse effects such as excessive bleeding acsociated with the ~minictration of other fibrino~en receptor antagonists such as the (3RS)-racernic mixture. Use of the (-)-(3R) compound also çlimin~t~s the liability or possibility of obtaining adverse effects associated with the ~dminict-ation of the therapeutically less effective (+)-(3S) compound which is a constituent of the (3RS)-racemic mixture. Use of the (-)-(3R) compound allows a clearer structure-activity-toxicity analysis and provides an improved Ih~la~ulic ratio. It is therefore desirable to use the (-)-(3R) compound of the present invention rather that the (3RS)-racemic ~ le of Ex~mple 132 of Tntçrn~tional Patent Application No. WO
94/22834.
Particular ph~rm~reutic~lly-acceptable salts of the (-)-(3R) colllpound of the invention inrhlde, for e~mple, salts with acids affording physiologically-acceptable anions, such as salts with mineral acids, for example a hydrogen halide such as hydrogen chloride or hydrogen bromide, sulphuric acid or phosphoric acid, and salts with organic acids, for example trifluoroacetic acid. Other pharm~reutic~lly-acceptable salts include, for ex~mple, salts with inorganic bases such as alkali metal and ~lk~linç earth metal salts e.g. sodium salts, ammonium salts, and salts with organic amines and q~l~t~.rn~ry bases forming physiologically-acceptable cations such as salts with methylamine, dimethylarnine, L,illletllylamine, ethylçn~ mine, piperidine, morpholine, pyrrolidine, pi~lazi~le~
ethanolamine, triethanolamine, N-methylgluc~min~, tetramethylarnrnonium hydroxide and benzyl~ rlllylammonium hydroxide.
Particular ph~rm~reutic~lly-acceptable esters of the (-)-(3R) compound of the invention include, for exarnple, ester derivatives of the carboxylic acid group in the compound of the invention, for example esters formed with alcohols such as ( 1-6C)alcohols (e.g. methanol, ethanol, propanol and tert-butanol), indanol, ~rl~m~ntol, ( 1-6C~alkanoyloxy-~- 21 94~97 (14C)alcohols (e.g. pivaloyloxymethanol) and (l4c)alkoxycall~ul~yl-(l4c)alcohûls (e.g.
methû~ycal l,u,lyl ~ nol) .
Particular ph~n~re~ltic~lly-acceptable amides of the (-)-(3R) compound of the invention in~h~e, for example, amide derivatives of the carboxylic acid group in the colll~oulld of the invention, for example amides formed with amines such as ammonia, (14C)alkyl~mines (e.g. methylamine), di-(14C)alkyl~min~s (e.g. dimethylarnine, N-ethyl-N-methylamine and diethylamine), (14C)alkoxy-(24C)alkylamines (e.g.
2-methoxyethylamine), phenyl-(l~C)alkyl~mines (e.g. benzylamine) and amino acids (e.g.
glycine or an ester thereof). Thus particular amides of the (-)-(3R) compound of the invention include the N-methyl-, N,N-dimethyl-, N-ethyl-N-methyl- and N,N-diethyl-bu~y, a",ides.
Particular ph~rm~re~ti~lly-acceptable solvates of the (-)-(3R) compound of the invention include, for example, hydrates e.g. a hemi-hydrate, mono-hydrate, di-hydrate or tri-hydrate or an ~ltçrn~tive quantity thereof.
The phrase "substantially free of the (+)-(3S) stereoisomer" as used hereinbefore means that there is at least 90% by weight of the (-)-(3R) isomer and 10% by weight or less of the coll~spollding (+)-(3S) isomer. Preferably there is at least 95% by weight of the (-)-(3R) isomer and 5% by weight or less of the (+)-(3S) isomer. More preferably there is at least 99% by weight of the (-)-(3R) isomer and 1% by weight or less of the (+)-(3S) isomer.
The (-)-(3R) colll~ound of the invention, or a ph~rm~reutirally-acceptable salt,ester, amide or solvate thereof may be prepared by any process known in the art for the p,e~ ion of such a compound. Suitable procedures include asymmetric synthesis involving an app~p,iate chiral interm~ te and resolution of the (3RS)-racemic mixture.
-Such procedures ,c~ sent a further feature of the invention and include the following:
a) Reaction of 4-[4-(4-pyridyl)~ ela~in- l-yl]phenol, or a reactive derivative thereof, with the chiral intermP~ te (3R)4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative thereof.
The reaction is conveniently performed in the presence of a strong base, such as an alkali metal hydride, for example, sodium hydride. Suitable solvents include amides, Wo 96/38416 2 1 9 4 3 9 7 PCT/GB96/01260 such as dimethylformAmi~e The reaction is conveniently ~c,Ç,l,lled at a telll~eldlule in the range of from 0 to 100 ~C.
Suitable esters of the chiral int~ iiAte (3R)4-hydroxy-3-methylbutyric acid jnelude for exarnple, the methyl, ethyl, propyl and tert-butyl esters. Suitable reactive derivatives thereof include, for example, (3R)-4-halogeno-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-chloro and 4-bromo derivatives, (3R)-4-AIk~neslllrhl nyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-m~thAnçculphonyloxy derivative or (3R)4-arylsulphonyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-(p-toluenesulphonyloxy) derivative.
b) Reaction of a compound of formula I
N~3L
in which L is a leaving atom or group, with the chiral i~ ",l ~iAte (3R)-3-methyl4-[4-(pi~,dzin-1-yl)phenoxy]butyric acid, or an acid addition salt thereof.
Examples of values for L include halogen, such as chlorine or blOll~ine, and cyano.
Exarnples of acid addition salts of (3R)-3-methyl4-[4-(pi~l~zin- l-yl)-phenoxy]butyric acid in~hlde for example, the hydrochlorides.
-- The reaction may conveniently be effected at a tel~lpel~tllle in the range of from -10 to 120 ~C, preferably from 10 to 100 ~C. Suitable solvents include, e.g. ethers such as tetrahydrofuran and dioxan, amides such as dimethylformamide, nitriles such as acetonitrile, halogenated hydl~c~bons such as dichlc~ rll~Ane, alcohols such as ethanol and water.
In some cilcu~ Ances for example when an acid addition salt of (3R)-3-methyl-4-[4-(pipel~zil -1-yl)phenoxy]butyric acid is used as starting material, the reaction may advantageously be pe~ lled in the presel ce of a base. Examples of suitable bases WO 96138416 2 1 q ~ 3 9 7 PCT/GB96/01260 .
include tertiary arnines, such as triethylamine, and alkali metal hydroxides, c~bollates and bicarbonates, such as sodium or pot,~.sium hydroxide, carbonate or bicarbonate.
c) Decomposition of an ester of formula II
Il ~N~
~N J II
N
in which R is a carboxyl protecting group.
R may be any conveîltion ~I ca.l,o~yl protecting group that may be removed without interfering with other parts of the molPcl~le. FY~mples of carboxyl p.ote-;ling groups include ( 1 -6C)alkyl groups (such as methyl, ethyl, propyl or t-butyl), phenyl and benzyl, the phenyl moiety in any of which may optionally bear 1 or 2 of halogeno, (l~C)alkyl, (l~C)alkoxy or nitro.
The decomposition may be carried out using any one of the conventional reagents and conditions known in the art for converting carboxylic esters into carboxylic acids. Thus, for çx~mple, the decol--position may be pel~lllled by base catalysed hydrolysis, e.g. using an alkali metal hydroxide such as lithium, l~otassiu~l~ or sodium hydroxide, or a tertiary amine such as triethylamine in the presence of water. The base catalysed hydrolysis may be performed in the presence of a solvent such as an alcohol, e.g.
methanol or ethanol, or an ether such as tetrahydrofuran or dioxan. ~ltem~tively the decomposition may be carried out by acid catalysed hydrolysis, e.g. using ~ueous acetic acid or trifluoroacetic acid. The te~ e~tul~ is conveniently in the range of from -10 to 100~C, for example from 10 to 50~C. When the alcohol residue is t-butyl, this may be removed by he~ting, e.g. at a temperature in the range of from 80 to 150~C, alone or in the presence of a suitable diluent such as diphenylether or diphenylsulphone. A benzyl group may be removed by catalytic hydrogenation, e.g. by hydrogenation in the presence of WO 96138416 2 1 9 4 3 ~ 7 PCTIGB96101260 p~ m on carbon at a telllyel~tul~ in the range of from -10 to 100~C in the presence of a solvent such as an alcohol, for exarnple methanol or ethanol.
d) Resolution of the (3RS)-racemic mixture, (3RS)-3-methyl4-~4-[4-(4-pyridyl)-pipelazin- 1 -yl]phenoxy ~butyric acid.
The resolution of the butyric acid derivative of the (3RS)-racemic mixture may be carried out by conventional means, for example by salt formation using an optically active base followed by separation, for exarnple by fractional cryst~lli.c~tion of the two salts so produced and regeneration of the separated (-)-(3R) and (+)-(3S) compounds byacirlific~tion of the separated salts.
The resolution of the butyric acid derivative of the (3RS)-racemic mixture rnay also be carried out by the conventional means of forming a diastereoisomeric pair of esters by reaction with an optically active alcohol, separation of the esters, for Py~mple by chromatography, and regcneldlion of the s~p~lt~ (-)-(3R) and (+)-(3S) compounds by hydrolysis of the separated esters. An analogous route involving the ~l~p~ation of a dia~l~l.,oisomeric pair of arnides may also be employed.
