United States Patent [19]
`Crow et a1.
`
`[54] TREATMENT OF CONGESTIVE HEART
`FAILURE
`
`[75] Inventors: James W. Crow, Raleigh; Walker A.
`Long, Chapel Hill, both of N.C.
`[73] Assignee: Burroughs Wellcome C0., Research
`Triangle Park, NC.
`[21] Appl. No.: 705,049
`[22] Filed:
`May 23, 1991
`[30]
`Foreign Application Priority Data
`May 24, 1990 [GB] United Kingdom ............... .. 9011588
`
`[51] Int. Cl.5 .................. .. A61K 31/19; A61K 31/557
`[52] U.S. Cl. ................................... .. 514/573; 514/530
`[58] Field of Search .............................. .. 514/573, 519
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,306,075 12/1981 Aristoff ............................... .. 560/56
`
`4,680,288 7/1987 Irmscher et a1. . . . . . . . .
`
`. . . .. 514/63
`
`4,971,987 11/1990 Vorbrueggen et al
`5,013,758 5/1991 Skuballa et al. ..
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`514/374
`..... .. 514/573
`
`5,028,628 7/1991 Tadepalli et a1. . . . .
`. . . . . .. 514/573
`5,153,222 10/1992 Tadepalli et al. ................. .. 514/571
`FOREIGN PATENT DOCUMENTS
`0347243A1 12/1989 European Pat. Off. .
`0458641A2 11/1991 European Pat. Off. .
`
`OTHER PUBLICATIONS
`Riegger A. J. G., Neurohumoral vasoconstrictor sys
`tems in heart failure, Eur. Heart .1 . 6: pp. 479-489, 1985.
`Packer M., Neurohumoral interactions and adaptations
`in congestive heart failure, Circulation 77: pp. 721-730,
`1986.
`Dzau,_V. J., Packer, M., Lilly, L. S., Swartz, S. L.,
`Hollenberg, N. K., Williams G. H., Prostaglandins in
`severe congestive heart failure. Relation to activation of
`the renin-angiotensin system and hyponatremia, N.
`England J. Med. 310: pp. 347-352, 1984.
`Punzengruber, E., Stanek, B., Sinzinger H., Silbert
`bauer, F., Bicyclo-prostaglandin E2 metabolites in con
`gestive heart failure and relation to vasoconstrictor
`
`mmnumnuummnlwgggglqglyynnlunuumnluu||||
`
`5,234,953
`Aug. 10, 1993
`
`[11]
`[45]
`
`Patent Number:
`Date of Patent:
`
`neurohumoral principles, Am. J. Cardiol 57: pp.
`619-623, 1986.
`Yui, Y., Nakajama, H., Kawai, C., Murakami, T., Pros
`tacyclin therapy in patients with congestive heart fail
`ure, Am. J. Cardiol. 50: pp. 320-324, 1982.
`Auingor 0., Virgolini, 1., Weissel, M., Bergmann, H.,
`Sinzinger, H., Prostacyclin I2 (PGIZ) increases left ven
`tricular ejection fraction (LVEF), Prosinglandine 36:
`pp. 149-254, 1989.
`(List continued on next page.)
`
`Primary Examiner-Leonard Schenkman
`Attorney, Agent, or Firm-Donald Brown; Robert T.
`Hrubiec; Lawrence A. Nielsen
`
`ABSTRACT
`[57]
`The present invention is concerned with the use of a
`compound of formula (I)
`
`wherein
`—W— is
`
`wherein Z is —V(CH2)1,CO2H where b is 1 or 2 and
`V is oxygen when b is 1 or methylene when b is 2;
`X is hydrogen, cyano, or —CECH; and
`the dotted line represents an optional double bond;
`and physiologically functional derivatives thereof,
`in the treatment of congestive heart ‘failure.
`
`8 Claims, No Drawings
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1054, p. 1 of 7
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`5,234,953
`Page 2
`
`OTHER PUBLICATIONS
`Yui, Y., Sakurai, T., Nakajina, H., Kawai, B, Effect of
`prostacyclin and prazocin in the treatment of conges
`tive heart failure, with special reference in the sympa
`thetic nervous system, Jpn. Circulation J ., pp. 365-372,
`1984.
