CN101355941A - Diaryl ureas for treating pulmonary hypertension - Google Patents
Diaryl ureas for treating pulmonary hypertension Download PDFInfo
- Publication number
- CN101355941A CN101355941A CNA2006800506642A CN200680050664A CN101355941A CN 101355941 A CN101355941 A CN 101355941A CN A2006800506642 A CNA2006800506642 A CN A2006800506642A CN 200680050664 A CN200680050664 A CN 200680050664A CN 101355941 A CN101355941 A CN 101355941A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- pulmonary hypertension
- drug regimen
- formula
- therapeutic agent
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to pharmaceutical compositions for treating, preventing or managing pulmonary hypertension comprising 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide optionally combined with at least one additionnal therapeutic agent.
Description
The present invention relates to treat, prevent or control the Pharmaceutical composition and the drug regimen of pulmonary hypertension, it comprises 4{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-urea groups that optional and at least a other therapeutic agent merges]-the 3-fluorinated phenoxy }-the pyridine-2-carboxylic acids Methanamide.
Di-aryl urea compounds, for example, for example be described in, the 4{4-[3-of US 20050038080 (4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-the pyridine-2-carboxylic acids Methanamide is to have various activity, comprises the inhibition of VEGFR, PDGFR, raf, p38 and/or flt-3 kinase signal molecule active effectively anticarcinogen and anti-angiogenic formation medicine.Previous these di-aryl urea compounds have shown has various active features, comprises and suppresses Raf/MEK/ERK passage, raf kinases, p38 kinases, VEGFR kinases, PDGFR kinases.These activity and their purposes in treatment various diseases and disease are disclosed in, for example among the WO 2005/009961.
Pulmonary hypertension refers to have the disease (LJ.Rubin, New England Journal of Medicine (The New England Journal of Medicine), 1997,336 (2), 111) of the feature that continues the pulmonary artery pressure that raises.Current treatment of pulmonary hypertension depends on the stage and the mechanism of disease.The typical treatment of pulmonary hypertension comprises anticoagulation, oxygen supply, conventional vasodilator therapy, transplanting and operative treatment.The therapeutic agent that is used for the treatment of pulmonary hypertension at present comprises, for example, and calcium channel blocker and lung vasodilation.
The invention provides the Pharmaceutical composition of treatment, prevention or control pulmonary hypertension, it comprises at least a formula I chemical compound and optional at least a other therapeutic agent.
For example, can adopt the present invention by di-aryl urea compounds, its pharmaceutically acceptable salt and derivant thereof etc. and other optional therapeutic agent of giving construction I.
Chemical compound with formula (I) structure, its pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite and prodrug, comprise diastereomeric form (separated stereoisomer and stereoisomer mixture), this paper is referred to as " formula I chemical compound ".
(I) is as follows for formula:
Wherein be used for the plural form of the word chemical compound, salt etc. of this paper, also be used to refer to unification compound, salt etc.
Invention also relates to the useful form of chemical compound disclosed herein, for example, and pharmaceutically acceptable salt, metabolite and prodrug.Term " pharmaceutically acceptable salt " refers to nontoxic relatively, the inorganic or organic acid addition salt of The compounds of this invention.For example, referring to S.M.Berge etc., " pharmaceutical salts, " J.Pharm.Sci.1977,66,1-19.Pharmaceutically acceptable salt comprises, main compound by having made the alkali effect and inorganic or organic acid reaction with form salt resulting those, for example, hydrochlorate, sulfate, phosphate, mesylate, camsilate, oxalates, maleate, succinate and citrate.Pharmaceutically acceptable salt also comprises those, and wherein main compound plays acid effect, and with suitable alkali reaction, form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salt.Those skilled in the art are approval further, and any method that can be in a large amount of known methods makes chemical compound and suitable inorganic or organic acid reaction, prepares the acid-addition salts of claimed compounds.As selection,, make The compounds of this invention and suitable alkali reaction, preparation alkali and alkali salt through multiple known method.
The typical salt of The compounds of this invention comprises, for example, by method well known in the art, the conventional nontoxic salts and the quaternary ammonium salt that form by inorganic or organic acid or alkali.For example, this class acid-addition salts comprises acetate, adipate, alginate, Ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cinnamate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, fumarate, glucoheptose salt, glycerophosphate, Hemisulphate, enanthate, caproate, the hydrogen chlorate, hydrobromate, hydriodate, the 2-isethionate, itaconate, lactate, maleate, mandelate, mesylate, the 2-naphthalene sulfonate, nicotinate, nitrate, oxalates, embonate, pectinic acid salt, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfonate, tartrate, rhodanate, toluene fulfonate, fluoroform sulphonate and caprate.
