CN101939322A - Virga N-oxide compound as prodrug - Google Patents
Virga N-oxide compound as prodrug Download PDFInfo
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- CN101939322A CN101939322A CN2008800220625A CN200880022062A CN101939322A CN 101939322 A CN101939322 A CN 101939322A CN 2008800220625 A CN2008800220625 A CN 2008800220625A CN 200880022062 A CN200880022062 A CN 200880022062A CN 101939322 A CN101939322 A CN 101939322A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present invention relates to the Virga N-oxide compound as prodrug, the pharmaceutical composition that comprises this compound, its preparation method and preparation of compositions method.The present invention relates to have formula (1
A) 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-ethoxyl phenenyl] alkylsulfonyl]-4-methyl-4-oxo bridge-piperazine:
Description
Catalogue page
Denomination of invention 1
Catalogue 1
Technical field 1
Background technology 2
Summary of the invention 4
Definition 6
Embodiment 1: analytical procedure 9
Embodiment 2: synthetic 12 of specific compound
Embodiment 3: pharmacological method 13
Embodiment 4: pharmacokinetics and pharmacology test result 14
Embodiment 5: pharmaceutical preparation 18
Bibliography 21
Claims are pagination separately
The pagination separately of making a summary
Technical field
The present invention relates to medicine and organic chemistry filed, and Virga N-is provided oxide compound: have following formula (1
A) 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-ethoxyl phenenyl] alkylsulfonyl]-4-methyl-4-oxo bridge-piperazine,
And the pharmaceutical composition that comprises this compound, the preparation method of this compound and preparation of compositions method.
Background technology
Virga is the potent and selective depressant of 5 type cGMP specific phosphodiesterase enzyme (PDE-V)
1-[4-oxyethyl group-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl) benzenesulfonyl]-the 4-methylpiperazine, Virga (EP 0 463 756)
In vitro study has shown that Virga is optionally to PDE-V.Its effect to PDE-V compare other known phosphodiesterase more potent (for PDE-VI, 10 times; For PDE-I,＞80 times; For PDE-II, PDE-III, PDE-IV, PDE-VII, PDE-VIII, PDE-IX, PDE-X and PDE-XI,＞700 times.With respect to PDE-III, be important to roughly 4,000 times the selectivity of PDE-V, because PDE-III is relevant with the control of cardiac contractile force.Compare with PDE-VI, only powerful about 10 times of Virgas, PDE-VI to the effect of PDE-V be in retina, find with the relevant enzyme of amphiblestroid light transduction passage.This lower selectivity is considered to and the relevant unusual basis of observed colour vision under more high dosage or blood plasma level.
Virga is mainly removed by CYP3A4 (main path) and CYP2C9 (minor path) hepatomicrosome isozyme.Main cyclic metabolism thing is produced by the N-demethylation of Virga.This metabolite also is called UK 103,320, has the PDE selectivity performance that is similar to Virga and is roughly 50% of parent drug to the vitro efficacy of PDE-V.The plasma concentration of this metabolite is approximately 40% of the seen plasma concentration of Virga, so that the pharmacological effect of this metabolite is about 20% of a Virga.
The N-oxide compound is just known since 1894.The present consistent N-of the generally acknowledging oxide compound metabolite that is many tertiary amines, and in most of the cases also be intermediate between tertiary amine and their the N-alkylation removal analogue.Great majority, but not all tertiary amine medicine produces the N-oxide compound.For example morphine, imipramine, promazine, CN and nicotine are exactly this situation.The N-oxidation takes place what from trace to changing near Quantitative yield.Some N-oxide compounds show stronger than their corresponding tertiary amine effects.The most famous example is a zeisin in them
One of the most frequently used medicine in psychosis and general medical science.Yet, under many circumstances, find that the N-oxide compound is more weak than their corresponding tertiary amine effects, and the most common metabolism inactivation that is considered to of N-oxidation.Though can easily the N-oxide compound be reduced into the tertiary amine of their correspondences by chemical means, this takes place with different degree in human body.Some N-oxide compounds can experience almost quantitative reduction and transform, and become corresponding tertiary amine and in other cases, conversion is the only reaction of trace, perhaps even fully do not have (Bickel, 1969).Therefore, the formation of N-oxide compound and their corresponding tertiary amine is unpredictable.In case form, the N-oxide compound may have more activity than they corresponding tertiary amine, poorer or even the complete non-activity of activity.The N-oxide compound can be reduced into corresponding tertiary amine or cannot.When they can the time, this reaction may only be trace or near quantitative.
