CN1761463A - Method for increasing the oral bioavailability of s-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate - Google Patents
Method for increasing the oral bioavailability of s-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate Download PDFInfo
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Abstract
The invention is directed to a method of increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate by administration of a therapeutically effective amount of the drug with food. The invention also provides a kit comprising a pharmaceutical composition comprising a therapeutically effective amount of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate and a pharmaceutically acceptable carrier, prescribing information, and a container, wherein the prescribing information includes advice to a patient regarding administration of the drug with food to improve bioavailability.
Description
Technical field
The present invention relates to treat or the method for angiocardiopathy preventing.
Background technology
For coronary heart disease, atherosclerosis particularly is a principal risk factor with the concentration of T-CHOL and low density lipoprotein, LDL (LDL) the cholesterol relevant hyperlipemia disease disease that raises.In addition, a large amount of researchs confirm: the low plasma concentration of high density lipoprotein (HDL) cholesterol is powerful risk factor for the development of atherosclerosis.
Cholesterol ester transfer protein (CETP) is a kind of plasma protein that moves between promotion cholesteryl ester and the various lipoproteins of triglyceride in blood.Cholesteryl ester by CETP has the effect that reduces the HDL cholesterol and increase the LDL cholesterol from HDL to the motion of LDL.The active inhibitory action of CETP has demonstrated and can change blood plasma HDL/LDL ratio effectively with reducing blood plasma LDL cholesterol by rising blood plasma HDL cholesterol.
Having proved S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester (thioate) is people (de Grooth etc., Circulation, 105,2159-2165 (2002)) and rabbit (Shinkai etc., J.Med.Chem., 43,3566-3572 (2000); Kobayahi etc., Atherosclerosis, 162,131-135 (2002); With Okamoto etc., Nature, 406 (13), 203-207 (2000)) the CETP activity inhibitor.Proved S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester improve the people (de Grooth etc., above) and rabbit (Shinkai etc., above; Kobayashi etc., above, Okamoto etc., blood plasma HDL cholesterol above).In addition, proved S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester reduce the people (de Grooth etc., above) and rabbit (Okamoto etc., LDL cholesterol above).In addition, S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester inhibition rabbit (Okamoto etc., atherosclerosis development above).S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method of 2-methyl-prop thioester and preparation and this chemical compound of use is described in United States Patent (USP) 6,426, in 365.
Need to improve S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] bioavailability of 2-methyl-prop thioester activity form, to improve degree to the therapeutic effect of user.Also need such method, for example, a kind of use S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method of 2-methyl-prop thioester treatment cardiovascular disease, this method has improved the bioavailability of its activity form, thereby has improved the curative effect behind patient's oral administration.The invention provides such method and a kind of test kit that comprises pharmaceutical composition, prescription information and container, described pharmaceutical composition comprises S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl for the treatment of effective dose] 2-methyl-prop thioester and pharmaceutical carrier, wherein prescription information comprise offer the patient about administration medicine to improve the suggestion of bioavailability.From the description that the present invention provides therein, these and other benefit of the present invention, and other inventive features will be tangible.
Summary of the invention
The invention provides a kind of to accepting S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] patient of 2-methyl-prop thioester treatment improves S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method of the bioavailability of 2-methyl-prop thioester activity form, S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl wherein] 2-methyl-prop thioester is contained in the pharmaceutical composition, this method is included under the condition of food, to the medicine of described patient's oral administration treatment effective dose.Show the raising of activity form bioavailability by the raising of the maximal plasma concentration of activity form.
The present invention also provides a kind of raising S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method of 2-methyl-prop thioester activity form trap, described trap is that the measurement of concetration by the activity form that obtains in blood flow as time goes by in the patient of the medicine of receiving port oral dosage form obtains.This method comprises: having under the condition of food, to S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of described patient's oral administration treatment effective dose] 2-methyl-prop thioester.
The present invention also provides a kind of patient's of reduction the active method of cholesterol ester transfer protein (CETP).This method comprises: having under the condition of food, to S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of described patient's oral administration treatment effective dose] 2-methyl-prop thioester.
The present invention provides the method for a kind of treatment or prevention patient's cardiovascular disease in addition.This method comprises: having under the condition of food, to described patient's oral administration S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester.