Alkali salt comprises alkali metal salt, for example potassium and sodium salt, and alkali salt, for example calcium and magnesium salt are with the ammonium salt that is become with organic base (for example dicyclohexylamine and N-methyl D-glycosamine).In addition, available elementary alkyl halide, for example this class reagent of the chloride of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate such as dimethyl, diethyl and dibutyl sulfide hydrochlorate; With diamyl sulfate, long-chain halogenide, the for example chloride of decyl, lauryl, myristyl and stearyl, bromide and iodide, aryl or aralkyl halogenide such as benzyl and phenethyl bromination thing and other single substituted aralkyl halogenide or polysubstituted aralkyl halide seasonization contain the group of basic nitrogen.
Solvate at the object of the invention is those forms of chemical compound, and wherein solvent molecule forms and is solid-state complex and for example includes, but not limited to ethanol and methanol.Hydrate is the particular form of solvate, and solvent molecule wherein is a water.
Some pharmacological activity reagent is further modified by available unsettled functional group, and giving in the body is provided after parent activating agent and the no pharmacological activity deriveding group functional group's cracking.These derivants that are commonly referred to prodrug can be used to, and for example, change the physicochemical properties of activating agent, make activating agent targeting particular organization, change the pharmacokinetics and the pharmacodynamic properties of activating agent, and reduce undesirable side effect.Prodrug of the present invention comprises, for example, the ester of suitable The compounds of this invention, they are well tolerable, pharmaceutically acceptable esters, for example Arrcostab comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or amyl group ester.Also can adopt other ester, for example phenyl-C
1-C
5Although alkyl is the preferable methyl ester.
The method that can be used to synthetic other prodrug is described in the following summary to this theme, and is by the quoting of description of these synthetic methods to them, incorporated herein:
Higuchi, T.; Stella, V. edits. as the prodrug of new drug delivery system.ACS symposium book series. american chemical association: Washington D.C. (1975).
Roche, E.B. is via the design of the biopharmaceutics character of prodrug and analog. American Pharmaceutical Association: Washington D.C. (1977).
·Sinkula，A.A.；Yalkowsky，S.H.J?Pharm?Sci.1975，64，181-210。
·Stella，V.J.；Charman，W.N.Naringrekar，V.H.Drugs?1985，29，455-473。
Bundgaard, H., editor. the design .Elsevier:New York (1985) of prodrug.
·Stella，V.J.；Himmelstein，K.J.J.Med.Chem.1980，23，1275-1282。
·Han，H-K；Amidon，G.L.AAPS?Pharmsci?2000，2，1-11。
·Denny，W.A.Eur.J.Med.Chem.2001，36，577-595。
Wermuth, C.G.in Wermuth, C.G. edits. and medical chemistry is put into practice .AcademicPress:San Diego (1996), 697-715.
Balant, L.P.; Doelker, E.in Wolff, M.E. edit .Burgers medicinal chemistry and drug development.JohnWiley&Sons：New?York(1997)，949-982。
The metabolite of The compounds of this invention comprises the derivant of the oxidation of formula I chemical compound, and one or more nitrogen is replaced by hydroxyl; It comprises derivant, and the nitrogen-atoms of pyridine group wherein is the oxide form that is called 1-oxo-pyridine in this area, perhaps has hydroxyl substituent, is called 1-hydroxyl-pyridine in this area.
General preparation method
The compounds of this invention can pass through to adopt known chemical reactions and for example program preparation described in the following International Application No. WO 2005/009961 of publishing.
Other therapeutic agent
According to formula I chemical compound of the present invention can with other therapeutic agent that is used for treating, preventing or control pulmonary hypertension at present, for example, comprise, but be not limited to, other curative of anticoagulant, diuretic, cardiac glycoside, calcium channel blocker, vasodilation, prostacyclin analogs, endothelium antagonist (endothelium antagonists), phosphodiesterase inhibitor, endopeptidase inhibitor, hypolipidemic, thromboxane inhibitor and known reduction pulmonary artery pressure merges.
