3
`
`
`
`Europaisches Patentamt
`European Patent Office
`Office europeen des brevets
`
`yO Publication number:
`
`0 3 4 7 2 4 3
`A 1
`
`EUROPEAN PATENT APPLICATION
`
`© Application number: 89306121.8
`
`© Date of filing: 16.06.89
`
`intci.*: A 61 K 3 1 / 5 5 7
`A 61 K 31/34, A 61 K 31/40,
`A 61 K 4 9 / 0 0
`
`Priority: 17.06.88 GB 8814438
`14.10.88 GB 8824187
`
`Date of publication of application :
`20.12.89 Bulletin 89/51
`
`Designated Contracting States:
`AT BE CH DE ES FR GB GR IT LI LU NL SE
`
`@ Applicant: THE WELLCOME FOUNDATION LIMITED
`183-193 Euston Road
`London NW12BP (GB)
`
`@ Inventor: Tadepalli, Anjaneyulu Seetharam
`3325 West Cornwallis Road
`Durham North Carolina 27705 (US)
`
`Long, Walker Anderson
`28 Wedgewood
`Chapel Hill North Carolina 27514 (US)
`Crow, James Walker
`5945 Sentinel Drive
`Raleigh North Carolina 27609 (US)
`Klein, Kenneth Bruce
`5312 Cascade Drive
`Chapel Hill North Carolina 27514 (US)
`Whittle, Brendan Joseph Richard
`Langley Court
`Beckenham Kent (GB)
`
`Representative : Garrett, Michael et al
`The Wellcome Research Laboratories Group Patents and
`Agreements Langley Court
`Beckenham Kent BR3 3BS (GB)
`
`The title of the invention has been amended (Guidelines for Examination in the EPO, A-lll, 7.3).
`@ Prostaglandin analogues for use in medicine.
`@ The present invention is concerned with the use of a where a is 0 or 1, U is hydr where a is 0 or 1, U is hydrogen or halogen and Z is
`
`-V(CH2)b-CO2H where b is an integer of from 1 to 3 and V is
`-V(CH2)b-CO2H where b is an in1
`compound of formula (I)
`oxygen or methylene;
`X is hydrogen, methyl, halogen, cyano, or -C=CH;
`Y is oxygen, methylene, - N = , or -N(Ar)- where Ar is an
`optionally substituted phenyl group;
`R is -(CH2)5R2 where R2 is hydrogen or methyl, or R is
`cyclohexyl, or Ft is -CH(CH3)CH2C = CCH3;
`Ri is hydrogen or methyl; and the dotted lines represent
`independently optional double bonds;
`and physiologically acceptable salts and acid derivatives
`thereof,
`in the manufacture of a medicament for the prophylaxis or
`treatment of pulmonary hypertension and in the manufacture of
`a diagnostic aid for identifying PPH (primary pulmonary
`hypertensive) patients having active pulmonary vasoconstric-
`tion.
`Medicaments and diagnostic aids obtained by the use of the
`invention which may be administered when primary or second- ,
`ary pulmonary hypertension is indicated are also within the
`scope of the invention.
`
`(I)
`
`O H -
`
`wherein
`-W- is selected from
`
`' - f t
`
`J U
`'w*
`
`LK
`X,
`<C^l>c.
`
`2
`
`2
`(when Y is
`-H-J
`
`Bundesdruckerei Berlin
`
`5
`CM
`
`3
`
`LU
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1021, p. 1 of 11
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`

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`EP 0 347 243 A1
`
`Description
`
`Compounds for use in medicine
`The present invention is concerned with prostaglandins for use in the prophylaxis, treatment, or diagnosis of
`pulmonary hypertension. Their use in the manufacture of medicaments for the prophylaxis or treatment of
`pulmonary hypertension and in the manufacture of diagnostic aids for identifying PPH patients having active
`pulmonary vasoconstriction and the medicaments and diagnostic aids obtained thereby are within the scope
`of the invention.
`All blood is driven through the lungs via the pulmonary circulation in order, among other things, to replenish
`the oxygen which it dispenses in its passage around the rest of the body via the systemic circulation. The flow
`through both circulations is in normal circumstances equal, but the resistance offered to it in the pulmonary
`circulation is generally much less than that of the systemic circulation. When the resistance to pulmonary
`blood flow increases, the pressure in the circulation is greater for any particular flow. This is referred to as
`pulmonary hypertension. Generally, pulmonary hypertension is defined through observations of pressures
`above the normal range pertaining in the majority of people residing at the same altitude and engaged in similar
`activities.
