WO2010018549A2 - Therapeutic compositions containing macitentan - Google Patents

Therapeutic compositions containing macitentan Download PDF

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Publication number
WO2010018549A2
WO2010018549A2 PCT/IB2009/053553 IB2009053553W WO2010018549A2 WO 2010018549 A2 WO2010018549 A2 WO 2010018549A2 IB 2009053553 W IB2009053553 W IB 2009053553W WO 2010018549 A2 WO2010018549 A2 WO 2010018549A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
acceptable salts
acceptable salt
diphenylpyrazin
Prior art date
Application number
PCT/IB2009/053553
Other languages
English (en)
French (fr)
Other versions
WO2010018549A3 (en
Inventor
Martine Clozel
Original Assignee
Actelion Pharmaceuticals Ltd
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.)
Filing date
Publication date
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Priority to US13/058,639 priority Critical patent/US8809334B2/en
Priority to SI200931770T priority patent/SI2315587T1/en
Priority to RU2011109084/15A priority patent/RU2519161C2/ru
Priority to BRPI0917661A priority patent/BRPI0917661B8/pt
Priority to KR1020117003547A priority patent/KR101678699B1/ko
Priority to PL17191033T priority patent/PL3300729T3/pl
Priority to PL09786912T priority patent/PL2315587T3/pl
Priority to HRP20171917TT priority patent/HRP20171917T1/hr
Priority to NZ591601A priority patent/NZ591601A/xx
Priority to JP2011522608A priority patent/JP5764061B2/ja
Priority to LTEP09786912.7T priority patent/LT2315587T/lt
Priority to NO09786912A priority patent/NO2315587T3/no
Priority to MX2011001625A priority patent/MX350011B/es
Priority to DK09786912.7T priority patent/DK2315587T3/en
Priority to AU2009280843A priority patent/AU2009280843B2/en
Priority to ES09786912.7T priority patent/ES2652590T3/es
Priority to CA2731370A priority patent/CA2731370C/en
Priority to CN2009801279936A priority patent/CN102099026B/zh
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to EP09786912.7A priority patent/EP2315587B1/en
Priority to SM20170592T priority patent/SMT201700592T1/it
Priority to EP17191033.4A priority patent/EP3300729B1/en
Publication of WO2010018549A2 publication Critical patent/WO2010018549A2/en
Publication of WO2010018549A3 publication Critical patent/WO2010018549A3/en
Priority to IL211143A priority patent/IL211143A0/en
Priority to MA33675A priority patent/MA32614B1/fr
Priority to ZA2011/01900A priority patent/ZA201101900B/en
Priority to US14/335,657 priority patent/US9173881B2/en
Priority to US14/873,787 priority patent/US9597331B2/en
Priority to CY20181100074T priority patent/CY1119826T1/el
Priority to CY20201100016T priority patent/CY1122641T1/el

