WO2008026156A2 - Therapeutic compositions comprising a specific endothelin receptor antagonist and a pde5 inhibitor - Google Patents

Therapeutic compositions comprising a specific endothelin receptor antagonist and a pde5 inhibitor Download PDF

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Publication number
WO2008026156A2
WO2008026156A2 PCT/IB2007/053448 IB2007053448W WO2008026156A2 WO 2008026156 A2 WO2008026156 A2 WO 2008026156A2 IB 2007053448 W IB2007053448 W IB 2007053448W WO 2008026156 A2 WO2008026156 A2 WO 2008026156A2
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Prior art keywords
compound
pde5
inhibitory properties
formula
pharmaceutically acceptable
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French (fr)
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WO2008026156A3 (en
Inventor
Martine Clozel
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Priority to DK07826167.4T priority Critical patent/DK2059246T3/en
Priority to US12/439,290 priority patent/US8268847B2/en
Priority to JP2009526239A priority patent/JP5208113B2/en
Priority to ES07826167.4T priority patent/ES2438792T3/en
Priority to PL07826167T priority patent/PL2059246T3/en
Priority to MX2009002057A priority patent/MX2009002057A/en
Priority to CA2659770A priority patent/CA2659770C/en
Priority to CN2007800321481A priority patent/CN101511365B/en
Priority to EP07826167.4A priority patent/EP2059246B1/en
Priority to HRP20131233TT priority patent/HRP20131233T1/en
Priority to SI200731367T priority patent/SI2059246T1/en
Priority to HK10101538.5A priority patent/HK1133597B/en
Priority to AU2007290099A priority patent/AU2007290099B2/en
Priority to NZ575702A priority patent/NZ575702A/en
Priority to BRPI0715698A priority patent/BRPI0715698B8/en
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2008026156A2 publication Critical patent/WO2008026156A2/en
Publication of WO2008026156A3 publication Critical patent/WO2008026156A3/en
Priority to IL197235A priority patent/IL197235A/en
Anticipated expiration legal-status Critical
Priority to NO20091254A priority patent/NO342554B1/en
Priority to US13/604,148 priority patent/US20130210830A9/en
Priority to US14/162,280 priority patent/US20140148460A1/en
Priority to US15/881,060 priority patent/US20180147205A1/en
Priority to US16/193,859 priority patent/US20190083494A1/en
Priority to US16/599,582 priority patent/US20200038401A1/en
Priority to US16/942,895 priority patent/US20200352944A1/en
Priority to US17/185,238 priority patent/US20210177849A1/en
Priority to FIC20240045C priority patent/FIC20240045I1/en
Priority to FR24C1054C priority patent/FR24C1054I2/en
Priority to LTPA2024537C priority patent/LTPA2024537I1/lt
Priority to NL301308C priority patent/NL301308I2/en
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a product containing the compound of formula (I) below
  • endothelin receptor antagonists including the compound of formula (I) and the use of said endothelin receptor antagonists in the treatment of various diseases wherein vasoconstriction is involved (i.a. heart failure, angina pectoris, pulmonary and systemic hypertension and erectile dysfunction).
  • ⁇ ⁇ ⁇ US 5,250,534 (describing pyrazolopyrimidinone derivatives as PDE-5 inhibitors and i.a. sildenafil as well as the use of the same for i.a. hypertension and heart failure) and EP 1 097 711 (describing i.a. sildenafil for pulmonary hypertension); ⁇ ⁇ WO 99/24433 (describing i.a. vardenaf ⁇ l as well as the use of the same for i.a. hypertension, angina pectoris and erectile dysfunction);
  • a subject of this invention is a product containing the compound of formula (I) as described before or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one (and preferably one) compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.
  • PDE-5" stands in the present application for cyclic guanosirse 3 " , 5 '-monophosphate (cGMP) phosphodiesterase type 5.