The example of anticoagulant for example includes, but not limited to, and is used for the treatment of the warfarin of the risk of the increase pulmonary hypertension patient, that have thrombosis and thromboembolism.
The example of calcium channel blocker includes, but not limited to be used in particular for the vascular reaction patient's that right heart catheter inserts diltiazem
, felodipine, amlodipine and nifedipine.
The example of vasodilation for example includes, but not limited to, prostacyclin, epoprostenol, bent prostaglandin, nitric oxide (NO).
The example of phosphodiesterase inhibitor for example includes, but not limited to, Phosphodiesterase V inhibitors especially, for example, tadalafil (tadalafil), sldenafil and Vardenafil.
The example of endothelin antagonist for example includes, but not limited to, bosentan and sitaxentan, preferred bosentan.
The example of prostacyclin analogs for example includes, but not limited to, iloprost, bent prostaglandin (treprostinil) and epoprostenol.
The example of hypolipidemic comprises, but be not limited to, for example, HMG CoA reductase inhibitor, for example simvastatin, pravastatin, atorvastatin, lovastatin, itavastatin, fluvastatin, Pitavastatin, rosuvastatin, ZD-4522 and cerivastatin.
The diuretic example for example includes, but not limited to, in particular for chlortalidone, indapamide, bendroflumethiazide, metolazone, cyclopenthiazide, polythiazide, mefruside, ximapid, chlorothiazide and the hydrochlorothiazide of control periphery edema.
The example of other curative of known reduction pulmonary artery pressure comprises, but be not limited to, for example, ACE inhibitor, enalapril for example, ramipril, captopril, cilazapril, trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril, or AT II inhibitor, for example, losartan, Candesartan, irbesartan, Embusartan, valsartan and telmisartan, or be used in particular for those patients' the iloprost of the hypoxemia of static or motion mediation, Beraprost (betaprost), the L-arginine, omapatrilat, oxygen, or be used in particular for the digoxin that the right ventricle failure patient improves the right ventricle function.
In addition, The compounds of this invention and drug regimen also can make up with inhibitors of kinases and/or elastase inhibitor.
The example of inhibitors of kinases comprises, but be not limited to, for example, BMS-354825, how card is for Buddhist nun (canertinib), erlotinib (erlotinib), gefitinib (gefitinib), imatinib, Lapatinib (lapatinib), come him to replace Buddhist nun (lestaurtinib), Luo Nafani (lonafarnib), piperazine Jia Tani (pegaptanib), Pei Li is for Buddhist nun (pelitinib), Si Mashani (semaxanib), smooth degree is for Buddhist nun (tandutinib), for pyrrole method Buddhist nun (tipifarnib), Wa Talani (vatalanib), lonidamine, fasudil, leflunomide, bortezomib (bortezomib), imatinib, erlotinib and imatinib mesylate.Preferably give imatinib mesylate.
Indication
Can be used for treating, preventing and control the preparation of the medicine of pulmonary hypertension according to chemical compound of the present invention and drug regimen.The present invention also provides the method for treatment, prevention and control pulmonary hypertension, and it comprises at least a formula I chemical compound that gives effective dose and optional at least a according to other therapeutic agent of the present invention." effective dose " is to be used for realizing required result, for example treats, the useful amount of the chemical compound of prevention and control disease or disease.
Comprise according to term of the present invention " pulmonary hypertension ", but be not limited to, associated or relate to left ventricular dysfunction, mitral disease, narrow pericarditis, aortic stenosis, cardiomyopathy, fibrosis of mediastinum, unusual pulmonary venous drainage, pulmonary veno-occlusive disease, collagen vascular disease, congenital heart disease, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep disordered breathing, the excessive property of alveolar ventilation disease, high height above sea level chronic exposure, introduction stage pneumonopathy, alveolar-capillary tube dysplasia, drepanocytosis, other blood coagulation disorders, chronic thromboembolism, connective tissue disease, lupus, schistosomicide, the primary pulmonary hypertension of sarcoidosis or pulmonary capillary angiomatosis, the Secondary cases pulmonary hypertension, the familial pulmonary hypertension, the pulmonary hypertension that distributes, the metarteriole pulmonary hypertension, Pulmonic, pulmonary hypertension, the spontaneous lung Arterial Hypertention, thrombotic pulmonary artery disease, Cong Yuan (plexogenic) pulmonary artery disease and pulmonary hypertension.