Links

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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a product containing macitentan, i.e. the compound of formula (I) below
  • IP prostacyclin receptor
  • endothelin receptor antagonists including the compound of formula (I) and the use of said endothelin receptor antagonists in the treatment of various diseases wherein endothelin is involved (i.a. heart failure, angina pectoris, pulmonary and systemic hypertension and erectile dysfunction).
  • IP prostacyclin receptor
  • WO 2004/017993 describes the use of the endothelin receptor antagonist bosentan together with the prostacyclin receptor agonist epoprostenol sodium for treating pulmonary arterial hypertension.
  • IP prostacyclin receptor
  • a first subject of this invention relates thus to a product containing macitentan or a pharmaceutically acceptable salt thereof, and at least one (and preferably one) compound having prostacyclin receptor (IP) agonist properties, or a pharmaceutically acceptable salt thereof.
  • IP prostacyclin receptor
  • a further subject of this invention is a product containing macitentan or a pharmaceutically acceptable salt thereof, in combination with at least one (and preferably one) compound having prostacyclin receptor (IP) agonist 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 endothelin is involved.
  • IP prostacyclin receptor
  • Macitentan is the recommended INN for the compound of formula (I) and this name will therefore be used to designate the compound of formula (I) in the present patent application.
  • “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.
  • Another therapeutic administration over a period of time consists in the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain points in time simultaneous administrations of all the active ingredients of the combination take place whereas at some other points in time only part of the active ingredients of the combination may be administered (for example, in the case of a combination of macitentan with NS-304, the therapeutic administration over a period of time could be such that macitentan will be administered once a day whereas NS-304 will be administered twice a day).
  • disease wherein endothelin is involved is meant in particular hypertension, pulmonary hypertension (including pulmonary arterial hypertension), diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris or pulmonary fibrosis.
  • IP prostacyclin receptor
  • IP prostacyclin receptor
  • Specific examples of compounds having prostacyclin receptor (IP) agonist properties include treprostinil and its pharmaceutically acceptable salts, epoprostenol and its pharmaceutically acceptable salts, iloprost and its pharmaceutically acceptable salts, beraprost and its pharmaceutically acceptable salts, 2- ⁇ 4-[(5,6-diphenylpyrazin- 2-yl)(isopropyl)amino]butoxy ⁇ - ⁇ /-(methylsulfonyl)acetamide (NS-304) and its pharmaceutically acceptable salts, and ⁇ 4-[(5,6-diphenylpyrazin- 2-yl)(isopropyl)amino]butoxy ⁇ acetic acid (MRE-269) and its pharmaceutically acceptable salts.
  • 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 macitentan or to a compound having prostacyclin receptor (IP) agonist 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 macitentan and the compound having prostacyclin receptor (IP) agonist properties are intended for a therapeutic use which takes place simultaneously or over a period of time.
  • IP prostacyclin receptor
  • macitentan and the compound having prostacyclin receptor (IP) agonist properties will be intended to be administered simultaneously.
  • macitentan and the compound having prostacyclin receptor (IP) agonist 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 macitentan will be alternated with administration of a compound having prostacyclin receptor (IP) agonist properties, and the interval between such administration will not exceed two or three days (and more preferably not exceed one day).
  • IP prostacyclin receptor
  • the therapeutic administration over a period of time could be such that macitentan will be administered once a day whereas NS-304 will be administered twice a day.
  • the compound having prostacyclin receptor (IP) agonist properties will be selected from 2- ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy ⁇ -
  • JV-(methylsulfonyl)acetamide (NS-304) and its pharmaceutically acceptable salts and ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy ⁇ acetic acid (MRE-269) and its pharmaceutically acceptable salts.
  • the compound having prostacyclin receptor (IP) agonist properties will be 2- ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy ⁇ - ⁇ /-(methylsulfonyl)acetamide (NS-304) or a pharmaceutically acceptable salt thereof.
  • the administration route of macitentan and that of the compound having prostacyclin receptor (IP) agonist properties is preferably the same.
  • the common administration route for macitentan and for the compound having prostacyclin receptor (IP) agonist properties will be the oral route.
  • a dose of 0.05 to 2 mg (and preferably 0.1 to 1 mg) of macitentan per kg of patient body weight and per day will be appropriate.
  • a dose of 0.5 to 30 ⁇ g (and preferably 1.5 to 15 ⁇ g) of compound having prostacyclin receptor (IP) agonist properties per kg of patient body weight given twice a day will be appropriate.
  • 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, angina pectoris and pulmonary fibrosis. 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, macitentan or a pharmaceutically acceptable salt of this compound, in combination with at least one (and preferably one) compound having prostacyclin receptor (IP) agonist properties, or a pharmaceutically acceptable salt thereof, as well as at least one excipient.
  • the invention further relates to the use of macitentan or a pharmaceutically acceptable salt of this compound, in combination with at least one (and preferably one) compound having prostacyclin receptor (IP) agonist properties, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to treat a disease wherein endothelin is involved.