The pl.,~lion of the (-)-(3R)-colllpoulld and chiral intf ~ tes are described within the accolllpa-lyillg non-limiting Examples which are provided for the purpose of illustration only.
Certain of the chiral intrrrn~ tes defined hereinbefore are novel, thus accordillg to a further aspect of the invenIion there is provided the colllpouild tert-butyl (3R)-3-methyl-4-hydloxybutyrate, or a reactive derivative thereof, subst~nti~lly free of the (3S) stereoisomer. A particular reactive derivative which may be mentioned is tert-butyl (3R)-3-methyl4-(p-toll~en~.sl~lrhonyloxy)butyrate.
The phrase "~.hsl~nti~lly free of the (3S) stereoisomer" as used hereinbefore has the same mr~ning as given in relation to the (-)-(3R) compound of the invention.
When a ph~ reutically-acceptable salt of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure. When a ph~rrn~rentir~lly-acceptable ester or amide of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reaction of said compound with a suitable alcohol or amine as a~ylu~liate using a conventional procedure.
21 9~397 ~ 9 The ability of the (-)-(3R) compound of the invention to inhibit platelet aggregation and to inhibit the binding of fibrinogen to GPIIbmIa may be demonstrated using the standard test procedures (a) and (b) disclosed in International Patent Application No. WO 94/22834, which test procedures are incorporated herein by way of reference.
The (-)-(3R) compound of the invention possesses activity against the adenosine diphosphate (ADP) indnced aggregation of human platelets with a pA2 = 7.3, and against the binding of fibrinogen to GPIIb/lIIa with a pICso = 7.65.
As stated previously, the (-)-(3R) compound of the invention may be used in the therapy or prevention of clice~ces in which cell adhesion (especially platelet aggregation) is involved, for e~mrle venous or arterial thrombosis (e.g. pulmonary embolism, stroke and thrombotic events accolllpanying unstable angina and transient icch~lomic attack), myocardial infarction, atherosclerosis, thromboembolism and reocclusion during and after thrombolytic therapy. The compounds may also be useful for the prevention of reocclusion and restenosis following ~-.;ulaneous tr~nclnmin~l coronary angioplasty (PTCA) and coronary artery bypass graft. It will also be appreciated that the compounds may be useful in the lrG~n--~nt of other ~lic~ces mr~ ted by binding of adhesion molecules to GPIIb/IIIa, for example cancer.
According to a further aspect of the invention there is provided the use of the (-)-(3R) co~ ound, or a ph~rm~euti~ ly-accept~ble salt, ester, amide or solvate thereof, sllbst~nti~lly free of the (+)-(3S) stereoisomer as a pharmaceutical.
According to a further aspect of the invention there is provided a method of inhibiting platelet aggregation in a warm-blooded animal requiring such treatm~nt which comprises a~minictering an effective amount of the (-)-(3R) compound, or a ph~rrn~reutir~lly-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method of inhibiting binding of fibrinogen to GP~b/IIIa in a warm-blooded animal requiring such treatment which comprises ~flminictering an effective arnount of the (-)-(3R) compound, or a ph~ ceu~ic~lly-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method of inhihiting thrombotic events accolllpanying unstable angina in a warm-blooded animal requiring such treatmf nt which comprises ~lminictf rin~ an effective amount of the (-)-(3R) colllpoulld, or a ph~rm~eutic,.lly-acceptable salt, ester, amide or solvate thereof, subst~nti~lly free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method of inhi~itin~ platelet ag~l~gaLion in a warm-blooded animal requiring such tre~tment while ~ b~ ti~lly re~uring adverse effects associated with the ~lminictration of the (3-RS)-racemic mixture, which comprises ~rlminictering an effective amount of the (-)-(3R) colll~oulld, or a ph~rm~r-eutic~lly-acceptable salt, ester, amide or solvate thereof, ~ub~ ially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided the use of the (-)-(3R) colll~oulld, or a ph~rm~ceuti~lly-acceptable salt, ester, amide or solvate thereof, 5 1,s~i-t;~l1y free of the (+)-(3S) stereoisomer, for the m~nllfa~tllre of a mf -lir~mf nt for the ,ntion or ~ .nt of a disease involving platelet ag~,gation.
~ ~ According to a further aspect of the invention there is provided the use of the (-)-(3R) colllpound, or a ph~ e~ lly-acceptable salt, ester, amide or solvate thereof, ~b~ t;~lly free of the (+)-(3S) stereoisomer, for the m~nllf~q~tllre of a medicament for the ,e.ltion or ~l~a~ nt of a disease involving binding of fibrinogen to GPIIb/IIIa.According to a further aspect of the invention there is provided the use of the (-)-(3R) colll~oulld, or a ph~rm~eutic~lly-acceptable salt, ester, arnide or solvate thereof, ~lbs~ lly free of the (+)-(3S) stereoisomer, for the m~nllf~rtnre of a mç(lic~mf nt for the prevention or t.~lllf~.l-t of ~hlulllbolic events ~rc-~..,r~nyillg unstable angina.
In general, the (-)-(3R) coll~oulld of the invention will be ~minictered for this purpose by an oral, rectal, topical, intravenous, ~.ubuul~leous, intr~ml.sclll~r or inhalation route, so that a dose in the range of from 0.01 to 50 mg/kg body weight will be given, depending upon the route of ~lmini.ctration, the age and sex of the patient, and the severity of the condition to be treated.
The (-)-(3R) compound of the invention will generally be used in the form of a ph~rrn~re~lrir~l composition comrricing the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, arnide or solvate thereof, subst~nti~lly free of the (+)-(3S) WO96/38416 2 1 9 4 3 q 7 PCT/GB96/01260 ._ . 11 -stereoisomer, in adllfi~ule with a ph~.~ eulic~lly-acceptable diluent or carrier. Such a composilion is provided as a further feature of the invention and may be in a variety of dosage forms. For exarnple, it may be in the form of tablets, capsules, solutions or suspensions for oral ~minictration; in the form of cream or oil~n~P~t!i or a tr~ncderm~l (skin) patch for topical ~rlminictration; in the form of a suppository for rectal a~lminictration;
in the form of a sterile solution or sllsperlcion for aflminictration by intravenous or intramuscular injection; in the form of an aerosol or a nebuliser solution or suspension, for ~Aminictration by inhalation; and in the form of a powder, together with rh~-."~l,euli~lly-acceptable inert solid tlilllPntc such as lactose, for ~lminictration by incllffl~tion Depending upon the route of ~timinictration, the composition may comprise, for example, for 0.1 to 99.9% by weight of the (-)-(3R) compound of the invention.
The ~h~, . "~eutir~l collll)osilions may be obtained by conventional procedures using ph~rm~.~e~ltic~lly-acceptable diluents and carriers well known in the art. Tablets and c~rslllec for oral a~1.,~i.,i~ilrd~ion may con~cniellLly be formed with an enteric coating, for ex~mrle cornpricing cellulose acetate phth~l~te, to ...in;.~.;ce contact of the (-)-(3R) co~ )oulld of the invention with ~Lulllacll acids.
The (-)-(3R) compound of the invention may be co-~ h-~t~ .ed or co-formlll~ted with one or more agents known to be of value in the ~lice~ce~c or conditions intçn-led to be treated, for example a known platelet aggregation inhibitor (e.g. aspirin, a olllboxane antagonist or a tlllulllboxane synthase inhibitor), hypolipidemic agent, anti-hyl,ellensi~e agent, thrombolytic agent (such as streptokinase, urokin~ce, prourokinase, tissue plasminogen activator and derivatives thereof), beta-adrenergic blocker or a vasodilator may usefully also be present in a ph~rTn~reutir~l composition of the invention for use in treating a heart or vascular disease or condition.
In addition to its use in theldpeuLic me~isinto, the (-)-(3R) compound of the invention is also useful as a ph~rm~cological tool in the development and standardisation of test systems for the evaluation of the effects of adhesion molecules in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. The (-)-(3R) compound of the invention may also be used because of its platelet aggregation inhibitory p,opelLies in helping to store blood and to m~int~in the viability of blood and blood vessels in warm-blooded ~nim~l.c (or parts thereof) under-going artificial extracorporeal circulation, for example during limb or organ transplants. When used for this purpose the (-)-(3R) compound of the invention will generally be a~mini.~t~red so that a steady state concentration in the range, for example, 0.1 to 10 mg per litre is achieved in the blood.
The invention will now be illustrated by the following non-limiting F~mpl~.s in which unless otherwise stated:
i) concentrations and evaporations were carried out by rotary evaporation in vacuo;
ii) operations were carried out at ambient temperature, that is in the range 1 8-26~C;
iii) column chromatography was carried out on silica gel (Merck 7736) available from E Merck and Co., Darmstadt, (~e. Illh~ly;
iv) yields are given for illustration only and are not necçss~rily the m~ximl~m hle by diligent process develop,l~nt;
v) proton NMR spectra were nor nally determined at 200 MHz or 250 MHz using teL~ thylsilane (TMS) as an internal standard, and are ~ r~ssed as ch~ l.iG~I
shifts (delta values) in parts per million relative to TMS using conventional abbreviations for ~l~.cign~tion of major peaks: s, singlet; m, multiplet; t, triplet;
br, broad; d, doublet; and vi) the following abbreviations have been used for particular organic solvents: T~F
for tetrahydrofuran, DMF for N,N-dimethylform~mide and DMSO for dimethylsulphoxide.