Can treat any type of pulmonary hypertension according to the present invention, include, but not limited to slightly, for example, comprise than resting state mean blood pressure about 20-30mm Hg that raises; Moderate, for example, comprise Hg than resting state rising 30-39mm; With serious, for example, comprise than resting state rising 40mm Hg or more.
Pulmonary hypertension comprises pulmonary hypertension (PAH), and comprises primary pulmonary hypertension (PPH), spontaneous PAH (IPAH), familial PAH (FPAH).Announce several categorizing systems of pulmonary hypertension, comprised Evian nomenclature and classification method (1998) and the revised PH nomenclature and the classification method (2003) of pulmonary hypertension (PH).Referring to, Lewis etc., Chest, 2004,
126, 73-10, it is incorporated herein by quoting in full.Can be according to the present invention, any disease PH in these classification charts is listed in treatment, control or prevention.PH risk factor and diagnostic criteria are described in McGoon etc., Chest,
126.14-34,2004, incorporated herein by quoting in full.
Following tabulation is 2003 classification: the PAH that propose in the third world's meeting about pulmonary hypertension, IPAH, FPAH, collagen vascular disease, it natural disposition systematicness lung short circuit is (big, little, can repair maybe and can not repair), portal hypertension, medicine and toxin, involve other relevant (glycogen storage disease with remarkable vein or capillary tube, dagger-axe thanks to (gaucher) disease, hereditary hemorrhagic telangiectasia, hemoglobinopathy, myeloproliferative disease, spleen is extractd), pulmonary venous hypertension, the pulmonary capillary angiomatosis, pulmonary venous hypertension, left front ventricle heart disease, left side lobe heart disease, the pulmonary hypertension relevant with hypoxemia, COPD, interstitial lung disease, sleep disordered breathing, the alveolar hypoventilation disease, high height above sea level chronic exposure, the PH of the sick mediation of chronic thrombosis and/or embolus, the Pulmonic thromboembolia type of near-end blocks, the Pulmonic thromboembolia type of tip blocks, pulmonary infarction (tumor, parasite, foreign body), sarcoidosis, histiocytosis X, Lymphangiomatosis, lung perstriction (adenopathy, tumor, fibrosis of mediastinum).
Any above-mentioned obstacle can be relevant with the risk of the increase of pulmonary hypertension, comprises that the patient suffers from, for example, and congenital heart disease (for example, eisenmenger's syndrome); Left side heart disease; Pulmonary vein disease (for example, fibrosis is organized stenosis or occlusion pulmonary vein and venule); The pulmonary artery disease; Cause the anoxybiotic disease of alveolar; Fibrosis pneumonopathy; William's spira's syndrome; The patient who suffers from the infringement of intravenous pharmacy abuse; Lung vasculitis (for example Wei Genei Cotard, Goodpasture's syndrome and Churg-Strauss syndrome); Emphysema; Chronic bronchitis; Scoliokyphosis; Cystic fibrosis; Fat high ventilation and sleep apnea obstacle; Pulmonary fibrosis; Sarcoidosis; Pneumosilicosis (silocosis); CREST (calcinosis cutis, Raynaud phenomenon; Esophagus mobility obstacle; Sclerodactylia and telangiectasia) and other conjunctive tissue disease.For example, the patient who suffers from BMPR2 sudden change (bone morphogenetic protein receptor II) has the lifelong risk of 10-20% that obtains FPAH.The patient who suffers from hereditary hemorrhagic telangiectasia also is considered to have the risk of IPAH, especially has those of ALK1 sudden change.Referring to, McGoon etc., Chest, 2004,
126, 14-34.
According to the present invention, term " treatment " refers to give Pharmaceutical composition after the pulmonary hypertension shape occurs, and " prevention " refer to before the pulmonary hypertension shape occurs to, the patient of pulmonary hypertension risk is especially arranged.Term " control " comprises that prevention suffers from the patient's of pulmonary hypertension the recurrence of pulmonary hypertension.
Administration
Can be in any form by any effective way, comprise, for example, per os, parenteral, (for example through intestinal, intravenous, intraperitoneal, part, transdermal, adopt any standard patch), eye, nose, part, per os for example in aerosol, suction, subcutaneous, intramuscular, oral cavity, Sublingual, rectum, vagina, intra-arterial and the sheath etc., does not give the combination of chemical compound of the present invention or medicine.They can be separately or unite with active or inactive any composition and to give.