  • Male Wistar rats are purchased from Harlan (Netherlands) and maintained under conditions in accordance with local guidelines (Basel-Landschaft cantonal veterinary office). All rats are housed in climate-controlled conditions with a 12:12 hour lightdark cycle, and had free access to chow and water.
  • a telemetry system is implanted under anaesthesia by inhalation of 2.5% isoflurane (in 70% O 2 + 30% N 2 O).
  • a pressure radio-frequency transmitter is implanted into the peritoneal cavity, and a sensing catheter is inserted in the pulmonary artery. The transmitter is sutured to the abdominal musculature and the skin is closed.
  • a receiver platform transforms the radio signal into digitized input, that is sent to a dedicated personal computer (Compaq, Deskpro). Pulmonary arterial blood pressure measurements are calibrated by using an input from an ambient pressure reference. Telemetry units are obtained from Data Sciences (St. Paul, MN, USA). Monocrotaline (MCT; Sigma Chemicals, St Louis, MO, USA) is administered as a single subcutaneous (sc) injection (60 mg/kg) in a volume of 3 ml/kg, and control age-matched rats receive an equal volume of saline.
  • sc subcutaneous
  • Variant 1 chronic effect assessment:
  • the animals are randomly assigned to experimental groups, and treatment is initiated within 24 h after MCT injection, for a duration of 4 weeks.
  • Macitentan and the compound having prostacyclin receptor (IP) agonist properties are administered by the oral route.
  • the effects of macitentan, the compound having prostacyclin receptor (IP) agonist properties and their combination on pulmonary arterial blood pressure are measured by collecting data at 5 -minute intervals. Hourly means of pulmonary arterial pressure are calculated for each rat.
  • rats are sacrificed. The heart is removed and weighed, and the ratio of organ weight to body weight (BW) is calculated.
  • RV right ventricle
  • RV/BW the ratio of right ventricular hypertrophy. The lower the ratio RV/BW, the stronger the effect of the item(s) tested for reducing right ventricular hypertrophy.
  • Variant 2 acute effect assessment: Four weeks after injection of MCT, the rats become pulmonary hypertensive and the respective effects of a single oral administration of Macitentan, of the compound having prostacyclin receptor (IP) agonist properties and of their combination can be evaluated on mean pulmonary arterial pressure. Sp . ontaneously . hypertensive rat . model
  • SHR spontaneously hypertensive rats
  • IP prostacyclin receptor
  • CHO cells stably expressing the human IP receptor are cultured in Ham's F-12 medium containing 10% fetal bovine serum in a humidified atmosphere of 95% air and 5% CO 2 at 37 0 C.
  • Cells are seeded at 1 x 10 5 cells/well in 24-well plates and cultured for 48 h. Following a wash and incubation with assay buffer for 1 h at 37 0 C, the cells are exposed to various concentrations of test compound in the presence of IBMX (500 ⁇ M). After removal of supernatant, the reaction is stopped by addition of 0.2 M perchloric acid.
  • Adherent cells are frozen for 2 h at -8O 0 C and thawed to extract intracellular cAMP.
  • EXAMPLE 1 acute effect of macitentan, NS-304 and their combination on mean pulmonary arterial pressure in monocrotaline treated rats:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
PCT/IB2009/053553 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan WO2010018549A2 (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
EP17191033.4A EP3300729B1 (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan
AU2009280843A AU2009280843B2 (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan
RU2011109084/15A RU2519161C2 (ru) 2008-08-13 2009-08-12 Терапевтические композиции, содержащие мацитентан
BRPI0917661A BRPI0917661B8 (pt) 2008-08-13 2009-08-12 produto, composição farmacêutica e uso da combinação de macitentan com um composto que é dotado de propriedades agonistas do receptor de prostaciclina
KR1020117003547A KR101678699B1 (ko) 2008-08-13 2009-08-12 마시텐탄을 포함하는 치료 조성물
PL17191033T PL3300729T3 (pl) 2008-08-13 2009-08-12 Kompozycje terapeutyczne zawierające macitentan
PL09786912T PL2315587T3 (pl) 2008-08-13 2009-08-12 Kompozycje terapeutyczne zawierające macitentan
HRP20171917TT HRP20171917T1 (hr) 2008-08-13 2009-08-12 Terapeutski pripravci koji sadrže macitentan
NZ591601A NZ591601A (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan and a prostacyclin receptor agonist
JP2011522608A JP5764061B2 (ja) 2008-08-13 2009-08-12 マシテンタン含有治療用組成物
LTEP09786912.7T LT2315587T (lt) 2008-08-13 2009-08-12 Terapinės kompozicijos, turinčios macitentano
NO09786912A NO2315587T3 (enEXAMPLES) 2008-08-13 2009-08-12
MX2011001625A MX350011B (es) 2008-08-13 2009-08-12 Composiciones terapeuticas que contienen macitentan.
DK09786912.7T DK2315587T3 (en) 2008-08-13 2009-08-12 THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN
ES09786912.7T ES2652590T3 (es) 2008-08-13 2009-08-12 Composiciones terapéuticas que contienen macitentan
US13/058,639 US8809334B2 (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan
SI200931770T SI2315587T1 (en) 2008-08-13 2009-08-12 A therapeutic composition comprising macitentan
CN2009801279936A CN102099026B (zh) 2008-08-13 2009-08-12 含美西特田的治疗组合物
CA2731370A CA2731370C (en) 2008-08-13 2009-08-12 Combination of macitentan and a prostacyclin receptor agonist for the treatment of pulmonary hypertension
EP09786912.7A EP2315587B1 (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan
SM20170592T SMT201700592T1 (it) 2008-08-13 2009-08-12 Composizioni terapeutiche contenenti macitentan
IL211143A IL211143A0 (en) 2008-08-13 2011-02-10 Therapeutic compositions containing macitentan
MA33675A MA32614B1 (fr) 2008-08-13 2011-03-07 Compositions therapeutiques contenant du macitentan
ZA2011/01900A ZA201101900B (en) 2008-08-13 2011-03-11 Therapeutic compositions containing macitentan
US14/335,657 US9173881B2 (en) 2008-08-13 2014-07-18 Therapeutic compositions containing macitentan
US14/873,787 US9597331B2 (en) 2008-08-13 2015-10-02 Therapeutic compositions containing macitentan
CY20181100074T CY1119826T1 (el) 2008-08-13 2018-01-19 Θεραπευτικες συνθεσεις που περιεχουν μακιτεντανη
CY20201100016T CY1122641T1 (el) 2008-08-13 2020-01-08 Θεραπευτικες συνθεσεις που περιεχουν macitentan