  • “Simultaneously” or “simultaneous”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients by the same route and at the same time.
  • “Separately” or “separate”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients at approximately the same time by at least two different routes.
  • therapeutic administration over a period of time is meant in the present application the administration of two or more ingredients at different times, and in particular an administration method according to which the entire administration of one of the active ingredients is completed before the administration of the other or others begins. In this way it is possible to administer one of the active ingredients for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs.
  • disease wherein vasoconstriction is involved is meant in particular hypertension, pulmonary hypertension (including pulmonary arterial hypertension), diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris.
  • compound having PDE5 -inhibitory properties is meant a compound that, when submitted to the "Test for the determination of PDE5 IC50" described in the present patent application, has an IC 50 equal or lower than 1 ⁇ M.
  • pharmaceutically acceptable salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • any reference to a compound of formula (I) or to a compound having PDE5 -inhibitory properties is to be understood as referring also to the pharmaceutically acceptable salts thereof, as appropriate and expedient.
  • the product according to this invention will be such that the compound of formula (I) and the compound having PDE5 -inhibitory properties are intended for a therapeutic use which takes place simultaneously or over a period of time.
  • the compound of formula (I) and the compound having PDE5 -inhibitory properties will be intended to be administered simultaneously.
  • the compound of formula (I) and the compound having PDE5 -inhibitory properties will be intended to be administered over a period of time.
  • the period of time intended for the therapeutic use of a product according to this invention will be at least one week, and preferably at least one or more months (for example six months). This period of time may also be the whole life of the patient that receives the product.
  • administration of compound of formula (I) will be alternated with administration of a compound having PDE5 -inhibitory properties, and the interval between such administration will not exceed two or three days (and more preferably not exceed one day).
  • the compound having PDE5 -inhibitory properties will be selected from sildenafil, vardenafil, tadalafil and udenafil. More preferably, the compound having PDE5 -inhibitory properties will be sildenafil or tadalafil.
  • the compound having PDE5 -inhibitory properties will be sildenafil.
  • the compound having PDE5 -inhibitory properties will be tadalafil.
  • the administration route of the compound of formula (I) and that of the compound having PDE5 -inhibitory properties is preferably the same.
  • the common administration route for the compound of formula (I) and for the compound having PDE5 -inhibitory properties will be the intravenous or oral route (and notably the oral route).
  • a dose of 0.05 to 2 mg (and preferably 0.1 to 1 mg) of compound of formula (I) per kg of patient body weight combined with a dose 0.01 to 1 mg (and preferably 0.05 to 0.5 mg) of tadalafil per kg of patient body weight, both compounds being intended to be administered by oral route, or combined with a dose 0.1 to 2 mg (and preferably 0.2 to 1 mg) of sildenafil per kg of patient body weight will be appropriate, both compounds being intended to be administered by oral route as well.
  • the disease intended to be treated by a product according to this invention will be selected from hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure,erectile dysfunction and angina pectoris. More preferably, the disease intended to be treated by a product according to this invention will be selected from hypertension and pulmonary hypertension. In particular, the disease intended to be treated by a product according to this invention will be pulmonary hypertension (and notably pulmonary arterial hypertension).
  • the invention also relates to a pharmaceutical composition containing, as active principles, the compound of formula (I) below
  • the invention further relates to the use of the compound of formula (I) below
  • the association of the compound of formula (I), administered orally at a dose of 0.3 mg/kg, with tadalafil, administered orally at a dose of 10 mg/kg has been studied in two different hypertension models, namely the Dahl salt-sensitive rat model and the spontaneously hypertensive rat model. Furthermore, the association of the compound of formula (I), administered orally at a dose of 0.3 mg/kg, with sildenafil, administered orally at a dose of 30 mg/kg, has been studied in the spontaneously hypertensive rat model.
  • the protocols used are detailed in the part entitled "Pharmacological properties of the invention compounds" hereafter.