`Awan, N. A., Evenson, M. K., Needham, K. E., Beattie,
`J. M. Armsterdam, E. A., Mason T. T., Cardiocircula
`tory and myocardial energic effects of prostaglandin E1
`in severe left ventricular failure due to chronic coro
`nary disease, Am. Heart J., 102: pp. 703-709, 1981.
`Popat, K. D., Pitt, B. P., Hemodynamic effects of pros
`taglandin E1 in patients with acute myocardial infarc
`1 tion and left ventricular failure. Am. Heart J. 103: pp.
`1 485-489, 1982.
`1 Jacobs, P., Naeije, R., Renard, M., Melot, C., Mois, P.,
`- Hallemmans, R., Effects of prostaglandin E1 on hemo
`’ dynamic and blood gases in severe left heart failure, J.
`5 Cardiovascular Pharmacol. 5: pp. 170-172, 1983.
`' Yui, Y., Takatsur, Y., Hattori, R., Susawa, T., Sakagu
`chi, K., Yui, N., Kawai, C., Vasodilator therapy with a
`new stable prostacyclin analog, OP-41483, for conges
`tive heart failure due to coronary artery disease and
`comparision of hemodynamic effects and platelet aggre
`gation with nitroprusside, Am. J. Cardiol. 58: pp.
`1042-1045, 1986.
`Elsner D. Kramer EP, Riegger AJG. Hemodynamic,
`humoral, and renal effects of the prostacyclin analogue
`iloprost in conscious dogs with and without heart
`failure, J. Cardiac Pharmacol 16; pp. 601-608, 1990.
`Rademacher, P., Santak, 13., Wust, H. J., Tarnow, J.,
`Falke, J. Prostacyclin for the treatment of pulmonary
`hypertension in the adult respiratory distress syndrome:
`Effects on pulonary capillary pressure and ventila
`tion-perfusion distributions. Anesthesiology 72: pp.
`238-244, 1990.
`Rubin, L. J., Mendoza, J., Hood, M., et al., Treatment
`of primary pulmonary hypertension with continuous
`intravenous prostacyclin (Epoprostenol), Results of a
`randomized trial. Annals Internal Medicine 112:
`485-491, 1990.
`;Malik, K. U., Weis M. T., Jaiswal, N., Mechanism‘ of
`action of adrenergic and cholinergic stimuli on cardiac
`prostaglandin, synthesis; pp. 327-330 In: Advances in
`Prostaglandin, Thromboxane, and Leukotriene Re
`search, vol. 19 ed (B. Samulsson, PY.-K. Wong, F. F.
`Sun eds) Raven Press, Ltd., New York, 1989.
`
`Omini, C., Daffonchio, L., Abbraccho, M. P., Cat
`tabeni, F., Berti, F., Beta adrenoceptor desensitization
`in lung: A role for prostagiandins. pp. 524-527 In: Ad
`vances in Prostaglandin, Thromboxane, and Leuko
`triene Research, vol. 19 ed (B. Samuelsson, PY.-K.
`Wong, F. F. Sun eds), Raven Press, Ltd., New York,
`1989.
`Zusman R. M., Crow, J. W., Cato, A. E., Talkoff-Ru
`bin N., Effects of prostacyclin infusion in uremic pa
`tients; Hematologic and hemodynamic response. Clin.
`Pharmaco. Ther 30: 251-257, 1981.
`Olivari, M. T., Levine, T. B., Goldenbert, I. F., Cohn,
`J. N., Hemodynamic consequences of prostaglandin B;
`activation of the renin-angiotensin system in heart fail
`ure, pp. 437-439 In: Advances in Prostacyclin, Throm
`boxane and Leukotriene, vol. 17 ed (B. Samuelsson, R.,
`Paoletti, R. W., Ramwell eds) Raven Press, New York,
`1987.
`Dzau, V. J ., Vascular and renal prostaglandin as coun
`, ter-regulatory system in heart failure, European Heart -
`Journal 9 (Suppl. H) pp. 15-19, 1988.
`FitzFerald, G. A., Hossmann, V., Hummerich, W.,
`Konrads, A., the renin-kallikrein-prostaglandin system;
`plasma active an inactive renin and urinary kallikrein
`during prostaglandin infusion in man, Prostaglandins
`and Medicine 5: pp. 445-456, 1980.
`_
`Fitzpatrick, T. M., Alter, 1., Corey, E. J ., Ramwell, E.
