WO2000043012A1 - Regulation de la frequence cardiaque ou de la pression arterielle chez des patients sous medication conjointe d'inhibiteurs de la phosphodiesterase pour un traitement de l'impuissance - Google Patents

Regulation de la frequence cardiaque ou de la pression arterielle chez des patients sous medication conjointe d'inhibiteurs de la phosphodiesterase pour un traitement de l'impuissance Download PDF

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Publication number
WO2000043012A1
WO2000043012A1 PCT/US2000/001284 US0001284W WO0043012A1 WO 2000043012 A1 WO2000043012 A1 WO 2000043012A1 US 0001284 W US0001284 W US 0001284W WO 0043012 A1 WO0043012 A1 WO 0043012A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
adrenergic receptor
blocking agent
receptor blocking
straight
Prior art date
Application number
PCT/US2000/001284
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English (en)
Inventor
William L. Matier
Ghanshyam Patil
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Selectus Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Selectus Pharmaceuticals, Inc. filed Critical Selectus Pharmaceuticals, Inc.
Priority to AU32105/00A priority Critical patent/AU3210500A/en
Publication of WO2000043012A1 publication Critical patent/WO2000043012A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the present invention relates to a method for attenuating acute onset of heart rate or blood pressure increase in patients where the use of nitrate-containing drugs is contraindicated.
  • the invention provides a method for the control of heart rate or blood pressure during short term activities following administration of drugs such as sildenafil for treatment of impotence .
  • NO activates guanylate cyclase, which elevates the levels of cyclic guanosine cyclase monophosphate (cGMP) to smooth muscle relaxation in the corpus cavernosum and allow inflow of blood.
  • PDE5 degrades cGMP in the corpus cavernosum.
  • Sildenafil enhances the effect of NO by inhibiting PDE5, thus prolonging the elevated concentration of cGMP in the corpus cavernosum.
  • the physical and sexual activities likely to be engaged in by a patient after administration of sildenafil are activities that commonly cause increases in heart rate and blood pressure. Control of heart rate and blood pressure during these short-term activities is particularly important for patients at risk due to coronary artery disease, such as myocardial ischemic disorder. Severe attacks of chest pain, angina pectoris, occur when cardiac work and myocardial oxygen demand exceed the ability of the coronary arterial system to supply oxygen. The major determinants of myocardial oxygen consumption are heart rate and systolic tension (arterial pressure) . Any increase in these determinants in the presence of reduced coronary blood flow may induce angina. The higher the blood pressure and the faster the heart rate, the greater the unmet myocardial oxygen need.
  • nitroglycerin (1 , 2 , 3-propanetriol trinitrate)
  • Nitroglycerin acts by relaxing the vascular smooth muscle, resulting in the dilation of peripheral arteries and veins, thereby promoting peripheral pooling of blood and decreasing the blood pressure around the heart.
  • sildenafil Although nitroglycerin may be needed by a patient after administration of sildenafil, its use in conjunction with sildenafil is contraindicated. Consistent with its known effect on the NO/cGMP pathway as described above, sildenafil has been shown to potentiate the hypotensive effects of nitrates. It is likely that sildenafil is inhibiting PDE5 in the smooth muscle of the vascular system as well as the corpus cavernosum, thus causing the observed potentiation of hypotension when taken in combination with other nitrate vasodilators, such as nitroglycerin.
  • the increased hypotension caused by combined administration of sildenafil and nitrate vasodilators may have life-threatening consequences.
  • Other symptoms of hypotension include headaches and vertigo. (PDR, 1994, p. 891) .
  • a non- nitrate agent for prophylaxis or treatment of acute onset angina pectoris is needed for use in conjunction with sildenafil, in patients requiring medication for both the heart condition and impotence.
  • a method for acutely treating or preventing angina, or other conditions arising from a sudden increase in heart rate or blood pressure, in patients requiring such treatment and who also are concurrently administered sildenafil or equivalent cGMP/NO pathway inhibitors.