  • Dahl salt-sensitive rats were purchased from Harlan (Netherlands). The rats were housed by group during the acclimatization period and single-housed after implantation of the telemetry device. All animals were maintained under identical conditions and had free access to normal pelleted rat chow and water. Dahl salt-sensitive rats develop hypertension only upon exposure to salt intake. They were administered a high-salt (8%) chow diet (Purina series 5500). Five weeks after starting salt administration, a telemetry system was implanted under anaesthesia by inhalation of 2.5% isoflurane (in 70% O 2 + 30% N 2 O).
  • a pressure radio-frequency transmitter was implanted into the peritoneal cavity, and a sensing catheter was inserted in the descending aorta and advanced pointing upstream to slightly below the renal artery bifurcation.
  • the transmitter was sutured to the abdominal musculature and the skin was closed.
  • a receiver platform transformed the radio signal into digitized input, that was sent to a dedicated personal computer (Compaq, deskpro).
  • Arterial blood pressure measurements were calibrated by using an input from an ambient pressure reference. Telemetry units were obtained from Data Sciences (St. Paul, MN, USA). The compounds were administered at least 2 weeks after telemetry system implantation.
  • the compound of formula (I) and the compound having PDE5 -inhibitory properties were prepared in 5% arabic gum and administered by oral gavage.
  • the acute effects of the compound of formula (I), the compound having PDE5 -inhibitory properties and their combination on blood pressure were measured by collecting data at 5 -minute intervals up to 72 h after oral administration. Hourly means of blood pressure were calculated for each rat. Each rat served as its own control, by using the blood pressure data of the last 24 hours before drug administration.
  • the two curves blood pressure of the control period and blood pressure of the treatment period
  • SHR spontaneously hypertensive rats
  • Phosphodiesterase ⁇ enzyme PDE 5 ⁇ is separated from human corpus cavernosa! tissues. About 3 g of tbis Hs&uo is homogenized wUh 12 ml of HEPBS buffer (20 raM HBPES, 250 raM sucrose, 1 mM EDTA, I raM PMSP, pH 7.2) at 4°C. The solution is filtered with double-layered gauze and centrifuged (100,000 xg) for 60 mm a ⁇ 4°C.
  • the supernatant is filtered with 0.2 ⁇ m filter paper and .separated by HPLC (Mono Q anion exchange column) with concentration gradient of 0-500 tnlvi NaCi ⁇ o elute PDE isozymes.
  • the enzyme activity is measured on each column fraction by the following process to separate the PDEo fraction and the PD E5 inhibition of the lest compound is measured using the PDE5 fraction.
  • 'H-cAMP or ⁇ H-cGMP 500 iiM. 2 ⁇ Ci/ml
  • the mixture is reacted in the incubator of 30 °C for about 1 hour and the reaction is quenched by putting the tube into boiling water for about 45 seconds to 2 min.
  • tbc tube is chilled in ice baih for abouf 5 min.
  • snake venom i mg/rnl. 100 ⁇ ! or 5 -nucleotidase (0. 1 unit/tube) and the mixture is reacted in an incubator at 37 °C for 10 min and chilled in an ice bath.
  • the supernatant (700 ⁇ l) is transferred to a liquid scintillation vial, and mixed with 10 mi of scintillation cocktail. After stabilizing the solution by leaving it overnight, the radioactivity of the tube is measured by ⁇ -eounter.
  • test compound has an IC 50 equal or lower than 1 ⁇ M, it is considered as having PDE5 -inhibitory properties for the purpose of this patent application. If the test compound has an IC 50 higher than 1 ⁇ M, it is considered as not having PDE5 -inhibitory properties for the purpose of this patent application.

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Abstract

The invention relates to a product containing the compound of formula (I) below (I) or a pharmaceutically acceptable salt of this compound, in combination with at least one compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.