Since Paracelsus (' Sola dosis facit venenum '), generally accepted is that the treatment of medicine and toxic action are relevant in the concentration of relevant target site with them.Because generally speaking, the latter is not easy to obtain, so with the approximation of blood plasma level as related drugs concentration.During drug development, the plasma concentration window that limit to be fit to, thus the lower limit of effect or lower bound and the side effect tangible upper bound that begins to become is provided.Under ideal state, these two kinds of concentration differences are apart from being so big so that with effectively but the method drug administration that does not have side effects is easy.In fact, situation may be an ideal hardly forever, and most drug shows side effect.In most of the cases, the generation of side effect may have relation with peak plasma concentrations, and this peak plasma concentrations surpasses and the relevant threshold level of side effect generation.
Virga produces the peak plasma concentrations that causes side effect.The most normal observed adverse events relevant with the use of Virga comprise sneeze, headache, flush, palpitaition, maldigestion, intraocular pressure rising, blurred vision, photophobia, serious hypopiesia, ventricular arrhythmia, myocardial infarction, apoplexy and priapism.These undesirable actions are dosage level, frequency and the time length of limit drug therapy significantly.Use special preparation can weaken adverse events, but different compounds also can address this problem.Therefore it will be desirable finding the advantage with Virga to avoid the compound of its shortcoming simultaneously.Prodrug has identical pharmacology performance, but has more favourable pharmacokinetics performance.
Summary of the invention
When oral administration, Virga-N-oxide compound serves as prodrug: it promptly is transformed into parent compound and converts N-demethyl Virga, the i.e. active metabolite of Virga to
The invention still further relates to acceptable salt, hydrate and solvate on the pharmacology of Virga N-oxide compound, they can be substantially free of acceptable salt, hydrate or solvate on Virga or its pharmacology.Virga N-oxide compound can by with the oxygenant that is fit to for example m-CPBA oxidation Virga prepare.Acceptable salt can use the standard program of knowing in this area in the pharmacy, for example passes through compound of the present invention and the acid that is fit to, and for example mineral acid or organic acid mix and obtain.
Virga N-oxide compound can be used for treating illness or the disease that available Virga is effectively treated (even side effect is arranged) with the composition that comprises them: erective dysfunction (impotence) and pulmonary hypertension (PAH)
The present invention also comprises:
For example be used for the treatment of, can be by the obstacle of Virga treatment or the pharmaceutical composition of situation, said composition comprises in Virga N-oxide compound or its pharmacy acceptable carrier on the acceptable salt and pharmacy;
Treatment can be by the obstacle of Virga treatment or the method for situation, and this method comprises acceptable salt in the administration Virga N-oxide compound of this kind of needs treatment or its pharmacy;
Treatment can be by the obstacle of Virga treatment or the method for situation, and this method comprises acceptable salt in the administration Virga N-oxide compound of this kind of needs treatment or its pharmacy;
Being used for the treatment of can be by the obstacle of Virga treatment or the pharmaceutical composition of situation, and said composition comprises in Virga N-oxide compound or its pharmacy acceptable carrier on the acceptable salt and pharmacy;
Treatment can be by the obstacle of Virga treatment or the method for situation, and this method comprises that the patient to the treatment of this kind of needs uses acceptable salt in Virga N-oxide compound or its pharmacy.
The present invention also provides Virga N-oxide compound or its salt to be used to make the purposes of medicament.
The invention further relates to combination treatment, wherein with compound of the present invention, or acceptable salt in its pharmacy, or comprise the pharmaceutical composition of The compounds of this invention or preparation simultaneously use successively or as with another kind of therapeutical agent (or several therapeutical agent) for example the combination preparation of Virga or N-demethyl Virga use, be used for the treatment of one or more listed situations.This type of other therapeutical agent can be before using The compounds of this invention, simultaneously or use afterwards.
The present invention also is provided for treating can be by the obstacle of Virga treatment or compound, pharmaceutical composition, kit (kits) and the method for situation, and this method comprises that the patient to the treatment of this kind of needs uses acceptable salt in Virga N-oxide compound or its pharmacy.
The present invention also provides the intermediate that uses in the preparation method of The compounds of this invention and those methods.
Some crystal formations of compound can be used as polymorph and exist: think that itself belongs to the present invention.In addition, some compounds can with water (being hydrate), or organic solvent commonly used forms solvate.This type of solvate also belongs to the scope of the invention.
Acceptable salt in isotope-labeled Virga N-oxide compound or its pharmacy (can detect by PET or SPECT) also belongs to the scope of the invention.The same applies to usefulness [
13C]-, [
14C]-, [
3H]-, [
18F]-, [
125I]-or be suitable for the compound of general formula (1) of atom mark of other isotopic enrichment of receptors bind or metabolism research.