`J ., Rose, J. C., Kot, P. A., Cardiovascular responses to
`PGI in the dog, Circ. Res. 42: pp. 192-194, 1978.
`Dusting, G. J., Moncada, S., Vane, J. R., Prostaglan
`dins, their intermediates and precursors; Cardiovascular
`actions and regulatory rates in normal and abnormal
`circulatory systems, Prigress in Cardiovascular Dis
`eases 21: pp. 405-426, 1979.
`Jentzer, J. H., Sonnerblick, E. H., Kirk, E. S., Coronary
`and systemic vasomotor effects of prostacyclin: implica
`tions for ischemic myocardium, pp. 323-338 In: Prosta
`cyclin (J. R. Vane, S. Bergstrom eds) Raven Press, New
`York, 1979.
`FitzGerald, G. A., Dargie, H. J., Watkins, J., Brown,
`M. J ., Friedman, L. A., Lewis, P. J ., Cardiac effects of
`prostacyclin in man, pp. 145-151 In: Clinical Pharma
`cology of Prostacyclin (P. J. Lewis, J. O’Grady eds)
`Raven Press, New York, 1981.
`R. Berkow et al., “The Merck Manual of Diagnosis and
`Therapy", 15th edition, 1987, pp. 415-429, MSD Re
`
`(List continued on next page.)
`
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`

`5,234,953
`Page 3
`
`OTHER PUBLICATIONS
`
`search Laboratories, Rahway, U.S., pp. 423-429.
`Prostaglandins, Leukotrienes and essential fatty acids,
`v01. 43, No. 4, Aug. 1991, pp. 277-286, GB; R. P. Stef
`fen et al.: “The effects of 15-AU81 a chemically stable
`prostacyclin renin-angiotensis systems of anesthetized
`dogs”.
`Walker A. Long and Lewis J. Rubin, Prostacyclin and
`PGE, Treatment of Pulmonary Hypertension; Am.
`Rev. Respir. Dis., 1987; 136; pp. 773-776.
`American Heart Journal; Oct. 1984, vol. 108, No. 4, part
`1; Siegel et a1.
`Hemodynamic effects of prostaglandin E], et al., 1982,
`The C. V. Mosby Co., PGE1 hemodynamic effects in
`AMI with CHFjPopat and Pitt et al., pp. 485-489.
`Effects of prostaglandin E1 on Hemodynamics and
`blood in severe heart failure, Journal of Cardiovascular
`Pharm. 5: pp. 170-171, 1983 Raven Press, New York.
`PGE, Therapy of Severe CHF in CHAD; Awan et al.,
`pp. 703-709, 1981.
`Effects of Prostacyclin on the Contractile Performance
`of Cardiac Muscle (1); Arch. Int. Pharm., 256, pp.
`161-162, 1982.
`Effect of Prostacyclin on Vascular Capacity in the Dog,
`Fulghum et al., The American Society for Clin. Inv.,
`Inc., vol. 76, pp. 999-1006; 1985.
`Effective of Prostacyclin and Prazosin in the Treatment
`of Congestive Heart Failure; with Special Reference on
`the Sympathetic Nervous System, Yoshiki Yui et al.,
`Jap. Circ. Journal, vol. 48, 1984.
`Newman et al., Increased Myocardial Release of Pros
`tacyclin in Dogs with Heart Failure, J. Cardiovascular
`Pharmacol. 5:194-201 (1983).
`Yui, et al., Prostacyclin Therapy in Patients with Con
`gestive Heart Failure, Amer. J. Cardiol. 50:320-324
`(1982).
`
`Stanek et al., Increase in Bicycloprostaglandin E2 Me
`tabolite in Congestive Heart Failure in Response to
`Captopril, Clin. Cardiol., 12(2):97—101 (1989).
`Elsner et al., Hemodynamic, Hormonal and Renal Ef
`fects of the Prostacyclin Analogue Iloprost in Con
`scious Dogs with and without Heart Failure, J. Cardi
`ovasc. Pharmacol., 16(4):60l-608 (1990).
`Long et al., Prostacyclin and PGE, Treatment of Pul
`monary Hypertension 1,2 Am. Rev. Respir. Dis.,
`136:773-776 (1987).
`Berkow, et al., ed., Diseases of the Heart and Peri
`cardium from the Merck Manual of Diagnosis and
`Therapy, 15th Edition, pp. 415-429 (1987).