The preferred oral administration.
Available known method makes The compounds of this invention or drug regimen change common dosage forms into, it can be the liquid or solid preparation, for example, be not limited to common and enteric coated tablets, capsule, pill, powder, granule, elixir, tincture, solution, suspensoid, syrup, solid and liquid aerosol and Emulsion.
The case description of oral solid formulation is in U.S. Provisional Patent Application number 60/605,752.
Can give drug regimen of the present invention with any effective form at any time.For example, can be used as single compositions or unit dosage forms (pill or the liquid agent that for example, contain two kinds of compositionss), for example, give chemical compound simultaneously, perhaps they are as the compositions of separating, but (for example, wherein a kind of medicine intravenous gives and another kind of per os or intramuscular administration) do not give not simultaneously.Also can one after the other give medicine in the different time.Can conventionally prepare medicament, to realize surpassing the time period of prolongation, for example, the release of 12 hours, 24 hours required speed.This can have the medicament and/or their derivant of suitable metabolic half life and/or pass through to adopt controlled release preparation to realize by employing.
Drug regimen can have synergism, and for example, the synergy of its Chinese medicine makes to merge the algebraical sum of back effect greater than their each self-applyings.Therefore, can give the medicine of reduction, for example, reduce toxicity or other infringement or unnecessary effect, and/or adopt same amount used when giving medicament separately, but obtain bigger effect.
Chemical compound of the present invention or drug regimen can further merge with any other suitable additive or pharmaceutically acceptable carrier.This class additive comprises any material and conventional any those materials that adopt of having introduced, and for example, is described in
Remington: pharmaceutics Science and practice(Gennaro and Gennaro, editor, 20 editions, Lippincott Williams ﹠amp; Wilkins, 2000);
The industrial pharmacy theory and practice(Lachman etc., editor, 3 editions, Lippincott Williams ﹠amp; Wilkins, 1986);
The pharmaceutical technology encyclopediaThose materials in (Swarbrick and Boylan, editor, 2 editions, Marcel Dekker, 2002).This paper claims that also these are " pharmaceutically acceptable carrier ", gives the patient safely to show that they and active medicine make up and can be therapeutic purposes.
In addition, can provide chemical compound of the present invention or drug regimen with other activating agent or other treatment that are used for treating any above-mentioned disease and/or disease.
Other treatment according to the present invention for example includes, but not limited to, physics or mechanotherapy, for example electricity irritation, pyonex, magnetic therapy or the local polyurethane film that adopts.
The present invention also provides at least a formula I chemical compound and at least a above-mentioned combination that is used for the treatment of other therapeutic agent of disease or obstacle.Being used for the object of the invention " combination " comprising:
-contain the single compositions or the dosage form of at least a formula I chemical compound and at least a above-mentioned other therapeutic agent;
-while or the assembly packaging that contains at least a formula I chemical compound and at least a above-mentioned other therapeutic agent that gives in succession;
-contain the kit of at least a formula I chemical compound and at least a above-mentioned other therapeutic agent, they are packaged into unit dosage forms separately mutually respectively or are the individual dosage form, with or without they being arranged by simultaneously or the description that gives in succession; With
The separate dosage forms of separating of-at least a formula I chemical compound and above-mentioned at least a other therapeutic agent, they realize therapeutic effect jointly, for example, and when simultaneously or when giving in succession, the treatment same disease.
Can select the dosage of each medicine in the combination, so that needed therapeutic activity to be provided with reference to other and/or disease type and/or morbid state.For example, can by fixed combination present and make up in activating agent." fixed combination " this paper plans to refer to pharmaceutical dosage form that wherein each component exists with the fixed ratio that required effect is provided.For particular patient, determine this tittle routinely, wherein utilize various parameters (for example, the type of disease, patient age, the patient's condition, patient's body constitution, body weight etc.) to select suitable dosage, maybe this amount can be the amount of relative standard.
According to the consideration to nature and extent, drug metabolism and the excretory speed of used specific compound and dosage unit, administering mode and number of times, treatment phase, the patient's age of being treated, sex and general status, the disease of being treated, possible drug regimen and interaction of medicine and medicine etc., the amount of the active component that is given can change in wide region.