Find that random events that Virga N-oxide compound can be used as prodrug provides and use the possibility of these compounds as alternatives, it has the clinical benefit that prolongs acting duration and weaken peak plasma concentrations, thus improved side effect performance.Therefore in some embodiments of the present invention; can provide and be substantially free of parent compound 1-[4-oxyethyl group-3-(6; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl) benzenesulfonyl]-The compounds of this invention of 4-methylpiperazine (Virga).So-called being substantially free of is meant that compound of the present invention comprises and is less than about Virga of 50%, 40%, 30%, 20%, 10%, 1%, 0.5% or do not contain Virga as impurity in limit of detection.Anticipate the pharmaceutical composition that is substantially free of Virga that comprises Virga N-oxide compound according to the present invention.
Definition
Metabolism and any compound of biologically active agent (being Virga) is provided is prodrugs in the application's scope and spirit in vivo.Prodrug is a therapeutical agent, itself is inactive, but is transformed into one or more active metabolites.Prodrug is the biological reversible derivatization thing of drug molecule, and it is used for overcoming some obstacles that application parent drug molecule is run into.These obstacles include but not limited to, metabolism and target restriction (Bundgaard, 1985 before solvability, perviousness, stability, the body circulation; King, 1994; Stella, 2004; Ettmayer, 2004;
2005).
Term " polymorphism " is defined as the ability of compound to exist more than a kind of crystalline form (so-called polymorphic).Polymorphism is the phenomenon that takes place usually.Polymorphism is subjected to some crystallization conditions, and for example temperature, supersaturation level, the existence of impurity, polarity of solvent, rate of cooling influence.Polymorphic can pass through for example solid state NMR, solubility test, DSC or fusing point test of several methods, IR or Raman spectroscopy and characterize.
For simpler and clearer description is provided, some quantity that this paper provides are explained term of no use " approximately " restriction.It should be understood that, no matter whether clearly use term " approximately ", each amount that this paper provides means the actual value that provides, and mean the approximation of this type of value that provides, this approximation will reasonably be derived based on the ordinary skill of this area, comprise by so test of the value of providing and/or the approximation that measuring condition causes.In the whole description and claim of this specification sheets, word " comprise " and the modified example of this word as " comprising " with do not get rid of " comprising " intention of other additive, component, integer or step.Term as used herein " composition " contains the product of the appointment composition that comprises predetermined amount or ratio, and the spawn that is directly or indirectly obtained by the appointment composition of combination specified amount.As for pharmaceutical composition, the product that comprises one or more activeconstituentss and contain the optional carrier of inert fraction contained in this term, and by combination, complexing or assemble any two or more compositions, or by one or more compositions that dissociate, or by the reaction of other type of one or more compositions or the spawn that interacts and directly or indirectly obtain.Generally speaking, be prepared as follows pharmaceutical composition: activeconstituents evenly and is closely associated with liquid vehicle or fine powder crushed solid carrier or both, then if necessary, this product is shaped as required preparation.Pharmaceutical composition comprises that enough active target compounds produce desired result with process or situation to disease.Therefore, pharmaceutical composition of the present invention is contained by any composition with acceptable carrier fusion preparation in The compounds of this invention and the pharmacy.
In the application's context, term ' combination preparation ' had both comprised true combination, promptly physically be combined in acceptable salt in Virga N-oxide compound in a kind of formulation example such as tablet or the injection liquid or its pharmacy, with other medicament, comprise ' kit box ' (kit of parts) again, this kit box is included in acceptable salt in Virga N-oxide compound in the individually dosed form or its pharmacy, with Virga or another kind of medicament, and working instructions, randomly be convenient to comply with the instrument of using of component composition in addition, for example label or figure.Adopt true combination, take place simultaneously according to definition pharmacological agent.The content of ' kit box ' can be used simultaneously or with different time at interval.Treatment will be depended on the feature of employed other medicament simultaneously or sequentially, beginning and the time length of feature as acting on, and blood plasma level, clearance rate etc., and depend on disease, the feature of its stage and individual patient.
So-called " acceptable in the pharmacy " means carrier, thinner or vehicle must be compatible with other composition of preparation and harmless to its recipient.