`Sprague et al., Differential Response of the Pulmonary
`Circulation to Prostaglandins E2 and F2a in the Pres
`ence of Unilateral Alveolar Hypoxia, J. Pharmacol. and
`Exp. Therap. 229:38-43 (1984).
`Prostacyclin Therapy in Patients With Congestive
`Heart Failure, Yoshiki Yui, et al., The American Journ.
`of Cardiology; vol. 50; August 1982.
`Rubin et al., Prostacyclin-induced Acute Pulmonary
`Vasodilation in Primary Pulmonary Hypertension, Cir
`culation 66:334-338 (1982).
`Soifer et al., The Development Effects of Prostaglandin
`D2 on the Pulmonary and Systemic Circulations in the
`Newborn Lamb, J. Develop. Physio1., 5:237-250 (1983).
`Aristoff et al., Synthesis and Structure-Activity Rela
`tionships of Benzindene Prostaglandins: Novel Potent
`Antiulcer Agents, 275-277 (1985).
`Chand et al., Differential Effects of Prostaglandins on
`Canine Intrapulmonary Arteries and Veins, Pharmacol.
`73:819-827 (1981).
`Angerio et al., Cardiovascular Responses to PDG2 in
`Dog (39943), Proc. Soc. Exp. Biol. and Med.,
`156:393-395 (1977).
`Grossman et al., Pulmonary Hypertension, Abnormali
`ties of Circulatory Function, 835-851.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1054, p. 3 of 7
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`

`

`1
`
`5,234,953
`
`TREATMENT OF CONGESTIVE HEART FAILURE
`
`The present invention is concerned with the treat
`ment of congestive heart failure (CHF).
`CHF is a clinical syndrome characterized by a limita
`tion of exercise tolerance due to dyspnea and/or fatigue
`which can be attributed to an abnormality of cardiac
`function. Such cardiac dysfunction may be secondary
`to alterations incardiac ?lling or cardiovascular trans
`port (or both) and can be associated with identi?able
`changes in systolic and diastolic function which may
`lead to pulmonary hypertension.
`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 these compounds have useful application
`as anti-thrombotic agents, anti-ulcer agents and anti
`asthma agents. There is no suggestion or disclosure that
`they may be used in the treatment of any type of CHF.
`Structure activity relationships of benzindene prosta
`glandins have also been described (P. A. Aristoff, A. W.
`Harrison, P. D. Johnson, and A. Robert, Advances in
`Prostaglandin, Thromboxane, and Leukotriene Re
`search, Vol. 15, edited by O. Hayaishi and S. Yama
`moto. Raven Press, New York, 1985., Pg. 275-277).
`European Patent Speci?cation 0347243 describes a
`class of benzindene and non-benzindene prostaglandins
`suitable for use in the prophylaxis, treatment and diag
`nosis of pulmonary hypertension and Raynaud’s dis
`ease. We have identi?ed a sub-class of the compounds
`described in European Patent Speci?cation 0347243(as
`well as U.S. Ser. No.'07/367,090) which have potent
`systemic and pulmonary vascular effects which render
`them suitable for use in the treatment of CHF.
`The present invention, therefore, lies in the use of a
`compound of formula (I)
`
`25
`
`35
`
`wherein
`-W— is
`
`(I)
`
`45
`
`55
`
`where Z is —V(CH2)bCO2H where b is l or 2 and V
`is oxygen when b is l or methylene when b is 2;
`X is hydrogen, cyano, or —CECH; and
`the dotted line represents an optional double bond;
`and physiologically acceptable base salts, esters and
`other physiological functional derivatives thereof,
`for the treatment of congestive heart failure.
`The term “physiological functional derivative” is
`used herein to denote a bioprecursor or “prodrug”
`which may be converted to a compound of formula (I)
`in-vivo, for example, an amide wherein the amide nitro
`
`65
`
`2
`gen is optionally substituted by one or two C14 alkyl
`groups.
`All references hereinafter to “a compound of formula
`(1)” include references to its physiologically acceptable
`base salts, esters, and other physiological functional
`derivatives.
`The present invention further lies in the use of the
`compounds of the present invention in the treatment of
`Cl-IF which is accompanied by pulmonary hyperten
`sion.