In addition, the invention provides a kind of test kit that comprises pharmaceutical composition, prescription information and container, described pharmaceutical composition comprises S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl for the treatment of effective dose] 2-methyl-prop thioester and pharmaceutical carrier.Described prescription information comprise offer the patient about administration S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl is being arranged under the condition of food] suggestion of 2-methyl-prop thioester.
Description of drawings
Fig. 1 is having food or is not having under the condition of food, oral administration 900mg S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] among the Caucasia male patient of 2-methyl-prop thioester, S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl in 36 hours] linear graph of geometric average plasma concentration (μ g/mL) of 2-methyl-prop thioester activity form.
Fig. 2 is having food or is not having under the condition of food, oral administration 900mg S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] among the Caucasia male patient of 2-methyl-prop thioester, S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl in 36 hours] semilog diagram of geometric average plasma concentration (μ g/mL) of 2-methyl-prop thioester activity form.
Fig. 3 is having food or is not having under the condition of food, oral administration 900mg S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] among the Caucasia male patient of 2-methyl-prop thioester, the CETP activity is from the average change of datum line (before the administration) in 24 hours.
Fig. 4 is having under the condition of food, at oral administration 900mg S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] behind the 2-methyl-prop thioester, the S-[2-among the male patient of Caucasia in 24 hours ([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] curve chart of the active and mean plasma concentration of the average CETP of 2-methyl-prop thioester activity form.
Fig. 5 is not having under the condition of food, at oral administration 900mg S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] behind the 2-methyl-prop thioester, the S-[2-among the male patient of Caucasia in 24 hours ([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] curve chart of the active and mean plasma concentration of the average CETP of 2-methyl-prop thioester activity form.
The present invention relates to improve administration S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method and/or the treatment of the efficient of 2-methyl-prop thioester (being called Compound I herein) or prevent the method for some angiocardiopathy. These diseases include but not limited to: cardiovascular disease, coronary heart disease, coronary artery disease, Hypoalphalipoproteinemia (low-level HDL cholesterol), hypercholesterolemia and atherosclerosis. Can be included but not limited to by the other disease of the inventive method treatment or prevention: hyperlipidemia, hypertension, hypertriglyceridemia and hyperlipoprotememia.
The structural formula of Compound I is as follows:
The previous pharmacokinetic that do not carry out is with the effect of assessment food to the pharmacokinetics of Compound I activity form. Generally speaking, food has variable effect to the bioavilability of active agents. The interaction of medicine-food can cause reduction, delay or the raising of systemic drug utilization degree. For example referring to Welling, Clin.Pharmacokinet., 9 (5), 404-34 (1984).
Have been found that: to improve Compound I to the instructions of taking of this class patient's therapeutic efficiency, can be to patient's administration Compound I. Advantageously, having under the condition of food, during oral administration, Compound I is presented at the bioavilability of the increase of Compound I activity form among the patient.
Thereby, the invention provides the method for the bioavilability of Compound I activity form among a kind of patient of raising, the method is included under the condition of food, to the Compound I of patient's drug treatment effective dose.
As used herein, term " bioavailability " typically refers to absorption becomes obtainable speed and degree from the active component of pharmaceutical product or its activity form and at site of action.Referring to: U.S.Code of Federal Regulations, Title 21, Part 320.1 (2001 editions).For peroral dosage form, bioavailability relates to such process, by this process, by peroral dosage form for example tablet discharge active component, change into activity form (if active component also is not an activity form), and move to site of action, for example be absorbed in the body circulation.
Though do not wish to be subjected to the constraint of any particular theory, but supposition is in patient's body, Compound I hydrolysis in blood plasma, liver and/or small intestinal generates S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] mercaptan (being called Compound I I herein).Known low-molecular-weight thiol component (promptly, R-SH) as cysteine and glutathion, with high-molecular weight thiol component (that is, Prot-SH) as peptide and albumen (for example, enzyme and cell membrane), be present in the body as blended disulphide, described disulphide contain between molecule or in the molecule oxidation disulfide bond (S-S key) (for example referring to, Shimade etc., J.Chromatogr.B, 659,227 (1994)).Thereby, suppose that in patient's body Compound I I and low or high-molecular weight mercaptan conjugation obtain blended disulphide or obtain the dimer of Compound I I.Because these forms are to be in the oxidation-reduction balance each other by Compound I I, therefore, these all forms and Compound I I, jointly but be not exclusively, at the following activity form of thinking and being referred to as Compound I.What following route was described is hypothesis recited above.