Dosage: the therapeutic dose of recommendation is identical with Virga: 50mg, take the circumstances into consideration to reduce or improve dosage then.Pharmacokinetics, pharmacodynamics and other consideration can be with the actual DM of using to higher or lower values.The dosage of the compound that is applied will depend on patient's relevant indication, age, body weight and sex and can determine by the doctor.This dosage will be preferably 0.01mg/kg-10mg/kg.The typical per daily dose of activeconstituents changes in wide region and will depend on various factors for example patient's relevant indication, route of administration, age, body weight and sex, and can be determined by the doctor.Generally speaking, oral and parenteral dosage will be 0.1-1,000mg/ days gross activity compositions.
Term as used herein " significant quantity in the treatment " is meant the amount of the situation that therapeutical agent treatment or prevention can be by using present composition treatment.This amount is the amount that is enough in tissue system, animal or human's class to show detectable therapeutic, the preventative or property improved response.This effect for example can comprise, the situation that treatment or prevention this paper list.Curee's accurate significant quantity will depend on this curee the size and healthy, the nature and extent of the situation of being treated, treatment doctor's (researchist, animal doctor, medical doctor or other clinician) recommendation and for to use the therapy of selection, or the combination of therapy.Therefore, it is useless specifying accurate significant quantity in advance.Term " acceptable salt in the pharmacy " is meant and is suitable in reliable medical judgment scope and human those salt that use and do not have excessive toxicity, stimulation, transformation reactions etc. and match with rational interests/risk ratio that contact with zootic tissue.Acceptable salt is well known in the art in the pharmacy.Can in-situ preparing when final separation and purifying The compounds of this invention they, perhaps can be individually by acceptable nontoxic alkali or acid (comprising inorganic or organic bases and inorganic or organic acid) reaction are prepared.Term as used herein " treatment " is meant Mammals, preferred human situation or any processing of disease, and comprise: (1) preventing disease or situation are not still made a definite diagnosis among the curee who suffers from this disease in easy this disease of trouble and are taken place, (2) suppress disease or situation, promptly stop its development, (3) palliate a disease or situation, promptly cause this situation to disappear, or (4) stop the symptom of disease.Term as used herein " therapeutic treatment " is intended to comprise to human or other Mammals in vivo or preventative, the diagnostic and the therapeutic scheme that exsomatize and carry out.Term as used herein " curee " is meant animal, and preferred mammal is most preferably human, and it is the object of treatment, observation or experiment.
Embodiment 1: analytical procedure
Except as otherwise noted, use Bruker DRX 600 (
1H:600MHz,
13C:150MHz) under 300K, in the solvent of pointing out, measure NMR (Nuclear Magnetic Resonance) spectrum (
1H NMR and
13CNMR, APT).Among the deuterate DMSO that obtains from Cambridge Isotope Laboratories Ltd., measure spectrum.From tetramethylsilane (
1H) downfield provides chemical shift (δ) with ppm.Provide coupling constant J with Hz.Peak shape in the NMR spectrum is represented with symbol ' q ' (quartet), ' dq ' (two quartet), ' t ' (triplet), ' dt ' (two triplet), ' d ' (doublet), ' dd ' (two doublet), ' s ' (unimodal), ' bs ' (wide unimodal) and ' m ' (multiplet).With sample and a D
2After mixing, identifies O NH and OH signal.
On B ü chi B-545 melting point apparatus, write down fusing point.
Hurried chromatography is meant uses the eluent point out and the purifying of silica gel (Acros:0.030-0.075mm or Merck silica gel 60:0.040-0.063mm).
Adopt the eluent monitoring reaction of pointing out by using tlc (TLC) to go up at the plastics sheet (Merck precoating silica gel 60F254) of silica-coating.By UV light (254nm) or I
2Make the spot video picture.
C/MS (liquid chromatography-mass spectrography) (LC-MS)
The LC-MS system is made of 2 Perkin Elmer series 200 micropumps.By the 50 μ l threeway mixing tanks that are connected with Gilson 215 automatic samplers pump is connected to each other.This method is as follows:
Step total time flow (μ l/min) A (%) B (%)
0 0 2000 95 5
1 1.8 2000 0 100
2 2.5 2000 0 100
3 2.7 2000 95 5
4 3.0 2000 95 5
A=100% water and 0.025%HCOOH and 10mmol NH
4HCOO, pH=+/-3
B=100%ACN and 0.025%HCOOH
Automatic sampler has 2 μ l injection ring.This automatic sampler with contain 3 μ m particulate Waters Atlantis C18,30 * 4.6mm post and be connected.Be in temperature constant state in the PerkinElmer series 200 post baking ovens of this post under 40 ℃.This post is connected with the Perkin Elmer series 200UV meter that contains 2.7 μ l flow cells (flowcel).Wavelength is set to 254nm.This UV meter is connected with Sciex API 150EX mass spectrograph.This mass spectrograph has following parameter:
Sweep limit: 150-900a.m.u.; Polarity: just; Scan pattern: curve; Resolving power Q1:UNIT; Step-length: 0.10a.m.u.; The time of each scanning: 0.500sec; NEB:10; CUR:10 IS:5200; TEM:325; DF:30; FP:225 is connected light scattering detector with EP:10. with Sciex API 150.Light scattering detector is at 50 ℃ and 3 crust N
2The Sedere Sedex 55 of following operation.By G3 powermac control total system.