`In animal tests, compounds of formula (I) are potent
`pulmonary vasodilators and markedly attenuate the
`pulmonary vasoconstriction induced by hypoxia. The
`overall acute bene?cial hemodynamic effects observed
`are substantial reductions in pulmonary vascular resis
`tance, pulmonary arterial pressure, systemic vascular
`resistance and mean arterial blood pressure and in
`creases in cardiac output and stroke volume. All of
`these effects are desirable in the treatment of CHF.
`In normotensive (i.e., absence of any indication of
`pulmonary or systemic hypertension) dogs, administra
`tion of an ACE-inhibitor, a cardiotonic, or a diuretic,
`either simultaneously with or immediately prior to, the
`administration of a compound of formula (I) respec
`tively blocks, attenuates, and potentiates the increase in
`Angiotensin II plasma concentration induced by the
`compounds of formula (I) without signi?cantly affect
`ing its hemodynamic pro?le. Pre-treatment with an
`ACE-inhibitor also enhanced the cardiovascular effects
`of the compounds of formula (I). However, it is not
`considered advisable to administer the compounds of
`formula (I) with a diuretic in the absence of an ACE
`inhibitor and/or a cardiotonic. Preferred compounds
`for co-administration with a compound of formula (I)
`include the ACE-inhibitors enalapril, captopril, and
`linsinopril; the cardiotonic digoxin; and the diuretics
`forosemide and butemenide.
`The compounds of the present invention can be ad
`ministered as either an acute treatment or a chronic
`treatment for CI-IF. The preferred methods of adminis
`tration of the compounds of the invention are via trans
`dermal delivery or intravenous injection.
`According to a further aspect of the invention, there
`fore, there is also provided a method for the treatment
`of CHF in a mammal, such as a human, which com
`prises the administration of a therapeutically effective
`amount of a compound of formula (I).
`Preferred compounds of formula (I) having particu
`larly advantageous properties in respect of the treat
`ment of CHF are
`(lR,2R,3aS,9aS)-([2,3,3a,4,9,9a-hexahydro-2
`hydroxy-l-((S)-3-hydroxyoctyl)-lH-benz[f]inden-5
`yl]oxy)acetic acid (which is also known as [1R-(la(S*)
`,2a,3aa,9aa)]-([2,3,3a,4,9,9a-hexahydro-2-hydroxy-l
`(3-hydroxyoctyl)-1I-I-benz-[f]inden-S-yl]oxy)acetic acid
`or
`9-deoxy-2’,9-methano-3-oxa-4,5,6-trinor-3,7-( l ’,3'
`interphenylene)-l3,l4-dihydro-prostaglandin F1) hav
`ing formula (A),
`(5Z,9R)-9-cyano-6a-carbaprostaglandin I; (B), and
`(5Z,9R)-9-ethynyl-Ga-carbaprostaglandin I; (C) which
`have the following structures:
`
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`

`5,234,953
`
`(A)
`
`(B)
`
`10
`
`20
`
`(C)
`
`25
`
`30
`
`4
`as an infusion of from 0.5 mg to 1.0 ug per kilogram per
`minute. Infusion ?uids suitable for this purpose may
`contain, for example, from 10 mg to 10 ug per milliliter
`of the active compound. Ampoules for injection may
`contain, for example, from 0.1 ug to 1.0 mg and orally
`administrable unit dose compositions, such as tablets or
`capsules, may contain, for example, from 0.1 to 100 mg,
`typically from 1 to 50 mg. 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).
`The ACE-inhibitors, cardiotonics and diuretics to be
`used in accordance with the present invention are ad
`ministered via the accepted routes and in the accepted
`dosages.
`The manufacture of a pharmaceutical composition in
`accordance with the invention typically involves ad
`mixing a compound of formula (I) or one of its physio
`logically acceptable salts with one or more carriers
`and/ or excipients. The latter must, of course, be accept
`able in the sense of being compatible with any other
`ingredients in the composition and must not be deleteri
`ous to the patient. The carrier may be a solid or a liquid,
`or both, and is preferably formulated with the active
`compound as a unit-dose composition, for example, a
`tablet, which may contain from 0.05% to 95% by
`weight of the active compound. The compounds of
`formula (I) may be incorporated in the compositions of
`the invention by any of the well known techniques of
`pharmacy consisting essentially of admixing the compo
`nents.