  • the method comprises administering to such patients a ⁇ -adrenergic receptor blocking agent or "beta- blocker" at specific time such that the therapeutic concentration of sildenafil and the beta-blocker coincide.
  • beta-blocker The half life and bioavailability of commercially available beta-blockers after oral administration vary greatly (Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, P.1712- p.1792).
  • beta-blockers may be dosed up to 3 hours prior to the administration of oral sildenafil (or similar anti- impotence agent) or, in preferred embodiments as described below, along with or after administration of the anti-impotence agent.
  • These "beta-blockers” may be administered by any commonly accepted routes such as orally, sublingually, intranasally or buccally.
  • a preferred embodiment of the present invention utilizes a rapid acting beta adrenergic receptor blocking agent ( "beta-blocker” ) having Formula 1 below.
  • X is a direct bond, -CH 2 or
  • Z is (CH 2 VB or
  • B when y is 1-10, is --NR 2 COR 3 , --NR 2 CONR 3 R 4 , --NR 2 S0 2 R 3 , --NR 2 S0 2 NR 3 R 4 or --NR 2 COOR 5 ;
  • R 2 , R 3 , R 4 and R 5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl , heteroaryl, or aralkyl, except that R 3 and R 5 are not hydrogen when B is --NR 2 S0 2 R 3 or --NR 2 COOR 5 ;
  • Y is C.-C 6 straight or branched carbon chain, or aralkyl ;
  • R 6 is hydrogen or -COJ wherein J is lower alkyl, wherein R x is lower alkyl, lower cycloalkyl, lower alkenyl , lower alky carboxymethyl , aryl carboxymethyl , aryl or aralkyl or C-4 to C-10 straight or branched carbon chain alkyl -cycloalkyl or a group -B-D, where B is C-2 to C-10 straight or branched carbon chain alkyl and D is hydroxy or alkyloxy or 2 , 3 -dihydroxypropyl or 2,3- dialkyloxypropyl or 2,2- dialkyl-1 , 3 -dioxolane- 5 -methyl , where alkyl is C-l to C-10 straight or branched carbon chain;
  • A is a direct bond, lower alkylene, or lower alkenylene; provided that when x is greater than 1, different occurrences of the
  • Ar is heterocyclic, unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, lower alkylamino, hydroxy, lower hydroxyalkyl or cyano, lower alkylcarbonyloxy, or pharmaceutically acceptable salts thereof.
  • Formula 1 above are represented by Formula 1A: (1A)
  • R represents hydrogen or C-l to C-10 straight or branched carbon chain alkyl or C-3 to C-6 cycloalkyl or C-4 to C-10 straight or branched carbon chain alkyl - cycloalkyl or a group -B-D, where B is C-2 to C-10 straight or branched carbon chain alkyl and D is hydroxy or alkyloxy or 2 , 3-dihydroxypropyl or 2,3- dialkyloxypropyl or 2,2- dialkyl-1 , 3 -dioxolane -5 -methyl , where alkyl is C-l to C-10 straight or branched carbon chain;
  • W represents CH(CH 3 )CH 2 -, C(CH 3 ) 2 CH 2 - Z represents hydrogen, -NHCOR 2 , -NHCONR 2 R 3 or -NHS0 2 R 2 or -NHS0 2 NR 2 R 3 or -NHCOOR 4 wherein R 4 is alkyl of from 1 to about 6 carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to about 6 carbon atoms, alkoxyaryl , cycloalkyl of from 3 to about 8 carbon atoms .
  • R 2 and R 3 may be the same or different and represent hydrogen, alkyl of from 1 to about 6 carbon atoms, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to about 6 carbon atoms, alkoxyaryl, cycloalkyl of from 3 to about 8 carbon atoms, a phenyl group substituted or unsubstituted, heteroaryl, furanyl , thiophenyl , imidazolyl, oxazolyl or indolyl or tetrahydrofuranyl , tetrahydropyranyl , dioxanyl, 2, 2 -dimethyl dioxolane-5- methyl, pyrrolidinyl , piperazinyl and tetrahydrooxazolyl , aralkyl except that R 2 and R 3 are not hydrogen when Z is -NHS02R 2 , or R 2 and R 3 may together with N form a 5 to 7 membere
  • Formula 1A wherein -Z represents isopropyl or t-butyl or Z represents -NHCOR 2 , where R 2 is isopropyl, tetrahydro- furanyl , tetrahydropyranyl and -NHCONR 2 R 3 ; wherein R 2 and R 3 together with N form a morpholino group and R is methyl, ethyl, n-propyl , cyclopropylmethyl , n- butyl , isobutyl or cyclopentyl .
  • the beta blocker is the compound levo SL-1050 hydrochloride ((S)-(-) ethyl 3- [2- [2-hydroxy-3- (isopropylamino) propoxy] - phenyl] propionate hydrochloride) .
  • the beta blocker is racemic ethyl 3-[2-[2- hydroxy-3- (isopropylamino) propoxy] -phenyl] ropionate hydrochloride .
  • the agent preferably is administered sublingually, intranasally or orally, concomitantly with, or at a pre-determined interval before or following administration of the sildenafil or equivalent therapeutic agent (hereinafter "anti -impotence agent").
  • the agent is administered sublingually or intranasally at the onset of symptoms of angina or abnormally increased heart rate or blood pressure.