Though the administration Compound I is a particularly preferred embodiment of the present invention, the present invention also pays close attention to other chemical compound that administration will produce the activity form of Compound I, i.e. other prodrug of Compound I activity form.For example, this prodrug can be to contain the different chemical compounds of dredging basic protecting group, but it still causes the activity form (for example, Compound I I) of (that is, in the body) formation Compound I in patient's body.Term " dredge basic protecting group " be meant normally used thin basic protecting group (for example, as Wolman, The Chemistry of the Thiol Group, D.Patai, editor., Wiley-Interscience, NewYork, 1974 is described).Can use can dissociated in vivo organic residue with being not particularly limited.The case description of Shi Yi thin basic protecting group is in United States Patent (USP) 6,426 especially, in 365.The present invention also pays close attention to Compound I ' administration of (wherein R ' the expression organic residue except that isopropyl), to obtain the activity form of Compound I.
Compound I '
In addition, compound III, IV and V (wherein R represents that organic residue and Prot represent peptide or albumen) are considered to be in poised state in vivo with Compound I I, can directly deliver medicine to the patient similarly.
As used herein, term " having under the condition of food " be restricted to usually between be illustrated in before the administration Compound I about 1 hour to the administration Compound I about 2 hour during the take food condition of food.Preferably, food is food, and its volume is enough big and fat content is abundant, makes it does not dissolved apace and absorb under one's belt.More preferably, food is meals, as breakfast, lunch or dinner.
Advantageously, Compound I is in any time administration that has under the condition of food at a day.During between about 1 hour before the administration Compound I to the administration Compound I about 2 hour, the food of can taking food at any time.For example, food can be before the administration Compound I about 1 hour, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes or take food in about 5 minutes time limit.Similarly, food can be after the administration Compound I about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours or take food in about 2 hours time limit.More preferably, to patient's administration Compound I be on the feed after the food immediately (that is, after the feed food within about 1 minute) carried out in about 1 hour to the feed foods at most.It is desirable to, with feed food administration Compound I simultaneously basically.Term " do not have under the condition of food " or " fasting " be restricted between be illustrated in before the administration Compound I about 1 hour to the administration Compound I about 2 hour during the do not take food condition of food.
Term " patient " is meant " human patients ".
Method of the present invention relates to the Compound I of drug treatment effective dose or the prodrug of Compound I activity form, as the prodrug of Compound I I.Usually, the optimal dose of the Compound I of patient's drug treatment effective dose is about 100mg extremely about 1800mg/ days.Appropriate dosage was preferably about 300mg to about 900mg/ days.Preferred dosage is about 600mg/ days
If desired, effectively the Compound I of daily dose can be in one day with suitable interval as two parts, three parts, four parts, five parts, six parts or more parts of sub-doses, optional form administration respectively with unit dose.Each sub-doses contains the Compound I for the treatment of effective dose.The method according to this invention can have under the condition of food, inferior more than a day administration Compound I, or alternatively, once a day.When time administration more than a day, each single dosage contains the Compound I for the treatment of effective dose.In embodiment preferred of the present invention, Compound I is having condition next day single administration of food.As used herein, term " unit dosage forms " is restricted to expression wherein to the form of patient's administration Compound I.Particularly, unit dosage forms can be for example pill, capsule or tablet.Preferably, unit dosage forms is a tablet.The typical amount that can be used for the Compound I of unit dosage forms of the present invention is extremely about 1800mg of about 100mg, is preferably about 100mg to about 900mg (for example, about 100mg is to about 300mg).In embodiment preferred of the present invention, unit dosage forms comprises the Compound I of about 300mg and is tablet form.Preferably, give two or three tablets of patient's administration every day, and every tablet comprises about 300mg Compound I (that is, the accumulated dose of every day is respectively about 600mg or about 900mg).
Can prove of the raising of Compound I activity form by any suitable mode to patient's bioavailability of accepting Compound I treatment.Ideally, with do not having under the condition of food the administration Compound I compare, having under the condition of food, the oral administration Compound I causes the raising of Compound I activity form bioavailability, as by the maximal plasma concentration of Compound I activity form increase proved.