`The compositions of the invention include those suit
`able for oral, buccal (e.g. sub-lingual), parenteral (e.g.
`subcutaneous, intramuscular, intradermal, and intrave
`nous), rectal, topical, transdermal, nasal and pulmonary
`administration, although the most suitable route in any
`given case will depend on the nature and severity of the
`condition being treated.
`Compositions suitable for oral administration may be
`presented in discrete units adapted for instant or con
`trolled release such as capsules, cachets, lozenges, or
`tablets, each containing a predetermined amount of a
`compound of formula (I); 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 compositions may be prepared by any suitable
`method of pharmacy which includes the step of bring
`ing into association the active compound and a suitable
`carrier (which may contain one or more accessory in
`gredients). In general, the compositions 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 pre
`pared by compressing or moulding a powder or gran
`ules 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-?owing 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.
`Compositions suitable for buccal (sub-lingual) admin
`istration include lozenges comprising a compound of
`formula (I) in a ?avored base, usually sucrose and aca
`
`COJH
`
`COgl-I
`
`WisZ
`
`and physiologically acceptable base salts, esters and
`other physiologically functional derivatives of any
`thereof.
`Of these preferred compounds of formula (I), com
`pound (A) and its physiologically acceptable base salts,
`esters and other physiologically functional derivatives
`are particularly preferred, especially compound (A)
`itself of formula (I) wherein
`
`40
`
`45
`
`LII 5
`
`60
`
`65
`
`X is H.
`Base salts in accordance with the invention include
`ammonium salts, alkali metal salts such as those of so
`dium and potassium, alkaline earth metal salts such as
`those of calcium and magnesium, salts with organic
`bases such as dicyclohexylamine and N-methyl‘D
`glutamine, and salts with amino acids such as arginine
`and lysine.
`The amount of a compound of formula (I), which is
`required for the treatment of CHF will depend on a
`number of factors, in particular the nature and severity
`of the condition being treated and the preferred mode of
`administration, and the condition of the patient. In gen
`eral, a daily dose for the treatment of CHF is in the
`range 25 ug to 250 mg, typically from 1.0 ug to 0.05 mg,
`per day per kilogram bodyweight. For example, an
`intravenous dose may be in the range 0.5 ug to 1.5
`mg/kg/day, which may conveniently be administered
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`5,234,953
`5
`cia or tragacanth; and pastilles comprising the com
`pound in an inert base such as gelatin and glycerin or
`sucrose and acacia.
`Compositions of the present invention suitable for
`parenteral administration conveniently comprise sterile
`aqueous preparations of a compound of formula (I),
`which preparations are preferably isotonic with the
`blood of the intended recipient. These preparations are
`preferably administered intravenously, although admin
`istration may also be effected by means of subcutaneous,
`intramuscular, or intradermal injection. Such prepara
`tions may conveniently be prepared by admixing the
`compound with water or a suitable buffer, for example,
`a glycine or citrate buffer, and rendering the resulting
`solution sterile and isotonic with the blood (pH range:
`3.5-8.5). Injectable compositions according to the in
`vention will generally contain about 0.5 mg/ml of ac
`tive ingredient and may be diluted to a concentration of
`from 0.0001 to 0.05% w/v of active ingredient prior to
`administration. Parenteral administration is typically
`carried out at a rate of 0.001 ml/min/kg or more.
`Compositions suitable for rectal administration are
`preferably presented as unit dose suppositories. These
`may be prepared by admixing a compound of formula
`(I) with one or more conventional solid carriers, for
`example, cocoa butter, and then shaping the resulting
`mixture.
`Compositions 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, lanolin, polyethylene
`glycols, alcohols, and combinations of two or more
`thereof. The active compound is generally present at a
`concentration of from 0.001 to 1.0% w/w, for example,
`from 0.005 to 0.2% w/w.
`Compositions for transdermal administration may be
`delivered by passive diffusion or by electrically-assisted
`transport, for example, iontophoresis (see, for example,
`Pharmaceutical Research 3(6), 318, (1986)) and may
`take the form of an optionally buffered aqueous solution
`of a compound of formula (I). Typical compositions
`comprise citrate or bis/tris buffer (pH 6) or ethanol/wa
`ter containing from 0.1 to 0.2M active ingredient, but
`other compositions suitable for administration by trans
`dermal iontophoresis are within the scope of the present
`invention.