  • a combination therapy of sildenafil or an equivalent anti -impotence therapeutic agent and the rapid acting beta-adrenergic receptor blocking agent is provided.
  • this combination therapy comprises a container containing separate appropriate dosages of the anti-impotence agent and the rapid acting beta-blocker, along with instructions for administration of the respective agents.
  • the combination therapy comprises a single pharmaceutical preparation for oral administration, containing both the anti -impotence agent and the rapid acting beta blocker.
  • the present invention provides a combination therapy that enables safer use of sildenafil for patients with ischemic heart disease.
  • the combination comprises a ⁇ -adrenergic receptor blocking agent ("beta-blocker”), preferably a composition represented by Formula 1 below and analogs or derivatives thereof (collectively referred to herein as "rapid-acting beta blockers”), in conjunction with sildenafil, to abort an angina episode or to prevent the occurrence of an angina episode, or to otherwise alleviate or prevent symptoms associated with sudden increases in blood pressure or heart rate.
  • beta-blocker ⁇ -adrenergic receptor blocking agent
  • rapid-acting beta blockers analogs or derivatives thereof
  • these rapid acting beta blockers are superior to nitroglycerin or other nitrate-containing vasodilators for treating patients co-medicated with sildenafil.
  • sildenafil is exemplified herein, the present invention contemplates a combination therapy with any therapeutic agent for treatment of erectile dysfunction having the same mechanism of action as does sildenafil, i.e. selective inhibition of penis-specific PDE or other aspects of the NO/cGMP pathway that regulates penile erection.
  • ester compounds of Formula 1A wherein W-Z represents isopropyl or t-butyl or Z represents -NHCOR 2 , where R 2 is isopropyl, tetrahydro- f ranyl , tetrahydropyranyl and -NHCONR 2 R 3 ; wherein R 2 and R 3 together with N form a morpholino group and R is methyl, ethyl, n-propyl , cyclopropylmethyl , n-butyl, isobutyl or cyclopentyl .
  • Ester compounds of Formula 1A are described in U.S. Patent Application Serial No. [ ], incorporated by reference herein in its entirety.
  • Beta-blockers suitable for use in the present invention include, but are not limited to: Betapace ® , commercially available from Berlex Laboratories, Inc., Wayne, N.J.; Blocadren ® , commercially available from Merck & Co, West Point, PA; Cartrol ® , commercially available from Abbott Laboratories, Inc., North Chicago, II; Inderal ® , commercially available from Wyeth-Ayerst Laboratories, Philadelphia, PA; Kerlone ® , commercially available from G.D.
  • Betapace ® commercially available from Berlex Laboratories, Inc., Wayne, N.J.
  • Blocadren ® commercially available from Merck & Co, West Point, PA
  • Cartrol ® commercially available from Abbott Laboratories, Inc., North Chicago, II
  • Inderal ® commercially available from Wyeth-Ayerst Laboratories, Philadelphia, PA
  • Kerlone ® commercially available from G.D.
  • Sildenafil is commercially available from Pfizer, Inc., New York, N.Y. Sildenafil and similar compounds also may be prepared by any suitable method known in the art. For instance, a process for the preparation of sildenafil is set forth in European Patent Application EP-A-0812845 , published December 17, 1997, the entirety of which is incorporated by reference herein. Processes for preparing the general class of compounds exemplified by sildenafil are set forth in EP- A-0463756 and EP-A-0526004 , both incorporated by reference herein in their entireties.
  • sildenafil preferably is formulated for oral administration as a tablet.
  • sildenafil and similar compounds also may be formulated as a tablet, capsule or liquid for intranasal, buccal or sublingual delivery (see EP-A-0463756 and EP-A-0526004) .
  • Levo SL-1050 hydrochloride is commercially available from Selectus Pharmaceuticals, Inc., Kennett Square, PA.
  • This and similar compounds also may be prepared by any suitable method known in the art .
  • processes for the preparation of compounds of Formula 1 are set forth in U.S. Patent No. 5,536,749 and U.S. Application Serial No. [ ] discussed above, and references cited therein, as well as 4,387,103, 4,692,446, 4,804,677, 4,810,717 and 4 , 959 , 390 , the entireties of all of which are incorporated by reference herein.
  • Pharmaceutical formulations comprising compounds of Formula 1 can be made according to standard procedures, e.g., as described in U.S. Patent No.