- 21 q4397 F.Y~mr-le 1 (-)-(3R)-3-Methyl-4- ~ 4-[4-(4-pyridyl)pi~~ - 1 -yllphenoxy }butyric acid hydrochloride Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)~ipel~zin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the Il~ixlulG stirred for 45 min. tert-Butyl (3R)-3-methyl-4-(p-tolllene~ phonyloxy)butyrate (20 g) was added and the ~ urG stirred for 20 hours. The mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and ev~ol~led. The residue was triturated under diethyl ether. The solid so obtained was recryst~ çd from ethyl acetate to give tert-butyl (-)-(3R)-3-methyl-4- { 4-[4-(4-pyridyl)~ipel~zirl- 1 -yl]phenoxy ~ -butyrate (10.6 g).
m.p. 112-113~C;
[alpha]D = -5.5~ (conc. = lg/lOOml of ,l,t~lh~nol; 20~C);
NMR (CDC13) ~ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
A ~ UlG of tert-butyl (-)-(3R)-3-methyl4-{4-[4-(4-pyridyl)~ in-1-yl]phenoxy}bulylale (10.53 g) and lN aqueous hydrochloric acid (250 ml) was stirred for 44 hours. lN aqueous sodium hydroxide solution (250 ml) was added and the mixture cooled to 5~C. The mixture was filtered and the filtrate evaporated. Water (150 ml) was added and the result~nt precipitate isolated and washed in turn with water, acetone and diethyl ether. The m~t~n~l so obtained was stirred with lN aqueous hydrochloric acid (25 ml) for 16 hours. The mixture was cooled to 5~C and filtered. The solid so obtained was washed in turn with water, ~cetolle and diethyl ether and dried to give (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)pi~lazin-l-yl]phenoxy)butyric acid hydrochloride (7.9 g).
m.p. 203-205~C;
[alpha]D = -6.2~ (conc. = lg/lOOml of methanol; 20~C);
NMR (d6DMSO) o 13.8(1H,br), 12.1(1H,br), 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.8(6H,m), 3.18(4H,t), 2.45(1H,m), 2.23(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+;
C~lrul~t~ for C20H25N3O3. HCI. H,O: C, 58.5; H, 6.8; N, 10.2;
Found: C, 58.3; H, 6.9; N, 10.2%;
The nP~e~c~,y chiral starting material was prepared as follows:
Sodium bis(trimethylsilyl)amide (lM in THF, 170 ml) was added dropwise to a solution of (4S)-4-isopropyl-3-propionyloxazolidin-2-one (J. Am. Chem. Soc., 1981, 103, 2127; 28.4 g) in dry THF (500 ml) which had been cooled to -70~C and placed under an atmosphere of argon. The rate of addition was adjusted such that the te.ll~ldlu~e of the reaction mixture did not rise above -67~C. The reslllt~nt solution was stirred at -70~C for 30 min. tert-Butyl bromo~ret~te (42.3 g) was added dropwise and the solution stirred at -70~C for 3 hours. The solution was then allowed to warm to room telll~lalule. The solvent was evaporated and the residue partitioned bet~ell diethyl ether and water. The organic phase was separated, filtered through phase sep~dL~ng paper (Whatman IPD) and c;vapolaled. The residue was llilu~ated under hexane at -40~C to give a solid (21.6 g). A
second crop of solid (4.4 g) was obtained by evaporation of the hexane solution and pnrifir~tion of the residue by filtration chromatography on silica gel starting with hexane and progressing to 1/10 ethyl acetate/h~Y~n~ The two batches of solid were colllbilled and ~c~;ly~lallised from hexane to give (4S)-3-[(2R)-3-tert-butoxyc~bollyl-2-methylpropionyl]-4-isopropyloY~7oli~1in-2-one (22.5 g)-m.p. 64-65~C;
NMR(CDCl3) o 4.41(1H,m), 4.21(2H,m), 4.12(1H,m), 2.79(1H,m), 2.28-2.4(2H,m), 1.41(9H,s), 1.16(3H,d), 0.9(6H,m).
Hydrogen peroxide (30%, 44 ml) and lithium hydroxide monohydrate (6.38 g) were added in turn to a stirred mixture of (4S)-3-[(2R)-3-tert-butoxyc~l,onyl-2-methylpropionyl]-4-isopropyloxazolidin-2-one (22.5 g), water (280 ml) and THF (800 ml) which had been cooled to 5~C. The resultant mixture was stirred at 5~C for 3 hours. A
saturated aqueous sodium metabisulphite solution was added to destroy the excess 21 ~4397 hydrogen peroxide and the solvent evaporated. The residue was extracted with dichlorom.oth~nç The aqueous solution was acidified by the addition of an aqueous citric acid solution and extracted with dichloromP-th~n~. The extracts were combined, washed with water and filtered through phase sepa,dLi,lg paper. The filtrate was evaporated to give l-tert-butyl (3R)-3-methylsuccinate as an oil (12.9g).
NMR(CDC13) ~ 2.9(1H,m), 2.64(1H,m), 2.37(1H,m), 1.4(9H,s), 1.23(3H,d).
Borane-dimethyl sulphide complex (lOM, 10.3 ml) was added over 15 min to a stirred mixture of 1-tert-butyl (3R)-3-methylsuccinate (12.9 g) and THF (200 ml) which had been cooled to -10~C and placed under an atmosphere of argon. The mixture was stirred at -10~C for 30 min. The mixture was allowed to warm to room te~ ,elaLu~c and stirred for 1 hour. The mixture was recooled to 5~C and methanol (50 ml) was added portionwise. The Illi~lUlC was allowed to warm to room tclllpcldlUlc and stirred for 30 min. The mixture was evapoldted and the residue partitioned b~ en dichlol~lllcLhafle (100 ml) ~nd water (100 ml). The organic phase was filtered through phase sep~dling paper and evdpoldted to give tert-butyl (3R)-4-hydroxy-3-methylbutyrate as an oil (11 g).
NMR(CDC13) o 3.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s), 0.98(3H,d).
p-Tol~lençs~lphonyl chloride (13.2 g) was added portionwise to a stirred llu~Lurc of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g), triethylamine (21 ml) and dichl~c.lllr~ n~ (120 ml) and the mixture stirred for 20 hours. The ~ ure was washed in turn with water and dilute aqueous sodium carbonate solution. The organic solution was filtered through phase sepa~dLillg paper and evaporated to give tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate as an oil (20 g).
NMR(CDC13) ~ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s), 2.18-2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).
WO 96/38416 2 1 9 4 ~ 9 7 PCT/GB96/01260 ExamPle 2 Illustrative ph~r~n~reutical dosage forms suitable for presenting the compound of the invention for therapeutic or prophylactic use include the following, which may be obtained by conventional procedures well known in the art:
a) Tablet I mg/tablet Active ingredient 1.0 Lactose Ph. Eur. 93.25 Crosc~nnr!lose sodium 4.0 Maize starch paste 0.75 (5% w/v aqueous paste) Magnesium stearate 1.0 b) Tablet II mg/tablet Active ingredient 50 Lactose Ph. Eur. 223.75 Crosc~rrnrllose sodium 6.0 Maize starch lS.0 Polyvinylpyrrolidone 2.25 (5% w/v aqueous paste) Magnesium stearate 3.0 c) TabletIII m&/tablet Active ingredient 100 Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Maize starch paste 2.25 (5% w/v aqueous paste) Magnesium stearate 3.0 (d) Capsule mg/capsule WO96/38416 ~ ~ 9 4 3 7PCT/GB96/01260 Active ingredient 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.5 (e) Injection m~/ml Active ingredient (acid addition salt) 1.0 Sodium chloride g.o Purified water to l.Oml FY~mr)le 3 The following is a description of a study of the effects of the (-)-(3R) co~llpoulld of the invention and the coll~ s~onding (3RS)-racemic mixture in the rat. Four groups of ten Alderley Park Wistar rats (each group comprising 5 male and 5 female rats) were dosed orally with the (3RS)-racemic llli~lule at daily doses of 0, 25, 100 or 500 mg/kg. Dosing was continlled for a total of seven days. The ~nim~l.c were killed and ex~mint.~l Adverse effects were noted in the livers of six of the group of ten rats dosed at 500 mg/kg/day.
Four groups of ten Alderley Park Wistar rats (each group compri~in~ 5 male and 5 female rats) were dosed orally with the (-)-(3R) compound of the invention at daily doses of 0, 50, 250 and 1000 mg/kg. The highest dose was not tolerated. After four or five days, four of the animals from this group were killed. The le.n~in;ng six animals were dosed at 500 mg/kg/day for the rem~inder of the study. Dosing was continued for a total of fourteen days. The animals were killed and ex~mine!l No adverse effects were noted in the livers of the group of rats dosed at 250 mg/kg/day. The six ~nim~lc dosed at 1000 mg/kg/day for three or four days and then at 500 mg/kg/day for ten or eleven days also showed no adverse effect on the liver.