`For nasal administration, a particle size in the range
`l0-500 um is preferred to ensure retention in the nasal
`cavity. For pulmonary administration via the mouth,
`the particle size of the powder or droplets is typically in
`the range 0.5-10 um, preferably 1-5 um, to ensure deliv
`ery into the bronchial tree.
`Metered dose inhalers are pressurized aerosol dis
`pensers, typically containing a suspension or solution
`composition of the active ingredient in a lique?ed pro
`pellant. During use these devices discharge the compo
`sition through a valve adapted to deliver a metered
`volume, typically from 10 to 150 ul, to produce a ?ne
`particle spray containing the active ingredient. Suitable
`propellants include certain chlorofluorocarbon com
`pounds, for example, dichlorodifluoromethane, trichlo
`rofluoromethane, dichlorotetralluoroethane and mix
`tures thereof. The composition may additionally con
`tain one or more co-solvents, for example, ethanol,
`surfactants, such as oleic acid or sorbitan trioleate or
`EXOSURF Neonatal ®, antioxidants and suitable fla
`voring agents.
`
`6
`EXOSURF Neonatal® is a protein-free synthetic
`lung surfactant consisting if an aqueous suspension of
`colfosceril palmitate(dipalmitoylphosphatidylcholine),
`cetyl alcohol, tyloxapol(formaldehyde polymer with
`oxirane and 4-(1,l,3,3-tetramethylbutyl)phenol) and
`sodium chloride with the pH adjusted to a value of from
`5 to 7.
`Nebuliz'ers are commercially available devices which
`transform solutions or suspensions of the active ingredi
`ent into a therapeutic aerosol mist either by means of
`acceleration of a compressed gas through a narrow
`venturi ori?ce, typically air or oxygen, or by mean of
`ultrasonic agitation. Suitable compositions for use in
`nebulizers consist of the active ingredient in a liquid
`carrier, the active ingredient comprising up to 40%.
`w/w of the composition, but preferably less than 20%
`w/w. The carrier is typically water or a dilute aqueous
`alcoholic solution, preferably made isotonic with body
`?uids by the addition of, for example, sodium chloride.
`Other suitable carriers include surfactants, such as EX
`OSURF Neonatal ®. Optional additives include preser
`vatives if the composition is not prepared sterile, for
`example, methyl hydroxybenzoate, antioxidants, flavor
`ing agents, volatile oils, buffering agents and surfac
`tants.
`Suitable compositions for administration by insuf?a
`tion include ?nely comminuted powders which may be
`delivered by means of an insuftlator or taken into the
`nasal cavity in the manner of a snuff. In the insuftlator,
`the powder is contained in capsules or cartridges, typi
`cally made of gelatin or plastic, which are either pierced
`or opened in situ and the powder delivered by air drawn
`through the device upon inhalation or by means of a
`manually-operated pump. The powder employed in the
`insufflator consists either solely of the active ingredient
`or of a powder blend comprising the active ingredient,
`a suitable powder diluent, such as lactose, and an op
`tional surfactant, for example, EXOSURF Neonatal ®.
`The active ingredient typically comprises from 0.1 to
`100 w/w of the composition.
`The compounds of the present invention are conve
`niently prepared by methods which are the same as or
`are analogous to those described in the aforementioned
`US. Pat. No. 4,306,075, which is incorporated in its
`entirety herein by reference.
`For a better understanding of the invention, the fol
`lowing EXAMPLES ar' given by way of illustration.
`EXAMPLES
`The cardiovascular effects of compound (A) were
`examined in animal models.
`(a) Aortic blood pressure, heart rate and the Lead II
`ECG were recorded from 6 conscious beagles with
`indwelling cannulae. Compound (A) was given orally
`(0.l and 0.5 mg/kg) or intravenously (0.3-3 ug/kg/
`min). Oral administration at 0.5 mg/kg, but not 0.1
`mg/kg, resulted in signi?cant hypotension. The maxi
`mum effect was observed within four minutes (mean
`fall: 42 mm Hg systolic, 31 mm Hg diastolic) and had
`recovered within 150 minutes of dosing. Heart rate
`was generally increased with a maximum change of
`25 bpm. Intravenous infusions at doses ranging from
`0.3-3 ug/kg/min resulted in a dose-dependent hypo
`tension (falls of 12-45 mm Hg diastolic) accompanied
`\by tachycardia.