  • Intranasal administration of beta blockers is described in U.S. Patent 4,428,883 issued January 31,1984; Pharmaceutical Research 2: 108-111, 1986; and U.S. Patent 5,242,949 issued September 7, 1993.
  • the use of intranasal propranolol is reported as a beta adrenergic agent is described in U.S. Patent 5,242,949 issued September 7, 1993 and Pharmaceutical Research 3 : 108, 1986.
  • Intranasal propranolol or any intranasal beta- adrenergic blocking agent can be administered so that the beta-blocking effect coincides with the effects of the anti -impotence agent.
  • the present invention provides a method for acutely treating or preventing angina, or other conditions arising from a sudden increase in heart rate or blood pressure, in patients requiring such treatment and who also are concurrently administered sildenafil or equivalent cGMP/NO pathway inhibitors.
  • the method comprises administering to such patients a rapid acting beta blocker, as described above, either shortly before, concurrently with, or shortly after the administration of sildenafil, or on an as- needed basis following administration of sildenafil, while the drug remains in the patient's circulation.
  • the respective drugs are administered as dosage units.
  • dosage units refers to a physically discrete unit of the pharmaceutical preparation appropriate for the patient undergoing treatment. Each dosage unit contains a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier.
  • a preferred single dose of sildenafil is 25-100 mg for an adult human (Physicians Desk Reference 1998) .
  • Appropriate dosages of compounds similar to sildenafil may be determined by standard methods.
  • a single dose of a rapid-acting beta blocker having Formula 1 ranges from about 10 mg to about 500 mg, expressed as weight of the free base, for an adult human (approx. 70 kg) .
  • a preferred single dose of the active ingredient is about 25-500 mg .
  • a preferred single dose of the exemplary compound, levo SL-1050 HC1 is 50-200 mg. Appropriate dosages of specific compounds of Formula 1 may be determined by standard methods .
  • the sildenafil (or similar anti -impotence agent) is administered, and the rapid-acting beta-blocker is administered on an as-needed basis thereafter, for at least as long as the anti-impotence agent remains in circulation.
  • the rapid-acting beta blocker is used exclusively as a replacement for nitrate- containing vasodilators by patients who regularly use a sildenafil-type of anti -impotence agent.
  • the sildenafil-type anti -impotence agent and the rapid-acting beta blocker are administered together.
  • co-administration of the anti-impotence agent and the beta-blocker ensures control of blood pressure or heart rate during the time physical exertion and sexual activity are likely to be occurring.
  • the beta-blocker may be administered at a pre-determined time e. g., 30 minutes before or 1 hour following administration of the anti-impotence agent.
  • Dosage units of sildenafil or similar agents and the rapid-acting beta blocker can be formulated separately, but packaged together along with appropriate instructions, for convenience and ease of use.
  • This embodiment is suitable for administration regimens in which the anti -impotence agent is taken separately, and the beta blocker is taken as needed, or at a predetermined interval before or following administration of the anti-impotence agent.
  • sildenafil and the rapid-acting beta blocker can be formulated together into an appropriate pharmaceutical preparation.
  • This embodiment is suitable for an administration regimen in which the anti-impotence agent and the beta blocker are taken simultaneously.
  • a preferred formulation comprising sildenafil and levo SL-1050 HC1 is a powder or rapidly- dissolving tablet, formulated as follows:
  • a sweetener (s) and/or a flavor (s) may be added if desired to mask an unpleasant taste, if any.
  • the (S) -Ethyl 3- [2- [2-hydroxy-3 - (isopropylamino) propoxy] phenyl] propionate hydrochloride is mixed with the appropriate excipients until blend uniformity is achieved.
  • This blend is packaged in appropriate size units in bottles, dosage container or powder paper for administration. Tablets are manufactured from the powder using conventional tableting equipment. The physical properties of the tablets preferably fall within the ranges shown below.
  • the dissolution (USP 23 ⁇ 711>) and disintegration test (USP 23 ⁇ 701>) are performed according to USP methods.