Based on such obsel v~tions, it is seen that the (-)-(3R) compound of the invention causes no .cignifi~nt adverse effect on the rat liver at 500 mg/kg/day.
By implication, the (-)-(3R) compound is less toxic than the (3RS)-racemic mixture.
CELLULAR ADHESION INHIBITOR
The present invention relates to the novel optically active compound (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)pipeld~in-1-yl]phenoxy)butyric acid, [hereinafter (-)-(3R)] and pharm~ceutir~lly-acceptable salts, esters, amides or solvates thereof. The invention also relates to processes for the preparation of the optically active compound, ph~rm~ceutir~l compositions cont~ining it and its use to inhibit cellular adhesion, for example platelet aggregation.
Organic compounds can exist in optically active forms. Such compounds possess the l,lop~lly of being able to rotate the plane of plane-polarised light in either a d~llul~t~ry [prefix (+)] or laevorotary [prefix (-)] manner. Typically an optically active compound possecses an asymmetric or chiral atom such as a tetrahedral carbon atom which is bonded to four different atoms or groups. The four dirr~ t atoms or groups can be arranged around the asyl~ ic carbon atom in two ways to give two chiral cGlllpoullds which are-structurally related as mirror images of one another. Such conlpounds are termed sl~r~oisolllel~ or enantiomers. Enantiomers have ide-ntic~l physical and çhem~ plu~)ellies except that they rotate the plane of plane-pol~riced light by an equal amount but in û~posile directions. A racemic lllixlule is a mixture of equal ~llounts of a pair of enantiomers. Such a mixture does not cause rotation of the plane of plane-polarised light.
The stereochemical purity of an organic colllpound can be of illl~l~lce in the fields of ph~rm~reu~ical chernistry and ph~rm~rology. Many llla~;folllolecules such as the enzymes and receptors within warm-blooded animals which are involved in the m~inten~nre of life are built up from chiral building blocks such as the chiral amino acids. The individual enantiomers which together make up a racemic mixture of a ph~ rologically- active compound may interact to differing extents with a chiral macromolecule such as an enzyme or receptor. The individual enantiomers may therefore possess different potencies as enzyme inhibitors or receptor antagonists. In addition the rate and extent of the absorption, distribution, metabolism and excretion observed when one enantiomer is dosed to a warrn-blooded animal may differ from that observed when the mirror image form is so dosed, i.e. the enantiomers may possess different pharmacokinetic pn~pcllies.
wo 96/38416 2 1 9 4 3 9 7 PCT/GB96/01260 Furthermore the stereoçhPmi~l purity of an organic colllpoulld may also be of importance to the nature and extent of the side effects which may be obtained when a pharmacologically-active compound is dosed. Thus one enantiomer may be a useful compound whereas the other enantiomer may give rise to deleterious side effects or toxicity. It has, for exarnple, been suggested that one of the enantiomers of thalidomide was a safe and effective sedative whereas the other enantiomer controlled the racernic mixture's teratogenic side effect.
The optically active c~ poulld of the present invention is an optical isomer of the racemic mixture (3RS)-3-methyl-4-{4-[4-(4-pyridyl)L,ipe,~ill-1-yl]-phenoxy~butyric acid [hereinafter the (3RS)-racemic mixture] which is disclosed, as the trifluoroacetic acid salt, in Fy~mple 132 of Tntern~tional Patent Application No. WO 94/22834 and Example 203 of Tnt~rn~tional Patent Application No. WO 94/22835. It is disclosed therein that such compounds are useful in the tre~tm~nt of a variety of ~ice~ces involving cell adhesion such as the formation of blood Llll~lllbi following platelet aggregation. Blood thrombi can lead to flice~cec such as thrombosis, stroke, ~olllbo~ic events accol"p~,ying unstable angina, myocardial infarction, atherosclerosis, lhlo~b~.l,bolism and reocclusion during or after thrombolytic therapy.
The anti-platelet agg,~gato~y effect of the compounds is stated to be based on the compounds' ability to inhibit the binding of adhesion molecules such as fibrinogen and von Willebrand Factor to glycGprolein IIb/IIIa (hereinafter GPIIb/IIIa) which is held within the membrane of each platelet. Thereby the n~cess~ry activation and ~lim~ric~tion of, for ex~mple, the platelet-carrying fibrinogen does not occur and processes such as thrombus formation and platelet aggregation are inhibited.
As a possible aid in the search for compounds with an improved therapeutic ratio, it would be desirable to find a compound with increased potency over the compounds disclosed in International Patent Applications Nos. WO 94/22834 and WO 94/22835.It is also known that there are several classes of adhesion molecules such as the integrins, selectins and cadherins. Integrins are found on leucocytes and platelets and selectins are found on leucocytes and endothelial cells. Within each class of adhesion molecules there are many m~mbers. The integrin family includes, for example, GPIIb/IIIa which binds fibrinogen, the integrin av~3 which binds vitronectin and the integrin ~s,B1 2~ 94397 which binds fibronectin. It is believed that the more useful thclal~e~lic platelet aggregation inhibitors will possess selectivity of inhibitory effect between classes of ~rlhecion molecules ~ and between family lllclllbel ~ of each class of adhesion molecules. Thus it would also be desirable to find a colllpoulld which possesses this selectivity or which ~ossesses greater selectivity than known platelet aggregation inhibitors.
Furthermore it is known that there are several classes of GPIIb/IIIa antagonists.
For çx~mrle, monoclonal antibody antagonists to GPIIb/IIIa have been raised. In ~klition, small molecules which inhibit the binding of adhesion molecules to GPIIb/ma are also known, for example from US Patent Nos. 5,039,805 and 5,084,446, from C~n~di~n Patent Application Nos. 2,008,161, 2,037,153 and 2,061,661, and from Alig et al, J. Med Chem., 1992, 35, 4393. Comrnonly the structures of these compounds are based upon the binding regions of the adhesion molecules, for example the amino acid se~lucnr~ RGD (arginyl glycyl as~ ~le) within the structure of fibrinogen. It is believed that such colll~ounds can be used to inhibit platelet aggregation and, for çY~mrle, Ihlo,l~bus fonn~tion for 5llffirient time to allow healing of ~l~m~d tissue without the deleterious sequel~ of over-robust platelet aggl.,~dtion pr~cGsses. It is a theoretical concell, relating to the various classes of GPIIb/IIIa antagonists that the inhibition of platelet agg~gation may lead to a decl~,ase in the rate of blood clotting and hence an in.,lcase in bleeding events and times. Although a small increase in bleeding times may be acceptable, certain çlinir~lly 1~ bleeding events such as intracranial h~.~mnrrh~ge could be life-thre~tening Thus it would be desirable to find a compound with the advantage of the potent GPIIb/IIIa antagonist activity disclosed for the compound of Example 132 of Tntern~tional Patent Application No. WO 94/22834 which did not possess, or which possesced to a lesser degree, the disadvantages of incl~ased bleeding times and/or deleterious clinir~lly relevant bleeding events ~ccoci~ted with the known GPIIb/IIIa antagonists.
According to the present invention there is provided the optically active compound (-)-(3R)-3-methyl-4-~4-[4-(4-pyridyl)~i~eldzin-1-yl]-phenoxy}butyric acid, or a ph~rm~relltic~lly-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
The (-)-(3R) compound possesces subst~nti~lly better potency as a GPIIb/IIIa antagonist than the corresponding (+)-(3S) isomer (greater than 10-fold more potent). The WO 96/38416 2 l 9 4 3 q 7 PCTIGB96/01260 (-)-(3R) co~ )oL~lld also possesses selectivity of inhibitory effect b~l~.,el classes of adhesion molecules and between family lllelll~l~. of those classes. For example, the compound possesses activity against the binding of GPIIb/IIIa to fibrinogen (pICso = 7.65) but not the binding of av~3 to vitronectin (pICso less than 4) or the binding of aS~1 to fibronectin (pICso less than 4).
Accordingly the (-)-(3R) compound is a novel, potent and selective fibrinogen receptor antagonist that substantially reduces the liability or possibility of obtaining adverse effects such as excessive bleeding acsociated with the ~minictration of other fibrino~en receptor antagonists such as the (3RS)-racernic mixture. Use of the (-)-(3R) compound also çlimin~t~s the liability or possibility of obtaining adverse effects associated with the ~dminict-ation of the therapeutically less effective (+)-(3S) compound which is a constituent of the (3RS)-racemic mixture. Use of the (-)-(3R) compound allows a clearer structure-activity-toxicity analysis and provides an improved Ih~la~ulic ratio. It is therefore desirable to use the (-)-(3R) compound of the present invention rather that the (3RS)-racemic ~ le of Ex~mple 132 of Tntçrn~tional Patent Application No. WO
94/22834.
Particular ph~rm~reutic~lly-acceptable salts of the (-)-(3R) colllpound of the invention inrhlde, for e~mple, salts with acids affording physiologically-acceptable anions, such as salts with mineral acids, for example a hydrogen halide such as hydrogen chloride or hydrogen bromide, sulphuric acid or phosphoric acid, and salts with organic acids, for example trifluoroacetic acid. Other pharm~reutic~lly-acceptable salts include, for ex~mple, salts with inorganic bases such as alkali metal and ~lk~linç earth metal salts e.g. sodium salts, ammonium salts, and salts with organic amines and q~l~t~.rn~ry bases forming physiologically-acceptable cations such as salts with methylamine, dimethylarnine, L,illletllylamine, ethylçn~ mine, piperidine, morpholine, pyrrolidine, pi~lazi~le~
ethanolamine, triethanolamine, N-methylgluc~min~, tetramethylarnrnonium hydroxide and benzyl~ rlllylammonium hydroxide.