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2008/053252 2008-08-13
IB2008053252 2008-08-13

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/058,639 A-371-Of-International US8809334B2 (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan
US14/335,657 Continuation US9173881B2 (en) 2008-08-13 2014-07-18 Therapeutic compositions containing macitentan

Publications (2)

Publication Number Publication Date
WO2010018549A2 true WO2010018549A2 (en) 2010-02-18
WO2010018549A3 WO2010018549A3 (en) 2010-07-29

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ID=41346591

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Application Number Title Priority Date Filing Date
PCT/IB2009/053553 WO2010018549A2 (en) 2008-08-13 2009-08-12 Therapeutic compositions containing macitentan

Country Status (30)

Country Link
US (3) US8809334B2 (enEXAMPLES)
EP (2) EP3300729B1 (enEXAMPLES)
JP (3) JP5764061B2 (enEXAMPLES)
KR (1) KR101678699B1 (enEXAMPLES)
CN (1) CN102099026B (enEXAMPLES)
AR (1) AR073031A1 (enEXAMPLES)
AU (1) AU2009280843B2 (enEXAMPLES)
BR (1) BRPI0917661B8 (enEXAMPLES)
CA (1) CA2731370C (enEXAMPLES)
CY (2) CY1119826T1 (enEXAMPLES)
DK (2) DK2315587T3 (enEXAMPLES)
ES (2) ES2652590T3 (enEXAMPLES)
HK (1) HK1253355B (enEXAMPLES)
HR (2) HRP20171917T1 (enEXAMPLES)
HU (2) HUE036071T2 (enEXAMPLES)
IL (1) IL211143A0 (enEXAMPLES)
LT (2) LT3300729T (enEXAMPLES)
MA (1) MA32614B1 (enEXAMPLES)
MX (1) MX350011B (enEXAMPLES)
MY (1) MY178894A (enEXAMPLES)
NO (1) NO2315587T3 (enEXAMPLES)
NZ (1) NZ591601A (enEXAMPLES)
PL (2) PL3300729T3 (enEXAMPLES)
PT (2) PT3300729T (enEXAMPLES)
RU (1) RU2519161C2 (enEXAMPLES)
SI (2) SI2315587T1 (enEXAMPLES)
SM (2) SMT201700592T1 (enEXAMPLES)
TW (1) TWI446911B (enEXAMPLES)
WO (1) WO2010018549A2 (enEXAMPLES)
ZA (1) ZA201101900B (enEXAMPLES)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2246336A4 (en) * 2008-02-28 2011-12-21 Nippon Shinyaku Co Ltd FIBROSIS INHIBITORS
US9371264B2 (en) 2013-01-11 2016-06-21 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US9394227B1 (en) 2015-06-17 2016-07-19 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US9505737B2 (en) 2013-01-11 2016-11-29 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US9643911B2 (en) 2015-06-17 2017-05-09 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
WO2020128017A1 (en) * 2018-12-21 2020-06-25 Actelion Pharmaceuticals Ltd Pharmaceutical composition for the treatment of pulmonary arterial hypertension
US11612600B2 (en) 2019-01-25 2023-03-28 Actelion Pharmaceuticals Ltd Pharmaceutical composition comprising macitentan for the treatment of chronic thromboembolic pulmonary hypertension
EP4065119B1 (en) 2019-11-29 2024-09-04 Actelion Pharmaceuticals Ltd Initial triple combination therapy with macitentan, tadalafil, and selexipag for treating pulmonary arterial hypertension

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20120957T1 (hr) 2005-09-12 2012-12-31 Actelion Pharmaceuticals Ltd. Stabilni farmaceutski sastav koji sadrži pirimidin-sulfamid
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DK2315587T3 (en) 2008-08-13 2018-01-02 Actelion Pharmaceuticals Ltd THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN
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