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Abstract

Cette invention a trait à une méthode visant à atténuer l'apparition brutale de l'augmentation de la fréquence cardiaque ou de la pression artérielle chez des patients pour qui l'administration de médicaments contenant du nitrate est contre-indiquée. Elle concerne, plus précisément une méthode et une polythérapie visant à réguler la fréquence cardiaque ou la pression artérielle lors d'activités de courte durée faisant suite à l'administration de médicaments, tels que le sildenafil, traitant l'impuissance. Cette méthode consiste à administrer des bêtabloquants, de préférence des bêtabloquants à action rapide tels que (S)-(-)-éthyl 3-[2-[2-hydroxy-3-(isopropylamino) propoxy]phényl]propionate hydrochloride dès l'apparition des symptômes, à un moment prédéfini avant ou après l'administration de sildenafil ou conjointement à la prise de sildenafil ou d'agents similaires agissant contre l'impuissance.
PCT/US2000/001284 1999-01-22 2000-01-20 Regulation de la frequence cardiaque ou de la pression arterielle chez des patients sous medication conjointe d'inhibiteurs de la phosphodiesterase pour un traitement de l'impuissance WO2000043012A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32105/00A AU3210500A (en) 1999-01-22 2000-01-20 Controlling heart rate or blood pressure in patients co-medicated with phosphodiesterase inhibitors for treatment of impotence

Applications Claiming Priority (2)

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US23558799A 1999-01-22 1999-01-22
US09/235,587 1999-01-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1923073A2 (fr) * 2003-06-06 2008-05-21 Universitätsklinikum Freiburg Associations médicamenteuses comprenant des inhibiteurs de PDE-5
WO2017165688A1 (fr) * 2016-03-23 2017-09-28 University Of Maryland, Baltimore Compositions et procédés pour modifier génétiquement un gène de la sous-unité cible de la myosine phosphatase (mypt1) pour abaisser la pression artérielle

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
US5536749A (en) * 1994-10-13 1996-07-16 Sl Pharmaceuticals, Inc. Method for attenuation of sympathetic nervous system activity or onset of migraine by selectively metabolized beta-blocking agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
US5536749A (en) * 1994-10-13 1996-07-16 Sl Pharmaceuticals, Inc. Method for attenuation of sympathetic nervous system activity or onset of migraine by selectively metabolized beta-blocking agents

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1923073A2 (fr) * 2003-06-06 2008-05-21 Universitätsklinikum Freiburg Associations médicamenteuses comprenant des inhibiteurs de PDE-5
EP1923073A3 (fr) * 2003-06-06 2008-07-09 Universitätsklinikum Freiburg Associations médicamenteuses comprenant des inhibiteurs de PDE-5
US9278097B2 (en) 2003-06-06 2016-03-08 Universitatsklinikum Freiburg Prophylaxis and/or treatment of portal hypertension
WO2017165688A1 (fr) * 2016-03-23 2017-09-28 University Of Maryland, Baltimore Compositions et procédés pour modifier génétiquement un gène de la sous-unité cible de la myosine phosphatase (mypt1) pour abaisser la pression artérielle
US11607461B2 (en) 2016-03-23 2023-03-21 University Of Maryland, Baltimore Compositions and methods for genetically modifying myosin phosphatase target subunit (Mypt1) gene for lowering blood pressure

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