Particular ph~rm~reutic~lly-acceptable esters of the (-)-(3R) compound of the invention include, for exarnple, ester derivatives of the carboxylic acid group in the compound of the invention, for example esters formed with alcohols such as ( 1-6C)alcohols (e.g. methanol, ethanol, propanol and tert-butanol), indanol, ~rl~m~ntol, ( 1-6C~alkanoyloxy-~- 21 94~97 (14C)alcohols (e.g. pivaloyloxymethanol) and (l4c)alkoxycall~ul~yl-(l4c)alcohûls (e.g.
methû~ycal l,u,lyl ~ nol) .
Particular ph~n~re~ltic~lly-acceptable amides of the (-)-(3R) compound of the invention in~h~e, for example, amide derivatives of the carboxylic acid group in the colll~oulld of the invention, for example amides formed with amines such as ammonia, (14C)alkyl~mines (e.g. methylamine), di-(14C)alkyl~min~s (e.g. dimethylarnine, N-ethyl-N-methylamine and diethylamine), (14C)alkoxy-(24C)alkylamines (e.g.
2-methoxyethylamine), phenyl-(l~C)alkyl~mines (e.g. benzylamine) and amino acids (e.g.
glycine or an ester thereof). Thus particular amides of the (-)-(3R) compound of the invention include the N-methyl-, N,N-dimethyl-, N-ethyl-N-methyl- and N,N-diethyl-bu~y, a",ides.
Particular ph~rm~re~ti~lly-acceptable solvates of the (-)-(3R) compound of the invention include, for example, hydrates e.g. a hemi-hydrate, mono-hydrate, di-hydrate or tri-hydrate or an ~ltçrn~tive quantity thereof.
The phrase "substantially free of the (+)-(3S) stereoisomer" as used hereinbefore means that there is at least 90% by weight of the (-)-(3R) isomer and 10% by weight or less of the coll~spollding (+)-(3S) isomer. Preferably there is at least 95% by weight of the (-)-(3R) isomer and 5% by weight or less of the (+)-(3S) isomer. More preferably there is at least 99% by weight of the (-)-(3R) isomer and 1% by weight or less of the (+)-(3S) isomer.
The (-)-(3R) colll~ound of the invention, or a ph~rm~reutirally-acceptable salt,ester, amide or solvate thereof may be prepared by any process known in the art for the p,e~ ion of such a compound. Suitable procedures include asymmetric synthesis involving an app~p,iate chiral interm~ te and resolution of the (3RS)-racemic mixture.
-Such procedures ,c~ sent a further feature of the invention and include the following:
a) Reaction of 4-[4-(4-pyridyl)~ ela~in- l-yl]phenol, or a reactive derivative thereof, with the chiral intermP~ te (3R)4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative thereof.
The reaction is conveniently performed in the presence of a strong base, such as an alkali metal hydride, for example, sodium hydride. Suitable solvents include amides, Wo 96/38416 2 1 9 4 3 9 7 PCT/GB96/01260 such as dimethylformAmi~e The reaction is conveniently ~c,Ç,l,lled at a telll~eldlule in the range of from 0 to 100 ~C.
Suitable esters of the chiral int~ iiAte (3R)4-hydroxy-3-methylbutyric acid jnelude for exarnple, the methyl, ethyl, propyl and tert-butyl esters. Suitable reactive derivatives thereof include, for example, (3R)-4-halogeno-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-chloro and 4-bromo derivatives, (3R)-4-AIk~neslllrhl nyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-m~thAnçculphonyloxy derivative or (3R)4-arylsulphonyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-(p-toluenesulphonyloxy) derivative.
b) Reaction of a compound of formula I
N~3L
in which L is a leaving atom or group, with the chiral i~ ",l ~iAte (3R)-3-methyl4-[4-(pi~,dzin-1-yl)phenoxy]butyric acid, or an acid addition salt thereof.
Examples of values for L include halogen, such as chlorine or blOll~ine, and cyano.
Exarnples of acid addition salts of (3R)-3-methyl4-[4-(pi~l~zin- l-yl)-phenoxy]butyric acid in~hlde for example, the hydrochlorides.
-- The reaction may conveniently be effected at a tel~lpel~tllle in the range of from -10 to 120 ~C, preferably from 10 to 100 ~C. Suitable solvents include, e.g. ethers such as tetrahydrofuran and dioxan, amides such as dimethylformamide, nitriles such as acetonitrile, halogenated hydl~c~bons such as dichlc~ rll~Ane, alcohols such as ethanol and water.
In some cilcu~ Ances for example when an acid addition salt of (3R)-3-methyl-4-[4-(pipel~zil -1-yl)phenoxy]butyric acid is used as starting material, the reaction may advantageously be pe~ lled in the presel ce of a base. Examples of suitable bases WO 96138416 2 1 q ~ 3 9 7 PCT/GB96/01260 .
include tertiary arnines, such as triethylamine, and alkali metal hydroxides, c~bollates and bicarbonates, such as sodium or pot,~.sium hydroxide, carbonate or bicarbonate.
c) Decomposition of an ester of formula II
Il ~N~
~N J II
N
in which R is a carboxyl protecting group.
R may be any conveîltion ~I ca.l,o~yl protecting group that may be removed without interfering with other parts of the molPcl~le. FY~mples of carboxyl p.ote-;ling groups include ( 1 -6C)alkyl groups (such as methyl, ethyl, propyl or t-butyl), phenyl and benzyl, the phenyl moiety in any of which may optionally bear 1 or 2 of halogeno, (l~C)alkyl, (l~C)alkoxy or nitro.
The decomposition may be carried out using any one of the conventional reagents and conditions known in the art for converting carboxylic esters into carboxylic acids. Thus, for çx~mple, the decol--position may be pel~lllled by base catalysed hydrolysis, e.g. using an alkali metal hydroxide such as lithium, l~otassiu~l~ or sodium hydroxide, or a tertiary amine such as triethylamine in the presence of water. The base catalysed hydrolysis may be performed in the presence of a solvent such as an alcohol, e.g.
methanol or ethanol, or an ether such as tetrahydrofuran or dioxan. ~ltem~tively the decomposition may be carried out by acid catalysed hydrolysis, e.g. using ~ueous acetic acid or trifluoroacetic acid. The te~ e~tul~ is conveniently in the range of from -10 to 100~C, for example from 10 to 50~C. When the alcohol residue is t-butyl, this may be removed by he~ting, e.g. at a temperature in the range of from 80 to 150~C, alone or in the presence of a suitable diluent such as diphenylether or diphenylsulphone. A benzyl group may be removed by catalytic hydrogenation, e.g. by hydrogenation in the presence of WO 96138416 2 1 9 4 3 ~ 7 PCTIGB96101260 p~ m on carbon at a telllyel~tul~ in the range of from -10 to 100~C in the presence of a solvent such as an alcohol, for exarnple methanol or ethanol.
d) Resolution of the (3RS)-racemic mixture, (3RS)-3-methyl4-~4-[4-(4-pyridyl)-pipelazin- 1 -yl]phenoxy ~butyric acid.
The resolution of the butyric acid derivative of the (3RS)-racemic mixture may be carried out by conventional means, for example by salt formation using an optically active base followed by separation, for exarnple by fractional cryst~lli.c~tion of the two salts so produced and regeneration of the separated (-)-(3R) and (+)-(3S) compounds byacirlific~tion of the separated salts.
The resolution of the butyric acid derivative of the (3RS)-racemic mixture rnay also be carried out by the conventional means of forming a diastereoisomeric pair of esters by reaction with an optically active alcohol, separation of the esters, for Py~mple by chromatography, and regcneldlion of the s~p~lt~ (-)-(3R) and (+)-(3S) compounds by hydrolysis of the separated esters. An analogous route involving the ~l~p~ation of a dia~l~l.,oisomeric pair of arnides may also be employed.
The pl.,~lion of the (-)-(3R)-colllpoulld and chiral intf ~ tes are described within the accolllpa-lyillg non-limiting Examples which are provided for the purpose of illustration only.
Certain of the chiral intrrrn~ tes defined hereinbefore are novel, thus accordillg to a further aspect of the invenIion there is provided the colllpouild tert-butyl (3R)-3-methyl-4-hydloxybutyrate, or a reactive derivative thereof, subst~nti~lly free of the (3S) stereoisomer. A particular reactive derivative which may be mentioned is tert-butyl (3R)-3-methyl4-(p-toll~en~.sl~lrhonyloxy)butyrate.
The phrase "~.hsl~nti~lly free of the (3S) stereoisomer" as used hereinbefore has the same mr~ning as given in relation to the (-)-(3R) compound of the invention.
When a ph~ reutically-acceptable salt of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure. When a ph~rrn~rentir~lly-acceptable ester or amide of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reaction of said compound with a suitable alcohol or amine as a~ylu~liate using a conventional procedure.