Use comprises the general biological analytical procedure of protein precipitation and has the HPLC analysis mice plasma of MS/MS detection and Virga and its N-oxide compound in the brain sample.
Specimen preparation: use the protein of acetonitrile precipitation in 100 μ l blood plasma, and analyze 5 μ l samples of the solution that is obtained.With full brain homogenizing and centrifugal, and analyze 10 μ l supernatant samples.
Use Sciex API4000 LC-MS/MS to carry out liquid phase chromatography-polyphone mass spectroscopy (LC-MS/MS).Use the calibration sample (it is carried out the processing identical with study sample) that extracts in the scope of 1-5000ng/ml and 5.0-5000ng/ brain, to carry out the quantification of sample respectively for blood plasma and brain sample.Use the compound peaks area to quantize.Working curve is fitted to model y=A+Bx+Cx
2(y is the peak area of analyte, and x is the nominal calibrated horizontal, and unit is ng/ml (blood plasma) or ng/g (brain), and A is an intercept, and B is a slope, and C is the description of curvature).Use 1/x
2Weighting.The reference solution monitoring LC-MS/MS system performance that use is injected in the normal space.At length do not verify employed method, therefore the concentration of report is good estimated value.For blood plasma and brain sample, quantized lower limit (LLOQ) is set up at 1.00ng/ml and 5.00ng/ brain respectively.Use gradient elution by Hypersil BDS C18100 * 4.6mm 3 μ m analytical columns, carrying out reversed-phase HPLC under 45 ℃ the temperature and under the flow of 1.00ml/min:
| Solvent orange 2 A | 100mM?NH 4FA/1％FA |
| Solvent B | Milli-Q water |
| Solvent C | Methyl alcohol |
| Solvent D | Acetonitrile |
Use positive MRM ionization to carry out detection on MS/MS.Measure following ion:
Virga N-oxide compound Virga
Q1 475.3 491.4
Q3 100.1 99.2
Embodiment 2: specific compound synthetic
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-oxyethyl group-phenyl] alkylsulfonyl]-4-methylpiperazine (Virga) and
Synthetic 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-oxyethyl group-phenyl as among the EP 0 463 756] alkylsulfonyl]-piperazine (N-demethyl Virga).
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-ethoxyl phenenyl] alkylsulfonyl]-4-methyl-4-oxo bridge-piperazine (Virga N-oxide compound):
(1.42g 3mmol) is dissolved in 75ml methylene dichloride and be cooled to-10 ℃ with the free alkali of Virga.Chloro peroxybenzoic acid between inciting somebody to action (m-CPBA, 0.74g, 3mmol, 70%, at H
2Among the O) add in this mixture with aliquot, and stirred this solution 2.5 hours down at-10 ℃.Add solid K
2CO
3(2g) and in the mixture of 0 ℃ of following restir gained 30 minutes.Filter (glass funnel) this reaction mixture, and use the DCM washing precipitation.Concentrate the solution of gained, be produced as solid title compound (1.36g, 92%).M.p.:＞200 ℃ (decomposition).LCMS；R
t：1.21min，([M+H]
+＝491)。
1H-NMR(600MHz，D
6DMSO)：δ7.89-7.85(m，2H)，7.39(d，J＝8Hz，1H)，4.18(q，J＝7Hz，2H)，4.16(s，3H)，3.51-3.43(m，4H)，3.04(s，3H)，3.02-2.96(m，2H)，2.93-2.88(m，2H)，2.78(t，J＝7Hz，2H)，1.77-1.70(m，2H)，1.30(t，J＝7Hz，3H)，0.93(t，J＝7Hz，3H)。
Embodiment 3: pharmacological method
The program of using extensively record is at CEREP (128, rue Danton, 92500Rueil-Malmaison, France) vitro inhibition of measurement phosphodiesterase: the PDE-I (Nicholson that derives from the ox brain, 1989), derive from the PDE-II (Torphy of people U-937 cell, 1992), derive from the PDE-III (Weishaar, 1986) of human blood platelets, derive from the monocytic pDE-IV (Torphy of people U937,1992), derive from the PDE-V (Weishaar, 1986) of human blood platelets and derive from the PDE-VI (Ballard, 1998) of bovine retina.