Description

THERAPEUTIC COMPOSITIONS
The present invention relates to a product containing the compound of formula (I) below
Figure imgf000002_0001
(I)
or a pharmaceutically acceptable salt of this compound, in combination with at least one compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.
PCT publication WO 02/053557 describes endothelin receptor antagonists including the compound of formula (I) and the use of said endothelin receptor antagonists in the treatment of various diseases wherein vasoconstriction is involved (i.a. heart failure, angina pectoris, pulmonary and systemic hypertension and erectile dysfunction).
PDE-5 inhibitors have been notably described in the following patent documents:
♦♦♦ US 5,250,534 (describing pyrazolopyrimidinone derivatives as PDE-5 inhibitors and i.a. sildenafil as well as the use of the same for i.a. hypertension and heart failure) and EP 1 097 711 (describing i.a. sildenafil for pulmonary hypertension); ♦♦♦ WO 99/24433 (describing i.a. vardenafϊl as well as the use of the same for i.a. hypertension, angina pectoris and erectile dysfunction);
♦♦♦ US 5,859,006 (describing i.a. tadalafil as well as the use of the same for i.a. hypertension, pulmonary hypertension, angina and congestive heart failure);
♦♦♦ WO 00/27848 (describing i.a. udenafil and the use thereof for impotence). The Applicant has now surprisingly found that the combination of the compound of formula (I) with a compound having PDE5 -inhibitory properties results in an unexpected synergistic effect in the treatment of diseases wherein vasoconstriction is involved.
Therefore a subject of this invention is a product containing the compound of formula (I) as described before or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one (and preferably one) compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.
The following paragraphs provide definitions of the various terms used in the present patent application and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition.
"PDE-5" stands in the present application for cyclic guanosirse 3", 5 '-monophosphate (cGMP) phosphodiesterase type 5.
"Simultaneously" or "simultaneous", when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients by the same route and at the same time.
"Separately" or "separate", when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients at approximately the same time by at least two different routes.
By therapeutic administration "over a period of time" is meant in the present application the administration of two or more ingredients at different times, and in particular an administration method according to which the entire administration of one of the active ingredients is completed before the administration of the other or others begins. In this way it is possible to administer one of the active ingredients for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. By "disease wherein vasoconstriction is involved" is meant in particular hypertension, pulmonary hypertension (including pulmonary arterial hypertension), diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris.
By "compound having PDE5 -inhibitory properties" is meant a compound that, when submitted to the "Test for the determination of PDE5 IC50" described in the present patent application, has an IC50 equal or lower than 1 μM.
Specific examples of compounds having PDE5 -inhibitory properties include the compounds having the following structures (names):
Figure imgf000004_0001
(sildenafil)
Figure imgf000004_0002
(vardenafϊl)
Figure imgf000004_0003
Figure imgf000005_0001
(udenafil)
The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
Besides, any reference to a compound of formula (I) or to a compound having PDE5 -inhibitory properties is to be understood as referring also to the pharmaceutically acceptable salts thereof, as appropriate and expedient.
Preferably, the product according to this invention will be such that the compound of formula (I) and the compound having PDE5 -inhibitory properties are intended for a therapeutic use which takes place simultaneously or over a period of time.
According to one preferred variant of this invention, the compound of formula (I) and the compound having PDE5 -inhibitory properties will be intended to be administered simultaneously.
According to another preferred variant of this invention, the compound of formula (I) and the compound having PDE5 -inhibitory properties will be intended to be administered over a period of time.
The period of time intended for the therapeutic use of a product according to this invention will be at least one week, and preferably at least one or more months (for example six months). This period of time may also be the whole life of the patient that receives the product. Preferably, administration of compound of formula (I) will be alternated with administration of a compound having PDE5 -inhibitory properties, and the interval between such administration will not exceed two or three days (and more preferably not exceed one day). Preferably, the compound having PDE5 -inhibitory properties will be selected from sildenafil, vardenafil, tadalafil and udenafil. More preferably, the compound having PDE5 -inhibitory properties will be sildenafil or tadalafil.