21 9~397 ~ 9 The ability of the (-)-(3R) compound of the invention to inhibit platelet aggregation and to inhibit the binding of fibrinogen to GPIIbmIa may be demonstrated using the standard test procedures (a) and (b) disclosed in International Patent Application No. WO 94/22834, which test procedures are incorporated herein by way of reference.
The (-)-(3R) compound of the invention possesses activity against the adenosine diphosphate (ADP) indnced aggregation of human platelets with a pA2 = 7.3, and against the binding of fibrinogen to GPIIb/lIIa with a pICso = 7.65.
As stated previously, the (-)-(3R) compound of the invention may be used in the therapy or prevention of clice~ces in which cell adhesion (especially platelet aggregation) is involved, for e~mrle venous or arterial thrombosis (e.g. pulmonary embolism, stroke and thrombotic events accolllpanying unstable angina and transient icch~lomic attack), myocardial infarction, atherosclerosis, thromboembolism and reocclusion during and after thrombolytic therapy. The compounds may also be useful for the prevention of reocclusion and restenosis following ~-.;ulaneous tr~nclnmin~l coronary angioplasty (PTCA) and coronary artery bypass graft. It will also be appreciated that the compounds may be useful in the lrG~n--~nt of other ~lic~ces mr~ ted by binding of adhesion molecules to GPIIb/IIIa, for example cancer.
According to a further aspect of the invention there is provided the use of the (-)-(3R) co~ ound, or a ph~rm~euti~ ly-accept~ble salt, ester, amide or solvate thereof, sllbst~nti~lly free of the (+)-(3S) stereoisomer as a pharmaceutical.
According to a further aspect of the invention there is provided a method of inhibiting platelet aggregation in a warm-blooded animal requiring such treatm~nt which comprises a~minictering an effective amount of the (-)-(3R) compound, or a ph~rrn~reutir~lly-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method of inhibiting binding of fibrinogen to GP~b/IIIa in a warm-blooded animal requiring such treatment which comprises ~flminictering an effective arnount of the (-)-(3R) compound, or a ph~ ceu~ic~lly-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method of inhihiting thrombotic events accolllpanying unstable angina in a warm-blooded animal requiring such treatmf nt which comprises ~lminictf rin~ an effective amount of the (-)-(3R) colllpoulld, or a ph~rm~eutic,.lly-acceptable salt, ester, amide or solvate thereof, subst~nti~lly free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided a method of inhi~itin~ platelet ag~l~gaLion in a warm-blooded animal requiring such tre~tment while ~ b~ ti~lly re~uring adverse effects associated with the ~lminictration of the (3-RS)-racemic mixture, which comprises ~rlminictering an effective amount of the (-)-(3R) colll~oulld, or a ph~rm~r-eutic~lly-acceptable salt, ester, amide or solvate thereof, ~ub~ ially free of the (+)-(3S) stereoisomer.
According to a further aspect of the invention there is provided the use of the (-)-(3R) colll~oulld, or a ph~rm~ceuti~lly-acceptable salt, ester, amide or solvate thereof, 5 1,s~i-t;~l1y free of the (+)-(3S) stereoisomer, for the m~nllfa~tllre of a mf -lir~mf nt for the ,ntion or ~ .nt of a disease involving platelet ag~,gation.
~ ~ According to a further aspect of the invention there is provided the use of the (-)-(3R) colllpound, or a ph~ e~ lly-acceptable salt, ester, amide or solvate thereof, ~b~ t;~lly free of the (+)-(3S) stereoisomer, for the m~nllf~q~tllre of a medicament for the ,e.ltion or ~l~a~ nt of a disease involving binding of fibrinogen to GPIIb/IIIa.According to a further aspect of the invention there is provided the use of the (-)-(3R) colll~oulld, or a ph~rm~eutic~lly-acceptable salt, ester, arnide or solvate thereof, ~lbs~ lly free of the (+)-(3S) stereoisomer, for the m~nllf~rtnre of a mç(lic~mf nt for the prevention or t.~lllf~.l-t of ~hlulllbolic events ~rc-~..,r~nyillg unstable angina.
In general, the (-)-(3R) coll~oulld of the invention will be ~minictered for this purpose by an oral, rectal, topical, intravenous, ~.ubuul~leous, intr~ml.sclll~r or inhalation route, so that a dose in the range of from 0.01 to 50 mg/kg body weight will be given, depending upon the route of ~lmini.ctration, the age and sex of the patient, and the severity of the condition to be treated.
The (-)-(3R) compound of the invention will generally be used in the form of a ph~rrn~re~lrir~l composition comrricing the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, arnide or solvate thereof, subst~nti~lly free of the (+)-(3S) WO96/38416 2 1 9 4 3 q 7 PCT/GB96/01260 ._ . 11 -stereoisomer, in adllfi~ule with a ph~.~ eulic~lly-acceptable diluent or carrier. Such a composilion is provided as a further feature of the invention and may be in a variety of dosage forms. For exarnple, it may be in the form of tablets, capsules, solutions or suspensions for oral ~minictration; in the form of cream or oil~n~P~t!i or a tr~ncderm~l (skin) patch for topical ~rlminictration; in the form of a suppository for rectal a~lminictration;
in the form of a sterile solution or sllsperlcion for aflminictration by intravenous or intramuscular injection; in the form of an aerosol or a nebuliser solution or suspension, for ~Aminictration by inhalation; and in the form of a powder, together with rh~-."~l,euli~lly-acceptable inert solid tlilllPntc such as lactose, for ~lminictration by incllffl~tion Depending upon the route of ~timinictration, the composition may comprise, for example, for 0.1 to 99.9% by weight of the (-)-(3R) compound of the invention.
The ~h~, . "~eutir~l collll)osilions may be obtained by conventional procedures using ph~rm~.~e~ltic~lly-acceptable diluents and carriers well known in the art. Tablets and c~rslllec for oral a~1.,~i.,i~ilrd~ion may con~cniellLly be formed with an enteric coating, for ex~mrle cornpricing cellulose acetate phth~l~te, to ...in;.~.;ce contact of the (-)-(3R) co~ )oulld of the invention with ~Lulllacll acids.
The (-)-(3R) compound of the invention may be co-~ h-~t~ .ed or co-formlll~ted with one or more agents known to be of value in the ~lice~ce~c or conditions intçn-led to be treated, for example a known platelet aggregation inhibitor (e.g. aspirin, a olllboxane antagonist or a tlllulllboxane synthase inhibitor), hypolipidemic agent, anti-hyl,ellensi~e agent, thrombolytic agent (such as streptokinase, urokin~ce, prourokinase, tissue plasminogen activator and derivatives thereof), beta-adrenergic blocker or a vasodilator may usefully also be present in a ph~rTn~reutir~l composition of the invention for use in treating a heart or vascular disease or condition.
In addition to its use in theldpeuLic me~isinto, the (-)-(3R) compound of the invention is also useful as a ph~rm~cological tool in the development and standardisation of test systems for the evaluation of the effects of adhesion molecules in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. The (-)-(3R) compound of the invention may also be used because of its platelet aggregation inhibitory p,opelLies in helping to store blood and to m~int~in the viability of blood and blood vessels in warm-blooded ~nim~l.c (or parts thereof) under-going artificial extracorporeal circulation, for example during limb or organ transplants. When used for this purpose the (-)-(3R) compound of the invention will generally be a~mini.~t~red so that a steady state concentration in the range, for example, 0.1 to 10 mg per litre is achieved in the blood.
The invention will now be illustrated by the following non-limiting F~mpl~.s in which unless otherwise stated:
i) concentrations and evaporations were carried out by rotary evaporation in vacuo;
ii) operations were carried out at ambient temperature, that is in the range 1 8-26~C;
iii) column chromatography was carried out on silica gel (Merck 7736) available from E Merck and Co., Darmstadt, (~e. Illh~ly;
iv) yields are given for illustration only and are not necçss~rily the m~ximl~m hle by diligent process develop,l~nt;
v) proton NMR spectra were nor nally determined at 200 MHz or 250 MHz using teL~ thylsilane (TMS) as an internal standard, and are ~ r~ssed as ch~ l.iG~I
shifts (delta values) in parts per million relative to TMS using conventional abbreviations for ~l~.cign~tion of major peaks: s, singlet; m, multiplet; t, triplet;
br, broad; d, doublet; and vi) the following abbreviations have been used for particular organic solvents: T~F
for tetrahydrofuran, DMF for N,N-dimethylform~mide and DMSO for dimethylsulphoxide.