It is desirable to, Compound I is offered the patient with prescription information in container, described prescription information is informed the patient: the oral administration Compound I is being arranged under the condition of food, and also it is desirable to, explain and do like this and will improve the bioavailability of Compound I activity form.Preferably, Compound I is offered the patient with prescription information in container, described prescription information is informed the patient: compare with the described medicine of administration under fasted conditions, having under the condition of food, the dosage of the Compound I of administration in pharmaceutical composition causes the raising of Compound I activity form trap, as by the Compound I activity form maximal plasma concentration reflected.
The present invention also provides a kind of method that improves Compound I activity form trap, and described trap is that the measurement of concetration by the activity form that obtains in blood flow as time goes by in the patient of its therapeutic effect of needs obtains.This method comprises: having under the condition of food, to the Compound I of the treatment effective dose of described patient's oral administration in pharmaceutical composition.The concentration of activity form is that plasma concentration (μ g/mL) as the Compound I activity form measures in the blood flow.The pharmacokinetic parameter that relates in determining plasma concentration comprises: observed maximal plasma concentration (C
Max), extremely at last can quantitative concentration (AUC from the plasma concentration time graph (AUC) of zero-time
0-tz) under area and the zero-time to infinitely-great AUC (AUC
0-∞).When this medicine of administration is compared under fasted conditions, having under the condition of food, patient's administration Compound I is improved the bioavailability of activity form, as (and ideally, all) pharmacokinetic parameter value added recited above is measured obtains by one or more.
The present invention also provides a kind of patient's of reduction the active method of cholesterol ester transfer protein (CETP), and this method comprises: having under the condition of food, to the Compound I of patient's oral administration treatment effective dose.With under fasted conditions, compare, having under the condition of food, the active reduction of CETP is bigger after the administration Compound I.
In addition, the invention provides the method for a kind of treatment or prevention patient's cardiovascular disease, this method comprises patient's administration Compound I, is included under the condition of food, to the Compound I of patient's oral administration treatment effective dose.These diseases include but not limited to: cardiovascular diseases, coronary heart disease, coronary artery disease, Hypoalphalipoproteinemia (low-level HDL cholesterol), hypercholesterolemia and atherosclerosis.Can include but not limited to by the other disease of the inventive method treatment or prevention: hyperlipemia, hypertension, hypertriglyceridemia and hyperlipoproteinemia.
Can be with the method administration Compound I of any routine, with the treatment patient.Though can be with Compound I as thick chemicals administration, preferably as the pharmaceutical composition administration.This pharmaceutical composition inclusion compound I and one or more pharmaceutical carriers or excipient, and optional other healing potion and/or component.Carrier or excipient must be with other component compatibility be acceptable on not to the deleterious meaning of its receptor.Being used for the carrier of oral administration or the example of excipient comprises: corn starch, lactose, magnesium stearate, Talcum, microcrystalline Cellulose, stearic acid, polyvinylpyrrolidone, crospolyvinylpyrrolidone, calcium hydrogen phosphate, sodium starch glycollate, hydroxypropyl cellulose are (for example, the low hydroxypropyl cellulose that replaces), hydroxypropyl emthylcellulose (for example, hydroxypropyl methylcellulose 2910) and sodium lauryl sulphate.
Pharmaceutical composition can be by the preparation of any suitable method, as those methods known in the pharmaceutics field, and for example at Gennaro etc., Remington ' s Pharmaceutical Sciences (18
ThVersion ..MackPublishing Co., 1990), those methods described in the part 8:Pharmaceutical Preparations and theirManufacture particularly.Such method comprises makes Compound I and carrier or excipient, and the optional bonded step of one or more auxiliary elements.This auxiliary element comprises those that use always in the art, as, filler, binding agent, diluent, disintegrating agent, lubricant, coloring agent, fumet and wetting agent.
Can be in the predetermined time limit, controlled, slow release is provided or continues to discharge the pharmaceutical composition of Compound I.This is controlled, slow release or the treatment chemical compound that continues to discharge can provide the concentration that remains on the Compound I activity form in patient's blood flow than conventional formulation for more time.This pharmaceutical composition comprises: coated tablet, pill and capsule, and the dispersion of treatment chemical compound in medium, described medium is insoluble to physiological fluid, or the release of wherein treating chemical compound is by machinery, chemistry or enzymatic activity after decomposing at pharmaceutical composition.