`Most often pulmonary hypertension is a manifestation of an obvious or explicable increase in resistance,
`such as obstruction to blood flow by pulmonary emboli, malfunction of the heart's valves or muscle in handling
`blood after its passage through the lungs, diminution in pulmonary vessel calibre as a reflex response to
`hypoventilation and low oxygenation, or a mismatch of vascular capacity and essential blood flow, such as
`shunting of blood in congenital abnormalities or surgical removal of lung tissue. Such pulmonary hypertension
`is referred to as secondary hypertension.
`There remain some cases of pulmonary hypertension where the cause of the increased resistance is as yet
`inexplicable. These are described as cases of primary pulmonary hypertension (PPH) and are diagnosed by
`and after exclusion of the causes of secondary pulmonary hypertension. Despite the possibility of a varied
`aetiology, cases of primary pulmonary hypertension tend to comprise a recognisable entity. Approximately
`65% are female and young adults are most commonly afflicted, though it has occurred in children and patients
`over 50. Life expectancy from the time of diagnosis is short, about 3 to 5 years, though occasional reports of
`spontaneous remission and longer survival are to be expected given the nature of the diagnostic process.
`Generally, however, progress is inexorable via syncope and right heart failure and death is quite often sudden.
`Until now, no successful treatment was known.
`U.S. Patent 4,306,075 describes novel benzindene prostaglandins which produce various pharmacological
`responses, such as inhibition of platelet aggregation, reduction of gastric secretion and bronchodilation. It is
`indicated that these compounds have useful application as anti-thrombotic agents, anti-ulcer agents and
`anti-asthma agents. Non-benzindene prostaglandins having similar properties have also been described
`(Progress in Medicinal Chemistry, 2\_, 237 (1984); Circulation, 72, 1219 (1985)). We are not aware of any
`disclosure to date that benzindene or non-benzindene prostaglandins other than prostacyclin and PGEi may
`be used in the prophylaxis, treatment, or diagnosis of pulmonary hypertension.
`We have now identified a class of prostaglandins comprising known benzindenes and non-benzindenes
`which have unexpectedly been found suitable for use in the prophylaxis, treatment and diagnosis of pulmonary
`hypertension. The compounds of the .invention may also be used in the prophylaxis and treatment of
`Raynaud's disease.
`The term "pulmonary hypertension" is used herein to include both primary and secondary pulmonary
`hypertension as ordinarily understood by clinicians (vide supra).
`PPH patients having active pulmonary vasoconstriction are considered suitable candidates for long-term
`oral vasodilator therapy (R J Lambert et al, Chest 89, 459S (1986)). The ability of the compounds of the
`invention to reduce pulmonary vascular resistance in such patients provides a useful diagnostic aid for
`identifying suitable candidates for long-term vasodilator therapy.
`The present invention, therefore, lies in the use of a compound of formula (I)
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1021, p. 2 of 11
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`EP 0 347 243 A1
`
`( I )
`
`r
`
`o
`
`
`
`wherein
`-W- is selected from
`
`O H
`
`-N=)
`
`where a is 0 or 1 , U is hydrogen or halogen and Z is -V(CH2)bCO2H where b is an integer of from 1 to 3 and V is
`oxygen or methylene;
`X is hydrogen, methyl, halogen, cyano, or -C = CH;
`Y is oxygen, methylene, -N = , or -N(Ar)- where Ar is an optionally substituted phenyl group;
`R is -(CH2>5R2 where R2 is hydrogen or methyl, or R is cyclohexyl, or R is -CH(CH3)CH2C = CCH3;
`R1 is hydrogen or methyl; and
`the dotted lines represent independently optional double bonds;
`and physiologically acceptable salts and acid derivatives thereof,
`in the manufacture of a medicament for the prophylaxis or treatment of pulmonary hypertension.
`The term "acid derivative" is used herein to described C1-4 alkyl esters and amides, including amides
`wherein the nitrogen is optionally substituted by one or two C1-4 alkyl groups.
`The invention also includes the use of bioprecursors or "pro-drugs" of the above-defined compounds, that
`is, compounds which are converted in vivo to compounds of formula (I) or physiologically active derivatives
`thereof.
`A further aspect of the present invention provides for the use of a compound of formula (I), or a
`physiologically acceptable salt or acid derivative thereof, in the manufacture of a diagnostic aid for identifying
`PPH patients having active pulmonary vasoconstruction. Medicaments and diagnostic acids obtained by the
`use of the invention which may be administered when primary or secondary pulmonary hypertension is
`indicated are also within the scope of the invention.