People's colon models TIM2 (TNO intestines model 2) is the dynamicmodel of people's large intestine of condition in the analogue body.It is the artificial Digestive tract that is confirmed by many researchs (Minekus, 1999).
Virga N-oxide compound, and acceptable salt is prodrug on the pharmacology.They can be used for treating the disease that available Virga is effectively treated (even side effect is arranged): erective dysfunction (impotence) and pulmonary hypertension.
Embodiment 4: pharmacokinetics and pharmacology test result
Virga and its N-oxide compound are used (intravenously (i.v.) or oral (p.o.)) respectively to male NMRI mouse (3 animals of each time point), after this analyze their blood plasma and two kinds of compounds in the brain by LC-MS (referring to method above).The mean value of data calculated (n=3), and be collected in the table 1.
When being administered to mouse (i.v. or p.o.), the Virga minimally is become its N-oxide compound by metabolism: its concentration in blood plasma is from being no more than the 1-2% of parent compound, and can not find trace fully in brain.When using Virga-N-oxide compound itself, it is reduced into parent compound.After Virga-N-oxide compound i.v. uses one hour, the Virga concentration in blood plasma and the brain surpassed the concentration of N-oxide compound.Effect is more remarkable after oral: at the high 10-100 of concentration that uses back Virga concentration ratio N-oxide compound in blood plasma and the brain in half an hour of N-oxide compound doubly.
Add in the TIM2 model described chamber (120ml) of (referring to above, Minekus, 1999) being suspended in Virga in 1% methylcellulose-N-oxide compound (1mg).Obtain sample in the various timed intervals from described chamber and dialyzate (latter is the model that is used for the vescular bed of intestines), and analyze Virga-N-oxide compound and Virga: table 2:
Can clearly be seen that from top result Virga N-oxide compound almost quantitatively has been reduced into Virga in 2 hours after administration.Because many TIM2 of studies confirm that are the external model that the gastrointestinal conditions among the living person is had high predictive value, so can expect, in the people, after oral, Virga N-oxide compound also will be reduced into Virga: it will be a prodrug.
* for the i.v. administration, with C
MaxValue is extrapolated to T
0(time zero)
From these data as can be seen these two kinds of compounds have different pharmacokinetics performances.
In the small-scale pilot scale, Virga and its N-oxide compound are used (intravenously (i.v.) or oral (p.o.)) respectively to male NMRI mouse (3 animals of each time point), after this analyze the existence of their blood plasma and the N-demethyl Virga in the brain by LC-MS (referring to method above).With data average (n=3), and be collected in the table 4.
As expected, when being administered to mouse (i.v. or p.o.), Virga is metabolised to its N-demethyl analogue, promptly also penetrates the metabolite of hemato encephalic barrier, and reason is that it is found in cerebral tissue.When using Virga-N-oxide compound, it also is found metabolism, and to become the observations of N-demethyl Virga (only observing after oral administration) be new.
In order to study the activity of Virga-N-oxide compound, after Virga itself, test this compound as the inhibitor of different phosphodiesterases.The collection that is obtained is in table 5.
For Virga, the data acknowledgement of collecting in the table 5 those that know from scientific literature: this compound is the strongly inhibited agent of PDE-V, and is high selectivity to this specific hypotype, the PDE-VI exception, it is also by strongly inhibited.Find Virga-N-oxide compound action intensity than low 10 times of Virga itself, and show suitable selectivity.
In a word: when oral administration, Virga-N-oxide compound serves as prodrug: it promptly is transformed into parent compound and converts N-demethyl Virga to, the Virga metabolite of the only about half of effectiveness with Virga of promptly being in the news.Find that also Virga-N-oxide compound itself is not complete non-activity: it has about 1/10th activity of parent compound.
Embodiment 5: pharmaceutical preparation
For clinical application, Virga N-oxide compound is formulated in the pharmaceutical composition, this pharmaceutical composition is an important and novel embodiment of the present invention, because they comprise compound disclosed herein, more particularly, specific compound.The type of operable pharmaceutical composition comprises: tablet, chewable tablet, capsule (comprising micro-capsule), solution, parenteral solution, ointment (emulsifiable paste and gel), suppository, suspension and disclosed herein, or concerning those of skill in the art, be conspicuous other type according to the common practise in this specification sheets and this area.For example, activeconstituents can also be in cyclodextrin, their ether or the clathrate complex form in their ester.That described composition can be used for is oral, in the intravenously, subcutaneous, tracheae, segmental bronchus, nose, lung, transdermal, buccal mucosa, rectum, parenteral or other administration.Pharmaceutical preparation comprise at least with at least a pharmacy on the Virga N-oxide compound of acceptable assistant, thinner and/or carrier fusion.The total amount of activeconstituents is suitably about 0.1% (w/w)-about 95% (w/w) of preparation, is suitably 0.5%-50% (w/w), preferred 1%-25% (w/w).In some embodiments, the amount of activeconstituents is greater than about 95% (w/w) or less than about 0.1% (w/w).