According to one particularly preferred variant of the invention the compound having PDE5 -inhibitory properties will be sildenafil.
According to another particularly preferred variant of the invention the compound having PDE5 -inhibitory properties will be tadalafil.
The administration route of the compound of formula (I) and that of the compound having PDE5 -inhibitory properties is preferably the same. In particular, the common administration route for the compound of formula (I) and for the compound having PDE5 -inhibitory properties will be the intravenous or oral route (and notably the oral route).
Though the exact administration doses of a product according to this invention will have to be determined by the treating physician, it is expected that a dose of 0.05 to 2 mg (and preferably 0.1 to 1 mg) of compound of formula (I) per kg of patient body weight combined with a dose 0.01 to 1 mg (and preferably 0.05 to 0.5 mg) of tadalafil per kg of patient body weight, both compounds being intended to be administered by oral route, or combined with a dose 0.1 to 2 mg (and preferably 0.2 to 1 mg) of sildenafil per kg of patient body weight will be appropriate, both compounds being intended to be administered by oral route as well.
Preferably, the disease intended to be treated by a product according to this invention will be selected from hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure,erectile dysfunction and angina pectoris. More preferably, the disease intended to be treated by a product according to this invention will be selected from hypertension and pulmonary hypertension. In particular, the disease intended to be treated by a product according to this invention will be pulmonary hypertension (and notably pulmonary arterial hypertension).
The invention also relates to a pharmaceutical composition containing, as active principles, the compound of formula (I) below
Figure imgf000007_0001
(I)
or a pharmaceutically acceptable salt of this compound, in combination with at least one (and preferably one) compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, as well as at least one excipient.
The invention further relates to the use of the compound of formula (I) below
Figure imgf000007_0002
(I)
or a pharmaceutically acceptable salt of this compound, in combination with at least one (and preferably one) compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to treat a disease wherein vasodilation is required.
Besides, preferences indicated for the product according to this invention of course apply mutatis mutandis to the pharmaceutical compositions and uses of this invention.
Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way. EXAMPLES
To illustrate the usefulness of this invention, the association of the compound of formula (I), administered orally at a dose of 0.3 mg/kg, with tadalafil, administered orally at a dose of 10 mg/kg, has been studied in two different hypertension models, namely the Dahl salt-sensitive rat model and the spontaneously hypertensive rat model. Furthermore, the association of the compound of formula (I), administered orally at a dose of 0.3 mg/kg, with sildenafil, administered orally at a dose of 30 mg/kg, has been studied in the spontaneously hypertensive rat model. The protocols used are detailed in the part entitled "Pharmacological properties of the invention compounds" hereafter.
PHARMACOLOGICAL PROPERTIES OF THE INVENTION COMPOUNDS
The experimental methods described hereafter can be used to show the pharmacological properties of the invention compounds.
Dahl salt-sensitive rat model
Dahl salt-sensitive (Dahl-S) were purchased from Harlan (Netherlands). The rats were housed by group during the acclimatization period and single-housed after implantation of the telemetry device. All animals were maintained under identical conditions and had free access to normal pelleted rat chow and water. Dahl salt-sensitive rats develop hypertension only upon exposure to salt intake. They were administered a high-salt (8%) chow diet (Purina series 5500). Five weeks after starting salt administration, a telemetry system was implanted under anaesthesia by inhalation of 2.5% isoflurane (in 70% O2 + 30% N2O). Under aseptic conditions, a pressure radio-frequency transmitter was implanted into the peritoneal cavity, and a sensing catheter was inserted in the descending aorta and advanced pointing upstream to slightly below the renal artery bifurcation. The transmitter was sutured to the abdominal musculature and the skin was closed. A receiver platform transformed the radio signal into digitized input, that was sent to a dedicated personal computer (Compaq, deskpro). Arterial blood pressure measurements were calibrated by using an input from an ambient pressure reference. Telemetry units were obtained from Data Sciences (St. Paul, MN, USA). The compounds were administered at least 2 weeks after telemetry system implantation. The compound of formula (I) and the compound having PDE5 -inhibitory properties were prepared in 5% arabic gum and administered by oral gavage. The acute effects of the compound of formula (I), the compound having PDE5 -inhibitory properties and their combination on blood pressure were measured by collecting data at 5 -minute intervals up to 72 h after oral administration. Hourly means of blood pressure were calculated for each rat. Each rat served as its own control, by using the blood pressure data of the last 24 hours before drug administration. The two curves (blood pressure of the control period and blood pressure of the treatment period) were plotted together and the area between curves (ABC) from 0 to 72 hours was calculated. The higher the ABC, the stronger the effect of the item tested for lowering blood pressure.