`Preferred compounds of formula (I) having particularly desirable pulmonary anti-hypertensive properties
`include those wherein
`-W- is
`
`H02CCH20-j()1
`(
`
`'
`
`or H02CCH2CH2CH2^
`X
`
`;
`
`
`
`•
`
`Y is methylene;
`R is -(CH2)5R2 where R2 is hydrogen; and
`R1 is hydrogen;
`and physioligically acceptable salts and acid derivatives thereof.
`Particularly preferred compounds of formula (I) having exceptional pulmonary anti-hypertensive properties
`are 9-deoxy-2',9 -methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydroprostaglandin F1 (A) and
`(5Z,9S)-9-methyl-6a-carbaprostaglandin I2 (B) which have the following structures:
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1021, p. 3 of 11
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`

`EP 0 347 243 A1
`
`(A)
`
`(b)
`
`OH
`
`. / \ . / C ° 2 H
`
`. x y
`>*
`K
`
`
`
`15
`
`20
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`25
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`30
`
`35
`
`40
`
`OK
`OH
`and physioligically acceptable salts and acid derivatives of both thereof.
`Other compounds of the invention which show pulmonary anti-hypertensive activity include :
`9-Deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)prostaglandin Fi
`9-Deoxy-2'9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-15-cyclohexylprostaglandin Fi
`9-Deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-20-methylprostaglandin Fi
`Carbacyclin (6a-carba-PGl2)
`5,6-Dihydroprostacyciin
`9-Deoxy-5R,9a-epoxyprostaglandin Fia
`9-Deoxy-9a,6-nitriioprostaglandin Fi
`(6R)-5-Oxa-6a-carbaprostaglandin h
`(5E)-5-Fluoro-6a-carbaprostaglandin \z
`9-Deoxy-5,9-methano-4,5-didehydroprostaglandin Fia
`(5Z,9R)-9-Chloro-6a-carbaprostaglandin I2
`(5Z,9R)-9-Cyano-6a-carbaprostaglandin I2
`(15S,16RS)-9-Deoxy-2'9a-methano-16-methyl-3-oxa-18,18,19,19-tetradehydro-4,5,6-trinor-3,7-(1',3'-inter-
`phenylene)prostaglandin Fi
`(5Z,9R)-9-Ethyny!-6a-carbaprostaglandin I2
`(5Z,9R,16RS)-9-Ethynyl-16-methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2
`(1 1£)-6a-(3-Methylthiopheny[)-6,7,8,9-tetradehydro-6a-azaprostag1andin H
`methyl ester 11 -methyl ether
`The present invention extends to non-physiologically acceptable salts of the compounds of formula (I)
`which may be used in the preparation of the pharmacologically-active compounds of the invention. The
`physiologically acceptable salts of compounds of formula (I) include salts derived from organic and inorganic
`acids as well as from bases. Suitable salts derived from acids include, for example, the acetate, adipate,
`alginate, aspartate, benzoate, benzenesulphonate, bisulphate, butyrate, citrate, camphorate, camphorsulpho-
`nate, cyclopentanepropionate, digluconate, dodecylsulphate, ethanesulphonate, fumarate, glucoheptanoate,
`glycerophosphate, hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hy-
`droxyethanesulphonate, lactate, maleate, methanesulphonate, 2-naphthalenesulphonate, nicotinate, oxalate,
`palmoate, pectinate, persulphate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
`thiocyanate, tosylate, and undecanoate.
`Base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth
`metal salts such as those of calcium and magnesium, salts with organic bases such as dicyclohexylamine and
`N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
`Quaternary ammonium salts can be formed, for example, by reaction with lower alkyl halides, such as
`methyl, ethyl, propyl, and butyl chlorides, bromides and iodides, with dialkyl sulphates, with long chain halides,
`such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides, and with aralkyl halides, such as
`benzyl and phenethyl bromides.
`The amount of a compound of formula (I), or a physiologically acceptable salt or acid derivative thereof,
`65 which is required in a medication or diagnostic aid according to the invention to achieve the desired effect will
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`

`

`EP 0 347 243 A1
`
`depend on a number of factors, in particular the specific application, the nature of the particular compound
`used, the mode of administration, and the condition of the patient. In general, a daily dose for the prophylaxis
`or treatment of pulmonary hypertension is expected to lie in the range 25 jig to 250 mg, typically from 0.5 jag to
`2.5 mg, per day per kilogram bodyweight. For example, an intravenous dose may be in the range 0.5 \ig to 1.5
`mg/kg/day, which may conveniently be administered as an infusion of from 0.5 ng to 1.0 jig per kilogram per
`minute. Infusion fluids suitable for this purpose may contain, for example, from 10 ng to 10 \ig per millilitre.
`Ampoules for injection may contain, for example, from 0.1 jig to 1.0 mg and orally administrable unit dose
`formulations, such as tablets or capsules, may contain, for example, from 0.1 to 100 mg, typically from 1 to 50
`mg. For diagnostic purposes, a single unit dose formulation may be administered. In the case of physiologically
`acceptable salts, the weights indicated above refer to the weight of the active compound ion, that is, the ion
`derived from the compound of formula (I).
`In the manufacture of a medicament or diagnostic aid according to the invention, hereinafter referred to as a
`"formulation", the compounds of formula (I) and their physiologically acceptable salts and acid derivatives are
`typically admixed with, inter alia, one or more carriers and/or excipients. The latter must, of course, be
`acceptable in the sense of being compatible with any other ingredient in the formulation and must not be
`deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the
`compound as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight
`of the active compound. One or more compounds of formula (I) and/or their physiologically acceptable salts or
`acid derivatives may be incorporated in the formulations of the invention, which may be prepared by any of the
`well known techniques of pharmacy consisting essentially of admixing the components.
`In addition to compounds of formula (I), other pharmacologically active substances may be present in the
`medicaments of the present invention, for example, the compounds of the invention may be present in
`combination with tissue plasminogen activator, a substance known to dissolve the fibrin network of blood
`clots which has found utility in the treatment of thrombotic disorders (see, for example, The New England
`Journal of Medicine, 312(14), 932, (1985)).
`The formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual),
`parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration,
`although the most suitable route in any given case will depend on the nature and severity of the condition
`being treated and on the nature of the particular compound of formula (I), or the physiologically acceptable salt
`or acid derivative thereof, which is being used.
`Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets,
`lozenges, or tablets, each containing a predetermined amount of a compound of formula (I) or a physiologically
`acceptable salt or acid derivative thereof; as a powder or granules; as a solution or a suspension in an
`aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations may be
`prepared by any suitable method of pharmacy which includes the step of bringing into association the active
`compound and a suitable carrier (which may contain one or more accessory ingredients). In general, the
`formulations of the invention are prepared by uniformly and intimately admixing the active compound with a
`liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example,
`a tablet may be prepared by compressing or moulding a powder or granules containing the active compound,
`optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a
`suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a
`binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Moulded tablets may be made by
`moulding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
`Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound of
`formula (I), or a physiologically acceptable salt or acid derivative thereof, in a flavoured base, usually sucrose
`and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin
`or sucrose and acacia.
`Formulations of the present invention suitable for parenteral administration conveniently comprise sterile
`aqueous preparations of a compound of formula (I), or a physiologically acceptable salt or acid derivative
`thereof, which preparations are preferably isotonic with the blood of the intended recipient. These
`preparations are preferably administered intravenously, although administration may also be effected by
`means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be
`prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile
`and isotonic with the blood. Injectable formulations according to the invention will generally contain from 0.1 to
`5% w/v of active compound and be administered at a rate of 0.1 ml/min/kg.
`Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These
`may be prepared by admixing a compound of formula (I), or a physiologically acceptable salt or acid derivative
`thereof, with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting
`mixture.
`Formulations suitable for topical application to the skin preferably take the form of an ointment, cream,
`lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanoline, polyethylene
`glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a
`concentration of from 0.1 to 15% w/w, for example, from 0.5 to 2% w/w.
`Formulations for transdermal administration may be delivered by iontophoresis (see, for example,
`Pharmaceutical Research 3(6), 318, (1986)) and typically take the form of an optionally buffered aqueous
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1021, p. 5 of 11
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`EP 0 347 243 A1
`
`solution of a compound of formula (I) or of a salt or acid derivative thereof. Suitable formulations comprise
`citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
`The compounds of the present invention are conveniently prepared by methods the same as or analogous
`to those described in U.S. Patent 4,306,075.
`For a better understanding of the invention, the following Examples are given by way of illustration.
`EXAMPLES
`The effects of 9-deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7(1',3'-interphenylene)-13,14-dihydro-prostaglan-
`din Fi (Example 1) and (5Z,9S)-9-methyl-6a-carbaprostaglandin h (Example 2) were monitored in
`experimental pulmonary hypertension models. In both Examples, the model used was an open chest
`preparation of an anaesthesised cat (anaesthetic: chloralose and urethane).
`Example 1
`A series of glycine buffer solutions (pH 10.5) of the test compound were successively administered to each
`of four animals by i.v. infusion at doses equivalent to 100ng, 300ng, 1 jxg, and 3p,g/kg/min. Each solution was
`infused over a period of 20 minutes, hypoxia being induced in the animal during the last 5 minutes of infusion
`by ventilating with 10% oxygen in nitrogen. A 15-minutes 'recovery' period was observed between successive
`infusions. Following surgery, the animal was allowed to stabilize for 30 minutes, after which two 5-minutes
`hypoxic challenges were given 15 minutes apart which were averaged to obtain the control hypoxic
`responses. 15 minutes after the second control hypoxic challenge, the animal started to receive the test
`compound. The averaged control hypoxic responses were compared with those obtained during infusion of
`the test compound.
`The following parameters were monitored during the course of each experiment: systemic arterial pressure
`(MAP), pulmonary arterial (PAP) and venous (PVP) pressures, and cardiac output (CO, aortic blood flow).
`From the values obtained, the systemic vascular resistance (MAP/CI where Cl = CO/body weight in kg) and
`the pulmonary vascular resistance (PAP/CI) were calculated.
`The test compound was found to reduce hypoxia-induced increase in pulmonary arterial pressure and
`pulmonary vascular resistance in a dose-related manner without appreciably affecting cardiac output or heart
`rate. At higher doses, the test compound reduced systemic arterial pressure and systemic vascular
`resistance. Thus hypoxia-induced pulmonary vasoconstriction could be reduced without disturbing the
`systemic haemodynamics by suitably adjusting the dose. The hypoxia-induced vasoconstriction did not return
`to its control value within 15 minutes of terminating the final infusion indicating a relatively long duration of
`action for the compound.
`
`Example 2
`A series of glycine buffer solutions (pH 10.5) of the test compound were successfully administered to each
`of five animals by i.v. infusion at doses equivalent to 300ng, 1|ig, 3ng, 10(ig and 30u.g/kg/min. Each solution
`was infused over a period of 20 minutes, hypoxia being induced in the animal during the last 5 minutes of
`infusion by ventilating with 1OO/o oxygen in nitrogen. A 15-minute 'recovery' period was observed between
`successive infusions. Following surgery, the animal was allowed to stabilize for 30 minutes, after which two
`5-minute hypoxic challenges were given 15 minutes apart which were averaged to obtain the control hypoxic
`responses. 15 minutes after the second control hypoxic challenge, the animal started to receive the test
`compound. The averaged control hypoxic responses were compared with those obtained during infusion of
`the test compound.
`The following parameters were monitored during the course of each experiment: systemic arterial pressure
`(MAP), pulmonary arterial (PAP) and venous (PVP) pressures, and cardiac output (CO, aortic blood flow).
`From the values obtained, the systemic vascular resitance (MAP/CI) and the pulmonary vascular resistance
`(PAP/CI) were calculated.
`The test compound was found to reduce hypoxia-induced increase in pulmonary arterial pressure and
`pulmonary vascular resistance in a dose-related manner without appreciably affecting cardiac output or heart
`rate. At higher doses, the test compound reduced systemic arterial pressure and systemic vascular
`resistance. Thus hypoxia-induced pulmonary vasoconstriction could be reduced without disturbing the
`systemic haemodynamics by suitably adjusting the dose. The hypoxia-induced vasoconstriction did not return
`to its control value within 15 minutes of terminating the final infusion indicating a relatively long duration of
`action for the compound.
`
`Claims
`
`1. Use of a compound of formula (I)
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`EP 0 347 243 A1
`
`( I )
`
`C H
`
`wherein
`-W- is selected from
`
`u
`
`Z
`
`; 2
`
`(when Y is
`-N=)
`
`where a is 0 or 1 , U is hydrogen or halogen and Z is -V(CH2)b-CO2H where b is an integer of from 1 to 3 and
`V is oxygen or methylene;
`Xis hydrogen, methyl, halogen, cyano, or-C=CH;
`Y is oxygen, methylene, - N = , or -N(Ar)- where Ar is an optionally substituted phenyl group;
`R is -(CH2)5R2 where R2 is hydrogen or methyl, or R is cyclohexyl, or R is -CH(CH3)CH2C = CCH3 ;
`R1 is hydrogen or methyl; and
`the dotted lines represent independently optional double bonds;
`and physiologically acceptable salts and acid derivatives thereof,
`in the manufacture of a medicament for the prophylaxis or treatment of pulmonary hypertension.
`2. Use of a compound of formula (I)
`
`p r o
`
`wherein
`-W- is selected from
`
`O H
`
`( I )
`
`L
`
`2
`^ J
`(when Y is
`-N=)
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`EP 0 347 243 A1
`
`where a is 0 or 1 , U is hydrogen or halogen and Z is -V(CH2)trCO2H where b is an integer of from 1 to 3 and
`V is oxygen or methylene;
`Xis hydrogen, methyl, halogen, cyano, or-C=CH;
`Y is oxygen, methylene, - N = , or -N(Ar)- where Ar is an optionally substituted phenyl group ;
`R is -(CH2)5R2 where R2 is hydrogen or methyl, or R is cyclohexyl, or R is -CH(CH3)CH2C = CCH3 ;
`R1 is hydrogen or methyl; and
`the dotted lines represent independently optional double bonds;
`and physiologically acceptable salts and acid derivatives thereof,
`in the manufacture of a diagnostic aid for identifying PPH patients having active pulmonary
`vasoconstruction.
`3. Use according to claim 1 or 2, wherein the compound of formula (I) is as shown in claim 1 wherein
`-W-is
`
`H02CCH20 -j 0}
`
`or H02CCH2CH2CH2-.
`
`Y is methylene;
`Ris-(CH2)4CH3;and
`R1 is hydrogen.
`4. Use according to claim 3, wherein the compound of formula (I) is 9-deoxy-2',9-methano-3-oxa-
`4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydroprostaglandin F1, (5Z,9S)-9-methyl-6a-carbaprosta-
`glandin I2, or a physiologically acceptable salt or acid derivative of either thereof.
`5. A medicament comprising a compound of formula (I) as described in claim 1, or a physiologically
`acceptable salt or acid derivative thereof, one or more acceptable carriers and/or excipients and,
`optionally, one or more other therapeutic ingredients, which is suitable for use in the prophylaxis or
`treatment of pulmonary hypertension.
`6. A diagnostic aid comprising a compound of formula (I) as described in claim 2, or a physioligically
`acceptable salt or acid derivative thereof, and one or more acceptable carriers and/or excipients, which is
`suitable for use in identifying PPH patients having active pulmonary vasoconstruction.
`7. A medicament according to claim 5 or a diagnostic aid according to claim 6, wherein the compound
`of formula (I) is as described in claim 3 or is a physiologically acceptable salt or acid derivative thereof.
`8. A medicament or diagnostic aid according to claim 7, wherein the compound of formula (I) is
`F-i,
`9-deoxy-2',9-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-13,14-dihydroprostagiandin
`(5Z,9S)-9-methyl-6a-carbaprostglandin I2, or a physiologically acceptable salt or acid derivative of either
`thereof.
`9. A medicament according to any of claims 5,7 or 8 or a diagnostic aid according to any of claims 6 to 8
`which is adapted for intravenous administration or administration by transdermal iontophoresis.
`
`5
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`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1021, p. 8 of 11
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`

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`Office
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`EUROPEAN SEARCH REPORT
`
`Application number
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation o( document with indication, where appropriate.
`of relevant passages
`
`Relevant
`to claim
`
`EP 8 9 3 0 6 1 2 1 . 8
`CLASSIFICATION OF THE
`APPLICATION (Int CM )
`
`1
`j
`
`Category
`
`X
`
`Y
`
`D , Y
`
`A
`
`CIRCULATION, v o l . 66, 1982,
`A m e r i c a n H e a r t A s s o c i a t i o n ,
`I n c .
`L . J . R U B I N et a l .
`" P r o s t a c y c -
`l i n - i n d u c e d A c u t e P u l m o n a r y
`V a s o d i l a t i o n in P r i m a r y
`P u l m o n a r y H y p e r t e n s i o n "
`p a g e s 3 3 4 - 3 3 8
`summary and l e f t
`* Page 334,
`r i g h t
`c o l u m n ; page 335,
`c o l u m n ; p a g e s 3 3 6 - 3 3 7 ;
`d i s c u s s i o n *
`summary and l e f t
`* Page 334,
`c o l u m n ; page 335,
`r i g h t
`c o l u m n ; p a g e s 3 3 6 - 3 3 7 ;
`d i s c