Pass through usual method, use for example liquid or solid of auxiliary substance, the powdery composition is pharmacy liquid or solid weighting agent and expansion agent, solvent, emulsifying agent, lubricant, correctives, tinting material and/or buffer substance commonly used for example, compound of the present invention can be made the formulation that is suitable for administration.Normally used auxiliary substance comprises for example Oils,glyceridic,cod-liver, Trisun Oil R 80, peanut oil or sesame oil, polyoxyethylene glycol and solvent sterilized water and monohydroxy-alcohol or polyvalent alcohol glycerine for example for example of magnesiumcarbonate, titanium dioxide, lactose, sucrose, Sorbitol Powder, mannitol and other sugar or sugar alcohol, talcum, milk-protein, gelatin, starch, amylopectin, Mierocrystalline cellulose and derivative thereof, animal and plant oil, and disintegrating agent and lubricant for example Magnesium Stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax.Mixture can be processed into particle then or be pressed into tablet.Use following composition to prepare tablet:
Said components fusion and compacting are formed the tablet of every heavy 230mg.
Before mixing the formation preparation, can be individually with activeconstituents and other non-active ingredient pre-mixing.Mix the formation preparation with non-active ingredient before, can also be with the activeconstituents intermingling.
Soft gelatin capsule can adopt and contain the capsule preparation of mixture that activeconstituents of the present invention, vegetables oil, fat or other are suitable for the carrier of soft gelatin capsule.Hard gelatin capsule can comprise the particle of activeconstituents.Hard gelatin capsule can also comprise activeconstituents and solid, powdery composition for example lactose, sucrose, Sorbitol Powder, mannitol, yam starch, W-Gum, amylopectin, derivatived cellulose or gelatin.
The dosage device that is used for rectal administration can be prepared as (i) suppository form, and this suppository comprises and neutral fat base-material blended active substance; (ii) gelatin rectal capsule form, this capsule comprise with vegetables oil, paraffin oil or are suitable for other carrier blended active substance of gelatin rectal capsule; The little enema forms that (iii) prepares; Or (iv) do slight irrigation Enteral formulations form, said preparation reconstituted in the solvent that is fit to before being about to administration.
Liquid preparation can be prepared into syrup, elixir, concentrate dropping liquid or suspension, for example contains the solution or the suspension of activeconstituents and rest part, and this rest part for example is made of the mixture of sugar or sugar alcohol and ethanol, water, glycerine, propylene glycol and polyoxyethylene glycol.If necessary, this type of liquid preparation can comprise tinting material, correctives, sanitas, asccharin and carboxymethyl cellulose or other thickening material.Liquid preparation can also prepare with dry powder form, and it used the solvent reconstruct that is fit to before using.The solution that is used for administered parenterally can be prepared as the solution of preparation of the present invention acceptable solvent in pharmacy.These solution can also comprise stable composition, sanitas and/or buffer composition.The solution that is used for administered parenterally can also be prepared as dry preparation, and it used the solvent reconstruct that is fit to before using.
According to the present invention, preparation and ' kit box ' also are provided, it comprises one or more containers that one or more compositions of pharmaceutical composition of the present invention are housed, and is used for therapeutic treatment.Such container can be with various written materials, working instructions for example, or the letter of information of the form of the statutory regulation of production, use or the sale of management medicament production, this letter of information can reflect the approval of described department for production, application or the sale of people or animal doctor's administration.The purposes of preparation of the present invention in medicament is made, this medicament is used for the treatment of the situation that wherein requires or want to suppress phosphodiesterase, and the method for therapeutic treatment, comprise that the Virga N-oxide compound of will treatment going up effective total amount is administered to and suffers from the situation that wherein requires or want to suppress phosphodiesterase or to the patient of this situation sensitivity.
For instance and without limits, provided the multiple medications composition, it comprises and is used for that whole body is used or the preferred active compound of topical application.Other compound of the present invention or its combination can be used for replacing described compound (or with described compound addition).The concentration of activeconstituents can change in the wide region of this paper discussion.The amount of the composition that can comprise and type are to know in this area.