Pharmaceutical composition in the context of the invention can for example be the form of pill, capsule or tablet, each contains the Compound I of scheduled volume, and coating preferably, so that swallow easily, its form is powder or granule, or its form is solution or suspension.Preferably, pharmaceutical composition is a tablet form, the tablet ingredients of utilizing and describing among described tablet inclusion compound I (or prodrug of Compound I activity form) and the embodiment herein.For oral administration, fine powder or granule can comprise diluent, dispersant and/or surfactant, and can be with the sachet of for example water or syrup, capsule or drying regime, or the non-aqueous solution or the suspension form that wherein can comprise suspending agent exist.Can also there be component in the pharmaceutical composition, as sweeting agent, fumet, antiseptic (for example, antibiotic antiseptic), buffer agent, solvent and their mixture.A kind of component of preparation can rise more than a kind of function.For example, Shi Yi buffer agent also can be used as fumet and as sweeting agent.
Suitable sweeting agent for example comprises: saccharin sodium, sucrose and mannitol.Can choose the mixture that uses two or more sweeting agents wantonly.The typical amount of sweeting agent or its mixture is that about 0.001 weight % of whole compositionss is to about 70 weight %.Suitable fumet may reside in the pharmaceutical composition, so that cherry flavor, Cotton Gossypii flavour of candy or other suitable local flavor to be provided, makes pharmaceutical composition easier for patient's picked-up.The typical amount of fumet or its mixture is that about 0.0001 weight % of whole compositionss is to about 5 weight %.
Suitable antiseptic comprises for example methyl hydroxybenzoate, propyl hydroxybenzoate, sodium benzoate and benzalkonium chloride.Can choose the mixture that uses two or more antiseptic wantonly.The typical amount of antiseptic or its mixture is that about 0.0001 weight % of whole compositionss is to about 2 weight %.
Suitable buffer agent comprises for example citric acid, sodium citrate, phosphoric acid, potassium phosphate and various other acid and salt.Can choose the mixture that uses two or more buffer agents wantonly.The typical amount of buffer agent or its mixture is that about 0.001 weight % of whole compositionss is to about 4 weight %.
The suitable solvent that is used for liquid solution or suspension for example comprises: Sorbitol (sorbital), glycerol, propylene glycol and water.Can choose the mixture that uses two or more solvents wantonly.The typical amount of solvent or dicyandiamide solution is that about 1 weight % of whole compositionss is to about 90 weight %.
The oral delivery method is subjected to the chemistry that applied by health and the restriction of physical barrier usually, contacts as the pH that changes in intestines and stomach, with enzyme and the impermeability of the intestines and stomach film.The oral administration of pharmaceutical composition can also comprise the co-administered of adjuvant.For example, non-ionic surface active agent such as polyoxyethylene oleyl ether and n-hexadecyl polyvinylether can improve the permeability of intestinal wall with the pharmaceutical composition administration or in conjunction with wherein administration with the artificially.Can be with enzyme inhibitor with the pharmaceutical composition administration or in conjunction with wherein administration.
In addition, the invention provides a kind of test kit that comprises pharmaceutical composition, prescription information and container, described pharmaceutical composition comprises the Compound I and the pharmaceutical carrier for the treatment of effective dose.Described prescription information can be the prescription information of discussing in addition according to method of the present invention and/or place like this.Described prescription information preferably include offer the patient about having under the condition of food, the suggestion of administration Compound I particularly improves the bioavailability of Compound I activity form.
The following examples further illustrate the present invention, still, not will be understood that it is limitation of the scope of the invention by any way certainly.
Embodiment 1
In the research of design, differentiate the influence of food, relatively food to be arranged and do not having under the condition of food, to the bioavailability of Caucasia male volunteers oral administration 900mg Compound I to patient's Compound I absorption.
To this research, interim in each two treatments, per 6 experimenters accept Compound I under the dosage level of 900mg, once (standard after the meal early) are being arranged under the condition of food and once at fasting state, between each treatment phase minimum 7 days.Be considered at interval suit in 7 days between the treatment for the effect of eliminating in any experimenter of carrying.