Spontaneously hypertensive rat model
The same protocol was used as for the Dahl salt-sensitive rat model, except that spontaneously hypertensive rats (SHR) replace the Dahl-S rats and that the SHR rats did not receive any salt diet. The SHR rats were purchased from Harlan (Netherlands).
Test for the determination of PDE5 IC50:
In order to estimate the extent of inhibition for PDE5 activity of a test compound, the following test is carried out. Phosphodiesterase^ enzyme (PDE 5} is separated from human corpus cavernosa! tissues. About 3 g of tbis Hs&uo is homogenized wUh 12 ml of HEPBS buffer (20 raM HBPES, 250 raM sucrose, 1 mM EDTA, I raM PMSP, pH 7.2) at 4°C. The solution is filtered with double-layered gauze and centrifuged (100,000 xg) for 60 mm a\ 4°C. The supernatant is filtered with 0.2 μm filter paper and .separated by HPLC (Mono Q anion exchange column) with concentration gradient of 0-500 tnlvi NaCi \o elute PDE isozymes. The enzyme activity is measured on each column fraction by the following process to separate the PDEo fraction and the PD E5 inhibition of the lest compound is measured using the PDE5 fraction. To 1.5 ml tube arc added 100 μl of reaction mixture (15 mivl Tris-HCK 5 mM MgCl.', 0.5 mg/ml BSA, pH 7.4) and the appropriate amount of rcsf compound fraction and lest compound and the mixture is mixed well. To tbis solution is added 'H-cAMP or λH-cGMP (500 iiM. 2 μCi/ml), the mixture is reacted in the incubator of 30 °C for about 1 hour and the reaction is quenched by putting the tube into boiling water for about 45 seconds to 2 min. Then tbc tube is chilled in ice baih for abouf 5 min. To this tube is added snake venom ( i mg/rnl. 100 μ!) or 5 -nucleotidase (0. 1 unit/tube) and the mixture is reacted in an incubator at 37 °C for 10 min and chilled in an ice bath. 3 tiroes volume of methanol tø fhe resin is added to the anion exchange resirs (Rio-Rad resin, ΛG1 -Xl, 200-400 meshj which has been already washed with 0.5/v HCl5 I I2O5 0.5;V NaOH. H^O, 0.5,VHCl and H:O in order and adjusted to pH 5. Then 1 ml of the pretrcated res. in is dispersed into each tube with vortex ing. The mixture is left at 4 °C for 15 min with occasional vortexing and eentrifugcd (10,000 rpm) for about 5 min to sediment the resin. The supernatant (700 μl) is transferred to a liquid scintillation vial, and mixed with 10 mi of scintillation cocktail. After stabilizing the solution by leaving it overnight, the radioactivity of the tube is measured by β-eounter.
If the test compound has an IC50 equal or lower than 1 μM, it is considered as having PDE5 -inhibitory properties for the purpose of this patent application. If the test compound has an IC50 higher than 1 μM, it is considered as not having PDE5 -inhibitory properties for the purpose of this patent application.