Bibliography
In order to reach below with reference to the document degree useful to those skilled in the art, or in order to describe the present invention more completely, by participating in incorporating them into this paper.These documents, or any other document of quoting of this paper or quote as proof, or do not have one piece to be admitted to be prior art document or quoted passage in the quoted passage of any reference.
People such as Ballard (1998) J.Urol.159:2164
Bickel，M.H.，：“The?pharmacology?and?Biochemistry?of?N-oxides”，
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21(4)，325-355，1969.
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Claims (12)
- (1.1-[[3-6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-oxyethyl group-phenyl] alkylsulfonyl]-4-methyl-4-oxo bridge-piperazine:
Acceptable salt, hydrate and solvate on its pharmacology. - 2. according to the compound of claim 1; it is substantially free of 1-[4-oxyethyl group-3-(6; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl) benzenesulfonyl]-4-methyl-piperazine, or acceptable salt, hydrate or solvate on its pharmacology.
- 3. medicament, it comprises according to each compound among the claim 1-2, or acceptable salt, hydrate or solvate on its pharmacology.
- 4. according to each compound among the claim 1-2, it is used for the treatment of erective dysfunction or pulmonary hypertension.
- 5. pharmaceutical composition, it is on comprising pharmacy in acceptable carrier and/or at least a pharmacy the acceptable auxiliary substance, at least a compound that also comprises among the claim 1-2 of live vol on the pharmacology each, or on its pharmacology acceptable salt, hydrate or solvate as activeconstituents.
- 6. combined pharmaceutical formulation, it comprises acceptable salt, hydrate or solvate on (i) Virga N-oxide compound or its pharmacology, and (ii) another kind of therapeutical agent, is used for simultaneously, independence or order treat erective dysfunction or pulmonary hypertension.
- 7. according to the combined pharmaceutical formulation of claim 6, wherein said other therapeutical agent is a Virga.
- 8. be used for the purposes of pharmaceutical compositions according to each compound among the claim 1-2, this pharmaceutical composition is used for the treatment of erective dysfunction or pulmonary hypertension.
- 9. the method for this erective dysfunction of treatment or pulmonary hypertension in the mankind of needs treatments erective dysfunction or pulmonary hypertension or animal patient, wherein this method comprises so that described treatment is effectively measured, and gives described patient with Virga N-oxide compound.
- 10. be used for the purposes of pharmaceutical compositions according to the combination preparation of claim 6, this pharmaceutical composition is used for the treatment of erective dysfunction or pulmonary hypertension.
- 11. the preparation method of Virga N-oxide compound wherein has the Virga of formula (1) with the oxygenant oxidation and produces the have formula Virga N-oxide compound of (1A)
- 12. according to the method for claim 11, wherein said oxygenant is a m-chloro benzoic acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07111030 | 2007-06-26 | ||
| EP07111030.8 | 2007-06-26 | ||
| PCT/EP2008/057940 WO2009000798A1 (en) | 2007-06-26 | 2008-06-23 | Sildenafil n-oxide as prodrug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101939322A true CN101939322A (en) | 2011-01-05 |
Family
ID=38657406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008800220625A Pending CN101939322A (en) | 2007-06-26 | 2008-06-23 | Virga N-oxide compound as prodrug |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2010531327A (en) |
| CN (1) | CN101939322A (en) |
| AR (1) | AR067128A1 (en) |
| BR (1) | BRPI0813657A2 (en) |
| TW (1) | TW200918533A (en) |
| ZA (1) | ZA200908868B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113884607A (en) * | 2021-11-17 | 2022-01-04 | 南京西默思博检测技术有限公司 | Method for detecting medicines sildenafil and N-demethylsildenafil |
-
2008
- 2008-06-23 TW TW97123309A patent/TW200918533A/en unknown
- 2008-06-23 AR ARP080102686 patent/AR067128A1/en not_active Application Discontinuation
- 2008-06-23 BR BRPI0813657A patent/BRPI0813657A2/en not_active IP Right Cessation
- 2008-06-23 JP JP2010513874A patent/JP2010531327A/en not_active Withdrawn
- 2008-06-23 CN CN2008800220625A patent/CN101939322A/en active Pending
-
2009
- 2009-12-11 ZA ZA200908868A patent/ZA200908868B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0813657A2 (en) | 2016-10-18 |
| ZA200908868B (en) | 2010-09-29 |
| JP2010531327A (en) | 2010-09-24 |
| AR067128A1 (en) | 2009-09-30 |
| TW200918533A (en) | 2009-05-01 |
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