The amount of formula I chemical compound is preferably with 20-2000mg, preferred 40-800mg, and more preferably 50-600mg gives.
4{4-[3-in Pharmaceutical composition (4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-the certain preferred amount of pyridine-2-carboxylic acids Methanamide is 20-3000mg, preferred 50-1500, more preferably 60-1000mg.
In another embodiment of the present invention, at least a other therapeutic agent of the amount that formula I chemical compound and those of ordinary skill in the art can determine according to its professional judgement be united and given.
Give every day preferably to be no more than three times, more preferably no more than twice according to Pharmaceutical composition one or many of the present invention.Preferred per os administration.During each administration, the quantity that tablet or capsule give simultaneously should be above two.
Yet according to body weight, the number of times and at interval of individual behavior, preparation type and administration to active component, in some cases, it is favourable departing from specified amount.For example, under some situation, it may be enough being lower than aforementioned minimum, and in other cases, has to surpass the specified upper limit.Under the situation of a large amount of relatively administrations, these can be divided into one day several parts the dosage that respectively separates.
Combination can comprise at least a formula I chemical compound of effective dose and above-mentioned at least a other therapeutic agent, the therapeutic efficiency that this is bigger in the time of can obtaining than any chemical compound of independent employing.Combination can be used to treatment, prevention and control pulmonary hypertension, wherein when adopting each medicament separately, does not observe therapeutic effect, perhaps, wherein when giving this combination, observes enhanced effect.
Also can select the relative scale of each chemical compound in the combination according to their mechanism of action and disease biologys separately.The relative scale of each chemical compound can extensively change and the present invention includes a plurality of combinations of treatment, prevention or control pulmonary hypertension, and the amount of its Chinese style I chemical compound and other therapeutic agent can be regulated routinely, and any is existed with higher amount.
When being single dosage form, assembly packaging, kit, perhaps, when being the separate dosage forms of separating, the also suitably release of one or more medicines of control combination is to provide needed therapeutic activity.
Preferably comprise at least a formula I chemical compound and at least a combination of compounds that is selected from Phosphodiesterase V inhibitors, endothelin antagonist, prostacyclin analogs, inhibitors of kinases and elastase inhibitor.More preferably adopt and comprise 4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-pyridine-2-carboxylic acids Methanamide and at least a combination of compounds that is selected from tadalafil, sldenafil, Vardenafil, bosentan, sitaxentan, iloprost, bent prostaglandin and epoprostenol.Most preferably adopt and comprise 4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-combination of pyridine-2-carboxylic acids Methanamide and bosentan or Vardenafil.
Embodiment:
The rat body build-in test of trouble pulmonary hypertension external and that monocrotaline was handled is according to the effect of chemical compound of the present invention and drug regimen to separated induced lung tremulous pulse.
Separated little pulmonary artery
With etherization male Wistar rat (250-300g), take out lung.Cut the left pulmonary artery blood vessel, place ice-cooled Krebs-Henseleit (KH) buffer solution: NaCl 112, KCl 5.9, the CaCl of following compositions (mmol/l)
22.0, MgCl
21.2, NaH
2PO
41.2, NaHCO
325, glucose 11.5, optional test 10
-10-10
-4The compound/combination of mol/l concentration.
Hold tension force for measuring to wait, a plurality of ring plates that 2mm is long are disconnected to be placed in the little lumen of vessels myograph.Introduce two leads (40 μ m diameter) through the segment inner chamber, and fix (Circulation Research 1977 according to Mulvany and the described method of Halpern; 41:19-26).Under 37 ℃ and the pH=7.4, balance is after 30 minutes in the KH of oxidation solution, make each fragment be stretched to their best intracavity diameter of active tension development, according to each segmental inner peripheral wall tension force ratio, be exposed to 90% of blood vessel had under the passive tension that is equal under the tension force that 30mmHg transmural pressure power produces inner peripheral if be set in them, determine best intracavity diameter by inner peripheral with them.
Then, use each fragment of KH solution washing three times, placed balance 30 minutes.Again by being exposed to high K at first
+Solution (120mmol/l K
+-KH solution, it is equal to KH solution, except substituting the NaCl with moles such as KCl) the test fragment contractility.