- 21 q4397 F.Y~mr-le 1 (-)-(3R)-3-Methyl-4- ~ 4-[4-(4-pyridyl)pi~~ - 1 -yllphenoxy }butyric acid hydrochloride Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)~ipel~zin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the Il~ixlulG stirred for 45 min. tert-Butyl (3R)-3-methyl-4-(p-tolllene~ phonyloxy)butyrate (20 g) was added and the ~ urG stirred for 20 hours. The mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and ev~ol~led. The residue was triturated under diethyl ether. The solid so obtained was recryst~ çd from ethyl acetate to give tert-butyl (-)-(3R)-3-methyl-4- { 4-[4-(4-pyridyl)~ipel~zirl- 1 -yl]phenoxy ~ -butyrate (10.6 g).
m.p. 112-113~C;
[alpha]D = -5.5~ (conc. = lg/lOOml of ,l,t~lh~nol; 20~C);
NMR (CDC13) ~ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
A ~ UlG of tert-butyl (-)-(3R)-3-methyl4-{4-[4-(4-pyridyl)~ in-1-yl]phenoxy}bulylale (10.53 g) and lN aqueous hydrochloric acid (250 ml) was stirred for 44 hours. lN aqueous sodium hydroxide solution (250 ml) was added and the mixture cooled to 5~C. The mixture was filtered and the filtrate evaporated. Water (150 ml) was added and the result~nt precipitate isolated and washed in turn with water, acetone and diethyl ether. The m~t~n~l so obtained was stirred with lN aqueous hydrochloric acid (25 ml) for 16 hours. The mixture was cooled to 5~C and filtered. The solid so obtained was washed in turn with water, ~cetolle and diethyl ether and dried to give (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)pi~lazin-l-yl]phenoxy)butyric acid hydrochloride (7.9 g).
m.p. 203-205~C;
[alpha]D = -6.2~ (conc. = lg/lOOml of methanol; 20~C);
NMR (d6DMSO) o 13.8(1H,br), 12.1(1H,br), 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.8(6H,m), 3.18(4H,t), 2.45(1H,m), 2.23(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+;
C~lrul~t~ for C20H25N3O3. HCI. H,O: C, 58.5; H, 6.8; N, 10.2;
Found: C, 58.3; H, 6.9; N, 10.2%;
The nP~e~c~,y chiral starting material was prepared as follows:
Sodium bis(trimethylsilyl)amide (lM in THF, 170 ml) was added dropwise to a solution of (4S)-4-isopropyl-3-propionyloxazolidin-2-one (J. Am. Chem. Soc., 1981, 103, 2127; 28.4 g) in dry THF (500 ml) which had been cooled to -70~C and placed under an atmosphere of argon. The rate of addition was adjusted such that the te.ll~ldlu~e of the reaction mixture did not rise above -67~C. The reslllt~nt solution was stirred at -70~C for 30 min. tert-Butyl bromo~ret~te (42.3 g) was added dropwise and the solution stirred at -70~C for 3 hours. The solution was then allowed to warm to room telll~lalule. The solvent was evaporated and the residue partitioned bet~ell diethyl ether and water. The organic phase was separated, filtered through phase sep~dL~ng paper (Whatman IPD) and c;vapolaled. The residue was llilu~ated under hexane at -40~C to give a solid (21.6 g). A
second crop of solid (4.4 g) was obtained by evaporation of the hexane solution and pnrifir~tion of the residue by filtration chromatography on silica gel starting with hexane and progressing to 1/10 ethyl acetate/h~Y~n~ The two batches of solid were colllbilled and ~c~;ly~lallised from hexane to give (4S)-3-[(2R)-3-tert-butoxyc~bollyl-2-methylpropionyl]-4-isopropyloY~7oli~1in-2-one (22.5 g)-m.p. 64-65~C;
NMR(CDCl3) o 4.41(1H,m), 4.21(2H,m), 4.12(1H,m), 2.79(1H,m), 2.28-2.4(2H,m), 1.41(9H,s), 1.16(3H,d), 0.9(6H,m).
Hydrogen peroxide (30%, 44 ml) and lithium hydroxide monohydrate (6.38 g) were added in turn to a stirred mixture of (4S)-3-[(2R)-3-tert-butoxyc~l,onyl-2-methylpropionyl]-4-isopropyloxazolidin-2-one (22.5 g), water (280 ml) and THF (800 ml) which had been cooled to 5~C. The resultant mixture was stirred at 5~C for 3 hours. A
saturated aqueous sodium metabisulphite solution was added to destroy the excess 21 ~4397 hydrogen peroxide and the solvent evaporated. The residue was extracted with dichlorom.oth~nç The aqueous solution was acidified by the addition of an aqueous citric acid solution and extracted with dichloromP-th~n~. The extracts were combined, washed with water and filtered through phase sepa,dLi,lg paper. The filtrate was evaporated to give l-tert-butyl (3R)-3-methylsuccinate as an oil (12.9g).
NMR(CDC13) ~ 2.9(1H,m), 2.64(1H,m), 2.37(1H,m), 1.4(9H,s), 1.23(3H,d).
Borane-dimethyl sulphide complex (lOM, 10.3 ml) was added over 15 min to a stirred mixture of 1-tert-butyl (3R)-3-methylsuccinate (12.9 g) and THF (200 ml) which had been cooled to -10~C and placed under an atmosphere of argon. The mixture was stirred at -10~C for 30 min. The mixture was allowed to warm to room te~ ,elaLu~c and stirred for 1 hour. The mixture was recooled to 5~C and methanol (50 ml) was added portionwise. The Illi~lUlC was allowed to warm to room tclllpcldlUlc and stirred for 30 min. The mixture was evapoldted and the residue partitioned b~ en dichlol~lllcLhafle (100 ml) ~nd water (100 ml). The organic phase was filtered through phase sep~dling paper and evdpoldted to give tert-butyl (3R)-4-hydroxy-3-methylbutyrate as an oil (11 g).
NMR(CDC13) o 3.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s), 0.98(3H,d).
p-Tol~lençs~lphonyl chloride (13.2 g) was added portionwise to a stirred llu~Lurc of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g), triethylamine (21 ml) and dichl~c.lllr~ n~ (120 ml) and the mixture stirred for 20 hours. The ~ ure was washed in turn with water and dilute aqueous sodium carbonate solution. The organic solution was filtered through phase sepa~dLillg paper and evaporated to give tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate as an oil (20 g).
NMR(CDC13) ~ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s), 2.18-2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).
WO 96/38416 2 1 9 4 ~ 9 7 PCT/GB96/01260 ExamPle 2 Illustrative ph~r~n~reutical dosage forms suitable for presenting the compound of the invention for therapeutic or prophylactic use include the following, which may be obtained by conventional procedures well known in the art:
a) Tablet I mg/tablet Active ingredient 1.0 Lactose Ph. Eur. 93.25 Crosc~nnr!lose sodium 4.0 Maize starch paste 0.75 (5% w/v aqueous paste) Magnesium stearate 1.0 b) Tablet II mg/tablet Active ingredient 50 Lactose Ph. Eur. 223.75 Crosc~rrnrllose sodium 6.0 Maize starch lS.0 Polyvinylpyrrolidone 2.25 (5% w/v aqueous paste) Magnesium stearate 3.0 c) TabletIII m&/tablet Active ingredient 100 Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Maize starch paste 2.25 (5% w/v aqueous paste) Magnesium stearate 3.0 (d) Capsule mg/capsule WO96/38416 ~ ~ 9 4 3 7PCT/GB96/01260 Active ingredient 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.5 (e) Injection m~/ml Active ingredient (acid addition salt) 1.0 Sodium chloride g.o Purified water to l.Oml FY~mr)le 3 The following is a description of a study of the effects of the (-)-(3R) co~llpoulld of the invention and the coll~ s~onding (3RS)-racemic mixture in the rat. Four groups of ten Alderley Park Wistar rats (each group comprising 5 male and 5 female rats) were dosed orally with the (3RS)-racemic llli~lule at daily doses of 0, 25, 100 or 500 mg/kg. Dosing was continlled for a total of seven days. The ~nim~l.c were killed and ex~mint.~l Adverse effects were noted in the livers of six of the group of ten rats dosed at 500 mg/kg/day.
Four groups of ten Alderley Park Wistar rats (each group compri~in~ 5 male and 5 female rats) were dosed orally with the (-)-(3R) compound of the invention at daily doses of 0, 50, 250 and 1000 mg/kg. The highest dose was not tolerated. After four or five days, four of the animals from this group were killed. The le.n~in;ng six animals were dosed at 500 mg/kg/day for the rem~inder of the study. Dosing was continued for a total of fourteen days. The animals were killed and ex~mine!l No adverse effects were noted in the livers of the group of rats dosed at 250 mg/kg/day. The six ~nim~lc dosed at 1000 mg/kg/day for three or four days and then at 500 mg/kg/day for ten or eleven days also showed no adverse effect on the liver.
Based on such obsel v~tions, it is seen that the (-)-(3R) compound of the invention causes no .cignifi~nt adverse effect on the rat liver at 500 mg/kg/day.
By implication, the (-)-(3R) compound is less toxic than the (3RS)-racemic mixture.
Claims (19)
1. The optically active compound (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-l-yl]phenoxy}butyric acid, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
2. The optically active compound according to claim 1, wherein there is at least 90%
by weight of the (-)-(3R) isomer and 10% by weight or less of the corresponding (+)-(3S) isomer.
by weight of the (-)-(3R) isomer and 10% by weight or less of the corresponding (+)-(3S) isomer.
3. The optically active compound according to claim 1, wherein there is at least 95%
by weight of the (-)-(3R) isomer and 5% by weight or less of the corresponding (+)-(3S) isomer.
by weight of the (-)-(3R) isomer and 5% by weight or less of the corresponding (+)-(3S) isomer.
4. The optically active compound according to claim 1, wherein there is at least 99%
by weight of the (-)-(3R) isomer and 1% by weight or less of the corresponding (+)-(3S) isomer.
by weight of the (-)-(3R) isomer and 1% by weight or less of the corresponding (+)-(3S) isomer.
5. The optically active compound according to any one of claims 1 to 4, wherein the pharmaceutically-acceptable salt is in the form of a hydrochloride salt.