EXAMPLE 1
Following the test protocol described previously in the part entitled "Dahl salt-sensitive rat model", oral administration of the compound of formula (I) and tadalafϊl decreased blood pressure in Dahl-S rats: the compound of formula (I) (0.3 mg/kg) decreased blood pressure with an ABC of 256 and tadalafϊl (10 mg/kg) with an ABC of 310. The ABC after oral administration of the combination (compound of formula (I) at 0.3 mg/kg and tadalafϊl at 10 mg/kg) was 923, demonstrating a synergistic effect.
EXAMPLE 2
Following the test protocol described previously in the part entitled "Spontaneously hypertensive rat model", oral administration of the compound of formula (I) and tadalafϊl decreased blood pressure in SHR rats: the compound of formula (I) (0.3 mg/kg) decreased blood pressure with an ABC of 44 and tadalafϊl (10 mg/kg) with an ABC of 286. The ABC after oral gavage of the combination (compound of formula (I) at 0.3 mg/kg and tadalafil at 10 mg/kg) was 444, confirming the synergistic effect.
EXAMPLE 3
Following the test protocol described previously in the part entitled "Spontaneously hypertensive rat model", oral administration of the compound of formula (I) and sildenafil decreased blood pressure in SHR rats: the compound of formula (I) (0.3 mg/kg) decreased blood pressure with an ABC of 38 and sildenafil (30 mg/kg) with an ABC of 229. The ABC after oral gavage of the combination (compound of formula (I) at 0.3 mg/kg and sildenafil at 30 mg/kg) was 317, confirming the synergistic effect.

Claims

Claims
1. A product containing the compound of formula (I) below
Figure imgf000012_0001
(I)
or a pharmaceutically acceptable salt of this compound, in combination with at least one compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.
2. A product according to claim 1, wherein the compound having PDE5 -inhibitory properties is selected from sildenafil, vardenafil, tadalafil and udenafil.
3. A product according to claim 2, wherein the compound having PDE5 -inhibitory properties is tadalafil.
4. A product according to claim 2, wherein the compound having PDE5 -inhibitory properties is sildenafil.
5. A product according to claim 1 , wherein the disease wherein vasoconstriction is involved is selected from hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction and angina pectoris.
6. A pharmaceutical composition containing, as active principles, the compound of formula (I) as described in claim 1 , or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, as well as at least one excipient.
7. A pharmaceutical composition according to claim 6, wherein the compound having PDE5 -inhibitory properties is selected from sildenafil, vardenafϊl, tadalafϊl and udenafϊl.
8. A pharmaceutical composition according to claim 7, wherein the compound having PDE5 -inhibitory properties is tadalafϊl.
9. A pharmaceutical composition according to claim 7, wherein the compound having PDE5 -inhibitory properties is sildenafil.
10. Use of the compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one compound having PDE5 -inhibitory properties, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to treat a disease wherein vasoconstriction is involved.
11. Use according to claim 10, wherein the compound having PDE5 -inhibitory properties is selected from sildenafil, vardenafϊl, tadalafϊl and udenafϊl.
12. Use according to claim 10, wherein the disease intended to be treated is selected from hypertension and pulmonary hypertension.
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PL2059246T3 (en) 2014-03-31
IL197235A (en) 2014-04-30
JP2010502588A (en) 2010-01-28
BRPI0715698B8 (en) 2021-05-25
HUS2400046I1 (en) 2025-01-28
RU2462249C2 (en) 2012-09-27
AR062501A1 (en) 2008-11-12
KR20090057009A (en) 2009-06-03
FIC20240045I1 (en) 2024-12-16
CA2659770A1 (en) 2008-03-06
US20200352944A1 (en) 2020-11-12
PT2059246E (en) 2013-12-16
US20130210830A9 (en) 2013-08-15
US20210177849A1 (en) 2021-06-17

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