Adopt K again
+(50mmol/l) KH solution preshrinking blood vessel.When contraction is stablized, set up the cumulative dose response curve of the compound/combination of being tested.By K
+(50mmol/l) stabilized contraction of KH solution mediation is defined as 100% tension force.Diastole is represented as percentage tension.The pulmonary artery pressure of the rat that monocrotaline was handled
With monocrotaline 60mg/kg subcutaneous treatment male Sprague Dawley rat (250-300g) (=0 day).After the monocrotaline injection treatment the 14th day gives the compound/combination that will test.The 28th day, measure hemodynamic parameters, that is, and right ventricular pressure, systemic blood pressure, heart rate, tremulous pulse and venous oxygen saturation, and with untreated control animal relatively.
The result:
Moderate pulmonary hypertension outbreak beginning behind injection MCT 14 days, the rat that monocrotaline (MCT) was handled receives 4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups at random by tube feed once a day]-the 3-fluorinated phenoxy }-pyridine-2-carboxylic acids Methanamide 3mg/kg or excipient, up to 28 days.Compare with the animal that excipient is handled, in the animal of the pulmonary hypertension of suffering from MCT-mediation, with 4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-treatment of pyridine-2-carboxylic acids Methanamide significantly reduces right ventricular hypertrophy, and (right ventricle/left ventricle+space ratio contrasts: 0.25 ± 0.01; 4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-the pyridine-2-carboxylic acids Methanamide: 0.28 ± 0.01 pair of placebo: 0.62 ± 0.02) (average ± SEM).4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-this effect of pyridine-2-carboxylic acids Methanamide improves survival (the mortality rate contrast: 0% of animal;
BAY73-4506:0% is to placebo: 40%).
Embodiment 1:4{4-[3-(4-chloro-3-trifluoromethyl)-urea groups]-the 3-fluorinated phenoxy }-preparation of the preparation solid dispersed phase of co-precipitation in 4: 1 of pyridine-2-carboxylic acids Methanamide and polyvinylpyrrolidone
In the phial that does not cover, with 4{4-[3-(4-chloro-3-the trifluoromethyl)-urea groups of portion as free alkali]-the 3-fluorinated phenoxy }-the pyridine-2-carboxylic acids Methanamide mixes with four parts of polyvinylpyrrolidones (PVP-25/Kollidon 25), and be dissolved in the acetone and alcoholic acid 1: 1 mixture of capacity, be solution up to all powder.The phial of lid is not put into and is set to 40 ℃ vacuum drying oven, drying 24-48 hour at least.
Claims (12)
1. formula I chemical compound or its pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereomeric form are used for the treatment of, prevent in preparation or control purposes in the medicine of pulmonary hypertension,
Wherein said formula I chemical compound is:
2. drug regimen, it comprises formula I chemical compound and at least a elastase inhibitor and/or a kind of inhibitors of kinases that limits at least a claim 1.
3. the drug regimen of claim 2, inhibitors of kinases wherein is an imatinib mesylate.
4. drug regimen, it comprises the drug regimen of each qualification among defined formula I chemical compound of at least a claim 1 or the claim 2-3 and is selected from least a therapeutic agent in other therapeutic agent of anticoagulant, diuretic, cardiac glycoside, calcium channel blocker, vasodilation, prostacyclin analogs, endothelium antagonist, phosphodiesterase inhibitor, endopeptidase inhibitor, hypolipidemic, thromboxane inhibitor and known reduction pulmonary artery pressure.
5. the drug regimen of claim 4, wherein said other therapeutic agent is Phosphodiesterase V inhibitors, endothelin antagonist or prostacyclin analogs.
6. the drug regimen of claim 4, wherein said other therapeutic agent is tadalafil, sldenafil, Vardenafil, bosentan, sitaxentan, iloprost, bent prostaglandin or epoprostenol.
7. each drug regimen is used for the treatment of, prevents in preparation or controls purposes in the medicine of pulmonary hypertension among the claim 2-6.
8. Pharmaceutical composition, it comprises the drug regimen of each qualification among the claim 2-6.
9. the Pharmaceutical composition of claim 8, it is used for the treatment of pulmonary hypertension.
10. a treatment, prevention or control have the method for this patient's who needs pulmonary hypertension, it comprises formula I chemical compound or its pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or the diastereomeric form that gives effective dose, and wherein said formula I chemical compound is:
11. the method for claim 10, formula I chemical compound wherein and at least a elastase inhibitor and/or the combination of a kind of inhibitors of kinases.