6. The optically active compound according any one of claims 1 to 4, wherein the pharmaceutically-acceptable ester is in the form of methyl, ethyl, propyl or tert-butyl ester.
7. The optically active compound according to any one of claims 1 to 4, wherein the pharmaceutically-acceptable amide is in the form of a N-methyl-, N,N-dimethyl-N-ethyl-N-methyl- or N,N-diethyl-butyramide.
8. The optically active compound according to any one of claims 1 to 4, wherein the pharmaceutically-acceptable solvate is in the form of a hydrate.
9. A process for the preparation of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of the preceding claims which comprises:
a) reaction of 4-[4-(4-pyridyl)piperazin-1-yl]phenol, or a reactive derivative thereof, with the chiral intermediate (3R)-4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative thereof;
b) reaction of a compound of formula I
in which L is a leaving atom or group, with the chiral intermediate (3R)-3-methyl-4-[4-(piperazin-1-yl)-phenoxy]butyric acid, or an acid addition salt thereof;
c) decomposition of an ester of formula II
in which R is a carboxyl protecting group;
d) resolution of the (3RS)-racemic mixture, (3RS)-3-methyl-4-{4-[4-(4-pyridyl)-piperazin-1-yl]phenoxy}butyric acid;
and when a pharmaceutically-acceptable salt of the (-)-(3R) compound is required, reaction of the resulting compound with a suitable acid or base; and when a pharmaceutically-acceptable ester or amide of the (-)-(3R) compound is required, reaction of the resulting compound with a suitable alcohol or amide.
a) reaction of 4-[4-(4-pyridyl)piperazin-1-yl]phenol, or a reactive derivative thereof, with the chiral intermediate (3R)-4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative thereof;
b) reaction of a compound of formula I
in which L is a leaving atom or group, with the chiral intermediate (3R)-3-methyl-4-[4-(piperazin-1-yl)-phenoxy]butyric acid, or an acid addition salt thereof;
c) decomposition of an ester of formula II
in which R is a carboxyl protecting group;
d) resolution of the (3RS)-racemic mixture, (3RS)-3-methyl-4-{4-[4-(4-pyridyl)-piperazin-1-yl]phenoxy}butyric acid;
and when a pharmaceutically-acceptable salt of the (-)-(3R) compound is required, reaction of the resulting compound with a suitable acid or base; and when a pharmaceutically-acceptable ester or amide of the (-)-(3R) compound is required, reaction of the resulting compound with a suitable alcohol or amide.
10. The optically active compound tert-butyl (3R)-3-methyl-4-hydroxybutyrate, or a reactive derivative thereof, substantially free of the (3S) stereoisomer.
11. A compound according to claim 10, wherein the reactive derivative is tert-butyl (3R)-3-methyl-4-(p-toluenesulphonyloxy)butyrate.
12. A pharmaceutical composition comprising the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8, in admixture with a pharmaceutically-acceptable diluent or carrier.
13. A method of inhibiting platelet aggregation in a warm-blooded animal requiring such treatment which comprises administering an effective amount of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8.
14. A method of inhibiting platelet aggregation in a warm-blooded animal requiring such treatment while substantially reducing adverse effects associated with the administration of the (3-RS)-racemic mixture, which comprises administering an effective amount of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8.
15. A method of inhibiting binding of fibrinogen to GPIIb/IIIa in a warm-bloodedanimal requiring such treatment which comprises administering an effective amount of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8.
16. A method of inhibiting thrombotic events accompanying unstable angina in a warm-blooded animal requiring such treatment which comprises administering an effective amount of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8.
17. The use of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention or treatment of a disease involving platelet aggregation.
18. The use of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention or treatment of a disease involving binding of fibrinogen to GPIIb/IIIa.
19. The use of the optically active compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention or treatment of thrombotic events accompanying unstable angina.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/457,538 US5652242A (en) | 1993-03-29 | 1995-06-01 | Heterocyclic derivatives |
| US08/457538 | 1995-06-01 | ||
| GBGB9518188.9A GB9518188D0 (en) | 1995-09-07 | 1995-09-07 | Optically active derivative |
| GB9518188.9 | 1995-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2194397A1 true CA2194397A1 (en) | 1996-12-05 |
Family
ID=26307696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002194397A Abandoned CA2194397A1 (en) | 1995-06-01 | 1996-05-28 | (-)-(3r)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy} butyric acid as cellular adhesion inhibitor |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0796247A1 (en) |
| JP (1) | JP2885941B2 (en) |
| KR (1) | KR100245957B1 (en) |
| AT (1) | AT406675B (en) |
| AU (1) | AU710105B2 (en) |
| BE (1) | BE1009520A5 (en) |
| BR (1) | BR9606409A (en) |
| CA (1) | CA2194397A1 (en) |
| CH (1) | CH691808A5 (en) |
| CZ (1) | CZ26997A3 (en) |
| DE (1) | DE19680509T1 (en) |
| DK (1) | DK10697A (en) |
| ES (1) | ES2137886B1 (en) |
| FI (1) | FI970393A7 (en) |
| GB (1) | GB2304340B (en) |
| GR (1) | GR1002702B (en) |
| HU (1) | HUP9700274A3 (en) |
| IE (1) | IE960405A1 (en) |
| IL (1) | IL118477A0 (en) |
| IT (1) | IT1290839B1 (en) |
| LU (1) | LU90008B1 (en) |
| MC (1) | MC2418A1 (en) |
| MX (1) | MX9700379A (en) |
| NL (1) | NL1003243C2 (en) |
| NO (1) | NO307460B1 (en) |
| NZ (1) | NZ308597A (en) |
| PL (1) | PL318440A1 (en) |
| SE (1) | SE510812C2 (en) |
| SK (1) | SK13097A3 (en) |
| TR (1) | TR199700020T1 (en) |
| WO (1) | WO1996038416A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100158A3 (en) * | 1982-07-28 | 1985-03-27 | The Upjohn Company | (3-pyridinyl)heteroalkarylalkanols, alkanoic acids and esters |
| GB8609630D0 (en) * | 1986-04-19 | 1986-05-21 | Pfizer Ltd | Anti-arrhythmia agents |
| JP3088016B2 (en) * | 1993-03-29 | 2000-09-18 | ゼネカ・リミテッド | Heterocyclic compounds as platelet aggregation inhibitors |
| PL310889A1 (en) * | 1993-03-29 | 1996-01-08 | Zeneca Ltd | Heterocyclic derivatives as inhibitors of thrombocytes aggregation |
-
1996
- 1996-05-28 PL PL96318440A patent/PL318440A1/en unknown
- 1996-05-28 SK SK130-97A patent/SK13097A3/en unknown
- 1996-05-28 BR BR9606409A patent/BR9606409A/en not_active Application Discontinuation
- 1996-05-28 CZ CZ97269A patent/CZ26997A3/en unknown
- 1996-05-28 ES ES009750006A patent/ES2137886B1/en not_active Expired - Fee Related
- 1996-05-28 CH CH00224/97A patent/CH691808A5/en not_active IP Right Cessation
- 1996-05-28 TR TR97/00020T patent/TR199700020T1/en unknown
- 1996-05-28 NZ NZ308597A patent/NZ308597A/en unknown
- 1996-05-28 JP JP8536281A patent/JP2885941B2/en not_active Expired - Fee Related
- 1996-05-28 GR GR960100176A patent/GR1002702B/en not_active IP Right Cessation
- 1996-05-28 AT AT0900596A patent/AT406675B/en active
- 1996-05-28 WO PCT/GB1996/001260 patent/WO1996038416A1/en not_active Ceased
- 1996-05-28 FI FI970393A patent/FI970393A7/en unknown
- 1996-05-28 MX MX9700379A patent/MX9700379A/en unknown
- 1996-05-28 GB GB9627127A patent/GB2304340B/en not_active Expired - Fee Related
- 1996-05-28 HU HU9700274A patent/HUP9700274A3/en unknown
- 1996-05-28 EP EP96919906A patent/EP0796247A1/en not_active Withdrawn
- 1996-05-28 KR KR1019970700532A patent/KR100245957B1/en not_active Expired - Fee Related
- 1996-05-28 DE DE19680509T patent/DE19680509T1/en not_active Withdrawn
- 1996-05-28 AU AU58272/96A patent/AU710105B2/en not_active Ceased
- 1996-05-28 CA CA002194397A patent/CA2194397A1/en not_active Abandoned
- 1996-05-29 MC MC2347A patent/MC2418A1/en unknown
- 1996-05-30 IL IL11847796A patent/IL118477A0/en unknown
- 1996-05-31 IE IE960405A patent/IE960405A1/en not_active IP Right Cessation
- 1996-05-31 IT IT96MI001113A patent/IT1290839B1/en active IP Right Grant
- 1996-05-31 BE BE9600491A patent/BE1009520A5/en not_active IP Right Cessation
- 1996-05-31 NL NL1003243A patent/NL1003243C2/en not_active IP Right Cessation
-
1997
- 1997-01-22 LU LU90008A patent/LU90008B1/en active
- 1997-01-24 SE SE9700203A patent/SE510812C2/en not_active IP Right Cessation
- 1997-01-30 DK DK010697A patent/DK10697A/en not_active Application Discontinuation
- 1997-01-31 NO NO970437A patent/NO307460B1/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |