United States Patent [19]
`Tadepalli et a1.
`
`[75]
`
`[73] Assignee:
`
`[54] METHOD OF TREATING PULMONARY
`HYPERTENSION WITH BENZIDINE
`PROSTAGLANDINS
`Inventors: Anjaneyulu S. Tadepalli, Durham;
`Walker A. Long, Chapel Hill; James
`W. Crow, Raleigh; Kenneth B. Klein,
`Chapel Hill, all of NC.
`Burroughs Wellcome Co., Research
`Triangle Park, NC.
`715,439
`Jun. 14, 1991
`
`[21]
`1221
`
`Appl. No.:
`Filed:
`
`Related US. Application Data
`Division of Ser. No. 367,090, Jun. 16, 1989, abandoned.
`[62]
`Foreign Application Priority Data
`[30]
`Jun. 17. 1988 [GB] United Kingdom ............... .. 8814438
`
`llllllllllllllllllllllIllllllllllllllllllllllllllllllllllllllllllllllllllll
`USOO5153222A
`Patent Number:
`5,153,222
`Oct. 6, 1992
`Date of Patent:
`
`[11]
`[45]
`
`Acute Pulmonary Vasodilation in Primary Pulmonary
`Hypertension, pp. 334-338.
`Whittle, et. al., The American Heart Association, Cir
`culation, vol. 72, No. 6, Dec., 1985, Platelet Actions of
`Stable Carbocyclic Analogues of Prostacyclin, pp.
`1219-1225.
`Long, et al., Am. Rev. Respir. Cns, 1987, 136, pp.
`773-776, Prostacyclin and Pge, Treatment of Pulmo
`nary Hypertension.
`Grossman, et al., Pulmonary Hypertension, 24, The
`Normal Pulmonary Circulation, pp. 835-851, 1981.
`Aristoff et al., Advances in Prostaglandin, Thranbox~
`ane, and Leukotriene Research, vol. 15, pp. 275-277,
`
`' 1985.
`
`'
`
`Primary Examiner-Frederick E. Waddell
`Assistant Examiner-Kimberly R. Jordan
`Attorney, Agent, or Firm-Donald Brown; Lawrence A.
`Nielsen
`
`[51] int. Cl.-‘ ............................................ ..A61K 31/19
`[52] us. c1. ............................................. .. 514/571
`[58] Field ofSearch ............... .. 524/454,569;514/571
`['56]
`References Cited
`U.S. PATENT DOCUMENTS
`
`ABSTRACT
`[57]
`The present invention is concerned with methods for
`the prophylaxis, treatment and diagnosis of pulmonary
`hypertension which comprise hte administrative of an
`effective amount of a compound of formula (I)
`
`5,028,628 7/1991 Tadepalli ......................... .. 514/573
`
`4.306.075 12/1981 Aristoff . . . . .
`
`. . . . . . .. 560/56
`
`4.499.085 2/1985 Masuda ............................... ., 514/58
`
`FOREIGN PATENT DOCUMENTS
`
`OOO5768A1 12/1979 European Pat. Off. .
`0217419A2 4/1987 European Pat. Off. .
`O229844A1 7/1987 European Pat. Off. .
`O347243A1 12/1989 European Pat. Off. .
`
`OTHER PUBLICATIONS
`Aristoff, et al., J. Amer. Chem. Soc., vol. 107, No. 26,
`1985, p. 7968, Total Synthesis of a Novel Antiulcer
`Agent via a Modification of the lntramolecular Wad
`sworth-Emmons-Wittig Reaction.
`Abstract Supplement—R. J. Lambert, et al., Chest. 89,
`p. 4595, Jun. (1986).
`Abstract—-New England Journal of Medicine, vol. 312,
`No. 14, pp. 932-936 (1985).
`Praveen Tyle, Review, Pharmaceutical Research, vol.
`3, No. 6, 1986, Iontophoretic Devices for Drug Deliv
`ery, pp. 318-326.
`Whittle, et al., Progress in Medicinal Chemistry, vol.
`21, pp. 235-279, 1984, 6 Antithrombotic Assessment
`and Clinical Protential of Protential of Prostacyclin
`Analogues.
`Rubin, et al., The American Heart Association, Circula
`tion, vol. 66, No. 2, Aug., 1982, Prostacyclin-induced
`
`HO:
`
`wherein a is an integer of from 1 to 3;
`X and Y, which may be the same or different, are
`selected from -O— and —CH3-—;
`R is —-(CH2)5R1 wherein R1 is hydrogen or methyl,
`or R is cyclohexyl, or
`R is -—CH(CH3)CH2CECCl-13; and
`the dotted line represents an’optional double bond;
`or of a physiologically acceptable salt or acid derivative
`thereof.
`Medicaments and diagnostic aids for use in the methods
`of the invention are also within the scope of the inven
`tion.
`
`2 Claims, No Drawings
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1025, p. 1 of 4
`
`

`

`1
`
`5,153,222
`
`2
`We have now discovered that within the class of
`benzindene prostaglandins described in the US. Patent,
`there is a sub-class of compounds of formula (I) as de
`fined hereinbefore which are suitable for use in the
`treatment of pulmonary hypertension. The term “pul
`monary hypertension" is used herein to include both
`primary and secondary pulmonary hypertension as or
`dinarily understood by clinicians (vide supra). The com
`pounds of the invention may also be used in the treat
`ment of Raynaud’s disease. PPH patients having active
`pulmonary vasoconstriction are considered suitable
`candidates for long-term oral vasodilator therapy (R J
`Lambert et al, Chest 89, 4595 (1986)). The ability of the
`compounds of the invention to reduce pulmonary vas
`cular resistance in such patients provides a useful diag
`nostic aid for identifying suitable candidates for long
`term vasodilator therapy.
`-
`According to the present invention, therefore, there
`is provided a compound of formula (I)
`
`1401c
`
`(I)
`
`no:
`
`for use in the treatment, or diagnosis of pulmonary
`hypertension
`wherein a is an integer of from 1 to 3;
`X and Y, which may be the same or different, are
`selected from —O— and —CH2——;
`R is ——(CI-I2)5R1 wherein R1 is hydrogen or methyl,
`or R is cyclohexyl, or
`R is —-CH(CH3)CH2CECCH3; and
`the dotted line represents an optional double bond;
`and pharmaceutically acceptable salts and acid deriva
`tives thereof.
`The term "acid derivative” is used herein to describe
`C1_4 alkyl esters and amides, including amides wherein
`the nitrogen is optionally substituted by one or two
`C14 alkyl groups.
`The invention also includes bioprecursors or “pro
`drugs" of the above-de?ned compounds, that is, com
`pounds which are converted in vivo to compounds of
`formula (I) or pharmaceutically active derivatives
`thereof.
`Further aspects of the present invention are con
`cerned with the use of a compound of formula (I), or a
`pharmaceutically acceptable salt or acid derivative
`thereof, in the manufacture of a medicament for the
`treatment of pulmonary hypertension or in the manu
`facture of a diagnostic aid for identifying PPH patients
`having active pulmonary vasoconstriction and with
`medicaments and diagnostic aids obtained thereby
`which may be administered when primary or secondary
`pulmonary hypertension is indicated.
`Preferred compounds of formula (I) having particu
`larly desirable pulmonary anti-hypertensive properties
`include those wherein
`
`Y is ——CH3—; and
`
`METHOD OF TREATING PULMONARY
`HYPERTENSION WITH BENZIDINE
`PROSTAGLANDINS
`
`This is a divisional of copending application(s) Ser,
`No. 07/367,090 ?led on Jun. 16, 1989, now abandoned.
`The present invention is concerned with prostaglan
`dins, speci?cally benzindene prostaglandins, for use in
`the treatment, or diagnosis of pulmonary hypertension.
`Their use in the manufacture of medicaments for the
`treatment of pulmonary hypertension and in the manu
`facture of diagnostic aids for identifying PPH patients
`having active pulmonary vasoconstriction and the med
`icaments and diagnostic aids obtained thereby are
`within the scope of the invention.
`All blood is driven through the lungs via the pulmo
`nary circulation in order, among other things, to replen
`ish the oxygen which it dispenses in its passage around
`the rest of the body via the systemic circulation. The
`?ow through both circulations is in normal circum
`stances 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 pul
`monary blood ?ow increases, the pressure in the circu
`lation is greater for any particular flow. This is referred
`to as pulmonary hypertension. Generally, pulmonary
`hypertension is defined through observations of pres
`sures 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 re?ex response to hypo
`ventilation and low oxygenation, or a mismatch of vas
`cular capacity and essential blood flow, such as shunt
`ing 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. They are described as primary pulmonary
`hypertension (PPI-I) and are diagnosed by and after
`exclusion of the causes of secondary pulmonary hyper
`tension. Despite the possibility of a varied aetiology,
`cases of primary pulmonary hyptertension tend to com
`prise a recognisable entity. Approximately 65% are
`female and yound 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 sponta
`neous 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. Pat. No. 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 the compounds have useful application as
`anti-thrombotic agents, anti-ulcer agents, and anti
`asthma agents. There is no indication that these com
`pounds may be used in the treatment of any form of
`hypertension.
`
`s..
`
`5
`
`25
`
`65
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1025, p. 2 of 4
`
`

`

`5,153,222
`3
`A particularly preferred compound of formula (I)
`having exceptional pulmonary anti-hypertensive prop
`erties is 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7
`(l',3'-interphenylene)-13,l4-dihydro-prostaglandin P],
`which has the following structure:
`
`10
`
`20
`
`25
`
`30
`
`no:
`
`on
`
`and pharmaceutically acceptable salts and acid deriva
`tives thereof.
`Other compounds of the invention which show pul~
`monary anti-hypertensive activity include:
`9-Deoxy-2',9a~methano-3-oxa-4,5,6-trinor-3,7-( l ’,3’
`interphenylene)-prostaglandin F1
`9-Deoxy-2’,9a-methano-3-oxa-4,5,6-trinor-3,7-(l',3’
`interphenylene)-1S-cyclohexylprostaglandin F1
`9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-( l ',3’
`interphenylene)-20-methylprostaglandin F1
`(155, l 6RS)-9-Deoxy-2',9a-methano- l 6-methyl~3-oxa
`l8,18,]9,l9-tetradehydro-4,5,6-trinor-3,7-(1',3’-inter
`phenylene)prostaglandin F1
`The present invention extends to non-physiologically
`acceptable salts of the compounds of formula (I) which
`may be used in the preparation of the pharmacologi
`cally active compounds of the invention. The physio
`logically acceptable salts of compounds of formula (I)
`include salts derived from bases. Base salts include am
`monium 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 exam
`ple, 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 chlo
`rides, bromides, and iodides, and with aralkyl halides,
`such as benzyl and phenethyl bromides.
`The amount of a compound of formula (I), or a physi
`ologically acceptable salt or acid derivative thereof,
`which is required in a medication or diagnostic aid
`according to the invention to achieve the desired effect
`will depend on a number of factors, in particular the
`specific application, the nature of the particular com
`pound used, the mode of administration, and the condi
`tion of the patient. In general, a daily dose per patient
`for the treatment of pulmonary hypertension is in the
`range 25 pg to 250 mg; typically from 0.5 pg to 2.5 mg,
`preferably from 7 pg to 285 pg, per day per kilogram
`bodyweight. For example, an intravenous dose in the
`range 0.5 pg to 1.5 mg per kilogram bodyweight per
`day may conveniently be administered as an infusion of
`from 0.5 rig to 1.0 pg per kilogram bodyweight per
`minute. Infusion fluids suitable for this purpose contain,
`for example, from 10 ng to 10 pg per milliliter. Am
`poules for injection contain, for example, from 0.1 pg to
`1.0 mg and orally administrable unit dose formulations,
`
`4
`such as tablets or capsules, 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 admin
`istered. 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 ofa 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, an acceptable carrier.
`The carrier must, of course, be acceptable in the sense
`of being compatible with any other ingredients 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 tech
`niques of pharmacy consisting essentially of admixing
`the components.
`In addition to compounds of formula (1), other phar
`macologically active substances may be present in the
`formulations of the present invention. For example, the
`compounds of the invention may be present in combina
`tion with tissue plasminogen activator, a substance
`known to dissolve the ?brin 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 suit
`able for oral, rectal, topical, buccal (e.g. sub-lingual),
`parenteral (e.g. subcutaneous, intramuscular, intrader
`mal, 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 com
`pound 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 physiologi
`cally 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 pre
`pared by any suitable method of pharmacy which in
`cludes 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 ?nely divided solid carrier, or both, and then,
`if necessary, shaping the resulting mixture. For exam
`ple, a tablet may be prepared by compressing or mould
`ing a powder or granules containing the active com
`pound, optionally with one or more accessory ingredi
`ents. Compressed tablets may be prepared by compress
`ing, in a suitable machine, the compound in a free-?ow
`ing 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
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1025, p. 3 of 4
`
`

`

`5,153,222
`5
`made by moulding. in a suitable machine. the powdered
`compound moistened with an inert liquid binder.
`Formulations suitable for buccal (sub-ligual) adminis
`tration include lozenges comprising a compound of
`formula (I), or a physiologically acceptable salt or acid
`derivative thereof, in a ?avoured 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 subcu
`taneous, intramuscular, or intradermal injection. Such
`preparations may conveniently be prepared by admix
`ing 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 generally contain from 0.1 to 5% w/v of
`active compound and are 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 deriva
`tive thereof, with one or more conventional solid carri
`ers, 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 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/wa
`ter and contain from 0.1 to 0.2M active ingredient.
`The compounds of the present invention are conve
`niently prepared by methods the same as or analogous
`to those described in U.S. Pat. No. 4,306,075.
`For a better understanding of the invention, the fol
`lowing Examples are given by way of illustration.
`
`55
`
`EXAMPLES
`The effects of 9-deoxy-2', 9a-methano-3-oxa-4,5-6
`trinor-3,7-(l’,3'-interpheny1ene)-13,14-dihydro-prosta
`glandin F1 monitored in experimental pulmonary hyper
`tension models. In Example I, the model used was an
`open chest preparation of an anaesthesised cat (anaes
`thetic: chloralose and urethane). In Example 2, the
`model was a conscious spontaneously hypertensive rat.
`
`60
`
`65
`
`5
`
`20
`
`30
`
`40
`
`6
`EXAMPLE 1
`A series of glycine buffer solutions of the test com
`pound were successively administered to each animal
`by iv. infusion at doses equivalent to 100 ng. 300 ng, 1
`ng, and 3 pg/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 ventilat
`ing with 10% oxygen in nitrogen. A 15-minute ‘recov
`ery‘ period was observed between successive infusions.
`Following surgery, the animal was allowed to stabilize
`for 30 minutes, after which two 5-minute hypoxic chal
`lenges were given 15 minutes apart which were aver
`aged to obtain the control hypoxic responses. 15 min
`utes after the second control hypoxic challenge, the
`animal started to receive the test compound. The aver
`aged 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)
`pressure, and cardiac output (CO, aortic blood ?ow).
`From the values obtained, the systemic vascular resis
`tance (MAP/Cl where CI=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 sys
`temic arterial pressure and systemic vascular resistance.
`Thus hypoxia-induced pulmonary vasoconstriction
`could be reduced without disturbing the systemic ha
`emodynamics by suitably adjusting the dose. The
`hypoxia-induced vasoconstriction did not return to its
`control value within 15 minutes of terminating the ?nal
`infusion indicating a relatively long duration of action
`for the compound.
`
`EXAMPLE 2
`The test compound was administered to a series of
`animal at doses of 0.1, 0.3, 1.0 and 3.0 mg/kg PO. and
`the systolic and diastolic pressures and heart rate of
`each animal were monitored for 24 hours after adminis
`tration of the compound. At doses of 0.3 mg/kg PD.
`and above, a dose-dependent fall in systolic and dia
`stolic pressures were observed for a period of up to 8
`hours after administration indicating that the compound
`had good oral bioavailability.
`What is claimed:
`1. A method of treating pulmonary hypertension in a
`patient, which comprises administering to said patient
`an effective pulmonary hypertension treatment amount
`of the compound 9-deoxy-2',9a-methano-3-oxa-4,5,6
`trinor-3,7-(l ’,3 ’-interphenylene)- l 3, l 4-dihydro-prosta
`glandin F1.
`2. A method of treating pulmonary hypertension in a
`patient, which comprises administering to said patient
`an effective pulmonary hypertension treatment amount
`of a pharmaceutically acceptable salt of the compound
`9-deoxy-2’,9a-methano-3-oxa-4,5,6-trinor-3,7-(1’,3’
`interphenylene)-l3, l4-dihydroprostaglandin F].
`
`i
`
`i t i
`
`i
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1025, p. 4 of 4
`
`