12. each method among the claim 10-11, its Chinese style I chemical compound also with other therapeutic agent that is selected from anticoagulant, diuretic, cardiac glycoside, calcium channel blocker, vasodilation, prostacyclin analogs, endothelin antagonist, phosphodiesterase inhibitor, endopeptidase inhibitor, hypolipidemic, thromboxane inhibitor and known reduction pulmonary artery pressure in the combination of at least a therapeutic agent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05024509.1 | 2005-11-10 | ||
| EP05024509 | 2005-11-10 | ||
| EP05027450.5 | 2005-12-15 | ||
| EP06012234.8 | 2006-06-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101355941A true CN101355941A (en) | 2009-01-28 |
Family
ID=40308383
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800506642A Pending CN101355941A (en) | 2005-11-10 | 2006-10-30 | Diaryl ureas for treating pulmonary hypertension |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101355941A (en) |
| UA (1) | UA91385C2 (en) |
| ZA (1) | ZA200803979B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885814A (en) * | 2012-01-17 | 2013-01-23 | 湖南有色凯铂生物药业有限公司 | Compound and use of compound as anti-cancer medicine |
-
2006
- 2006-10-30 CN CNA2006800506642A patent/CN101355941A/en active Pending
- 2006-10-30 UA UAA200807897A patent/UA91385C2/en unknown
-
2008
- 2008-05-09 ZA ZA200803979A patent/ZA200803979B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885814A (en) * | 2012-01-17 | 2013-01-23 | 湖南有色凯铂生物药业有限公司 | Compound and use of compound as anti-cancer medicine |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200803979B (en) | 2009-09-30 |
| UA91385C2 (en) | 2010-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5084736B2 (en) | Diarylureas for treating pulmonary hypertension | |
| EP1948176B1 (en) | Diaryl ureas for treating pulmonary hypertension | |
| CN101352426B (en) | Osmotic pump controlled release preparation composition and preparation thereof | |
| JP2019123738A (en) | Dialkyl fumarate-containing pharmaceutical preparations | |
| KR20180073665A (en) | Gemcabin combination for the treatment of cardiovascular disease | |
| ES2215680T3 (en) | UNIQUE ADMINISTRATION UNIT CONTAINING A COMBINATION OF TRAMADOL AND DICLOFENACO. | |
| JP2011521915A (en) | Niacin and NSAID combination therapy | |
| JP2003531171A (en) | Compositions and treatments for hyperlipidemia-related diseases | |
| US9867865B1 (en) | Mesalamine for the treatment of cancer | |
| KR101594709B1 (en) | Pharmaceutical combination preparation comprising a HMG-CoA reductase inhibitor and a cholesterol absorption inhibitor | |
| CN103690955A (en) | Ticagrelor-containing drug composition as well as preparation method and application thereof | |
| TWI630928B (en) | Oral formulation for the treatment of cardiovascular diseases | |
| CN102076338A (en) | Diaryl ureas for treating heart failure | |
| EA012261B1 (en) | Pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent | |
| CN101355941A (en) | Diaryl ureas for treating pulmonary hypertension | |
| CN105431140B (en) | Compound formulation containing slow release of metformin and quick-release HMG-CoA reductase inhibitor | |
| CN101385729B (en) | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof | |
| CN101385731A (en) | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof | |
| TWI657825B (en) | Pharmaceutical compositions and methods of treating cardiovascular disease | |
| CN107213138B (en) | Method and pharmaceutical composition for treating hypertension by timed release of drugs | |
| CA2546793A1 (en) | Use of stating for the treatment of metabolic syndrome | |
| CN101385730B (en) | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof | |
| KR20130074808A (en) | The pharmaceutical composition comprising losartan for treating or preventing statin-induced muscle toxicity | |
| RU2431484C2 (en) | Diarylcarbamide for treating pulmonary hypertension | |
| ES2356931T3 (en) | DIARIL UREAS TO TREAT PULMONARY HYPERTENSION. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1128621 Country of ref document: HK |
|
| ASS | Succession or assignment of patent right |
Owner name: BAYER SCHERING PHARMA AG Free format text: FORMER OWNER: BAYER HEALTHCARE AG Effective date: 20091127 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20091127 Address after: Berlin Applicant after: Bayer Schering Pharma AG Address before: Germany Leverkusen Applicant before: Bayer Healthcare AG |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090128 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1128621 Country of ref document: HK |