`(b) The model used was a open chest preparation of an
`anesthetized cat(anesthetic: chloralose and urethane).
`
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`50
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`5,234,953
`
`7
`A series of glysine buffer solutions of compound (A)
`were successively administered to each animal by i.v.
`infusion at doses equivalent to 100 mg, 300 ng, 1 ug,
`and 3 ug/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 venti
`lating with 10% 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 S-minute
`hypoxic challenges were given 15 minutes apart
`which were averaged to obtain the control hypoxic
`responses. 15 minutes after the second control hyp
`oxic 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.
`Compound (A) was found to a potent pulmonary vaso
`dilator in this model and markedly attenuated the
`pulmonary vasoconstriction induced by hypoxia. The
`overall acute bene?cial hemodynamic effects ob
`served were substantial reductions in pulmonary vas
`cular resistance, pulmonary arterial pressure, sys
`temic vascular resistance and mean arterial blood
`pressure and increases in cardiac output and stroke
`volume.
`In another series of experiments, it was found that
`separate pretreatment of anesthetized dogs with enala
`pril (0.3 mg/kg), digoxin (100 mg/kg) and furosemide
`(1.0 mg/kg) 30-40 minutes prior to intravenous infusion
`of the compound of formula (A) respectively blocked,
`attenuated and potentiated the increase in Angiotensin
`II plasma concentration induced by the latter without
`signi?cantly affecting its hemodynamic pro?le.
`In yet another series of experiments, two anesthetized
`dogs were given a 20 ug/kg intratracheal bolus dose of
`the compound of formula (A), one as a solution in 5%
`40
`ethanol/saline and the other as a solution in 5% ethanol
`/EXOSURF Neonatal ®. The plasma concentration of
`the compound of formula (A) was monitored for each
`animal and the mean terminal half-life determined in
`each case. The half-life of the EXOSURF-treated ani
`mal was found to be signi?cantly longer than that of the
`saline-treated animal. Mean bioavailability with EX
`OSURF was 88% and without EXOSURF wa 46%.
`
`25
`
`45
`
`50
`
`TOXICITY
`The compound of formula (A) was tested by oral and
`intravenous routes in acute and subchronic tests in mice,
`rates and dogs. These experiments established no effect
`levels and full reversibility was observed. Most effects
`were attributable to the known pharmacological activ
`ity of the compound of formula (A) which has a half-life
`measured in minutes for the species examined.
`All of the effects observed in the animal models are
`desirable in the treatment of CI-IF.
`
`PHARMACEUTICAL COMPOSITIONS
`The active compound is the compound of formula (A).
`mg per tablet
`
`65
`
`Instant Release Tablet
`Active Compound
`Lactose
`
`1
`79
`
`8
`-continued
`PHARMACEUTICAL COMPOSITIONS
`The active compound is the compound of formula (A).
`mg per tablet
`l2
`4
`3
`I
`I00
`
`Microcrystalline Cellulose
`Sodium Starch Glycollate
`Povidone BP
`Magnesium Stearate
`
`Instant Release Capsule
`Active Compound
`Microcrystalline Cellulose
`Pregelatinised Starch NF
`Magnesium Stearate
`
`Active Compound
`Lactose
`Methocel K4M
`Povidine K30 BP
`Magnesium Stearate
`
`mm
`Disodium citrate solution, 0.lM
`0.lN NaOI-l solution
`Active Compound
`Water for Injections
`Subcutaneous and Intramuscular Solution
`Disodium citrate solution, 0.1M
`0.1N NaOH solution
`Active Compound
`Dextrose
`Water for Injections
`
`1
`20
`178
`;_
`200
`
`5.0
`147.5
`87.5
`7.5
`2.5
`250.0
`
`0.6 ml
`qs to pH 6
`0.5 mg
`to 1 ‘ml
`
`0.5 ml
`qs to pH 6.8
`0.25 mg
`25 mg
`to 1 ml
`
`Transdermal Solution
`0.01-0.2M solution of the active compound in a ci
`trate or bis/tris buffer (pH 6) or ethanol/water.
`What is claimed is:
`1. A method of increasing the cardiac output and
`stroke volume of blood provided from the heart of a
`mammal identified as exhibiting congestive heart failure
`disorder having low cardiac