The experimenter accepts the Compound I of 900mg by the tablet of 3 every 300mg of administration.The program of the manufacturing tablet of use standard prepares the not white tablet of coating.Tablet comprises: the Compound I of 300mg, the hydroxypropyl methylcellulose 2910 of 18mg as the magnesium stearate of the Talcum of binding agent, 18mg and 1.2mg as lubricant and 119.8mg crospolyvinylpyrrolidone and the low hydroxypropyl cellulose that replaces of 90mg as disintegrating agent.
When standing, treat with the clothes administration of the 150mL mouth of a river.Behind dosed administration, do not allow to be subjected to reagent to press down and crouched 2 hours, only Yan Jiu program.
During each treatment, be subjected to reagent to every, with similar time administration dosage.Dosed administration starts from about 08:30.The one day 22:00 (the-1 day) before dosed administration up to breakfast of the 1st day (under the state on the feed (promptly, have under the condition of food) accept the experimenter of Compound I) or first day lunch (for the experimenter's Compound I under the fasting state), and the evening of back before the research during carrying out the laboratory safety assessment one day after, forbid all experimenters take food food and fluid (except the water).Drinking water at any time during studying just when not allowing to take food fluid, cannot drink water in 2 hours behind dosed administration.
Under the state during to experimenter's administration Compound I, they accepted breakfast of standard in 45 minutes in the dosed administration precontract on the feed.In 15 minute time limit, have meal with stable speed, to finish dining in preceding 30 minutes at dosed administration.Standard breakfast is made up of following:
The 200mL orange juice
Two parcel cereals (about 60g)
Two whole wheat zwiebacks
The 10g low fat smears thing (parcel)
20g fruit jam (bag)
242mL whole milk (about 250g)
Total energy content: 711Kcal
Total lipid content: 15.72g (total calorie of 19.9%)
Total protein: 20.82g (total calorie of 11.7%)
Before being about to administration and the following time after the administration: after the administration 1,2,4,6,7,10,12,24, and 36 hours, gather the blood sample that pharmacokinetic analysis is used immediately.
For two aspects (feed thing and fasted conditions), the pharmacokinetic parameter that assessment is following:
t
MaxThe time of maximum observation plasma concentration;
C
MaxMaximum observation plasma concentration;
t
1/2The half-life of Compound I activity form plasma concentration;
AUC
0-tzBut from the zero-time to the end quantitative concentrations (AUC (
0-tz)) plasma concentration-time
Area under the half interval contour (AUC); With
AUC
0-∞Zero-time is to infinitely-great AUC
By analyzing, pharmacokinetic parameter is carried out logarithmic transformation, and use SAS Least SquareMeans to assess derived from experimenter, treatment and cycles three approach variable analysis (ANOVA) fitting effect.Treatment relatively is to carry out for the difference of the logarithm SAS Least Square Means between the parameter of corresponding treatment and 95% confidence interval (CIs) of this difference by calculating.Difference and difference CIs are transformed into original form are used for report.
The plasma concentration of Compound I activity form is by following test determination.Isolate plasma sample on one's body from patient with the Compound I treatment.(Wako PureChemical Industries Ltd.) handles, and makes the Compound I activity form in the blood plasma change into mercaptan form (being Compound I I) with sodium hydroxide with plasma sample.Then (Wako PureChemical Industries Ltd.) handles, with the oxidation (be about to mercapto and remain on reducing condition) that prevents mercapto with dithiothreitol, DTT (DTT) with plasma sample.(Wako Pure Chemical Industries Ltd.) to stablize mercaptan form (being Compound I I), it is believed that NEM seals free sulfhydryl groups by deriving to the NEM-addition product to add N-ethyl maleimide (NEM).Use high performance liquid chromatography (HPLC) analytic sample then.At last, the HPLC analysis result and the known standard of plasma sample compared, to determine the plasma concentration of Compound I activity form.The standard of concentration known prepares basically as mentioned above, and difference is never with separation of human blood plasma on the person of Compound I processing.Compound I combination with these " blank plasma " samples and dose known amounts.
The blood plasma pharmacokinetic parameter of Compound I activity form, AUC
0-∞(μ gh/mL), AUC
0-tz(μ gh/mL), C
Max(μ g/mL), t
1/2(h) and t
Max(h) average result of the test is summarized in the table 1.
Table 1
The blood plasma pharmacokinetic parameter of [2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester activity form
| The treatment draft | Ratio (feed: fasting) | ||
| Parameter | Fasting | Feed | |
| AUC(0-t z) * (μg h/mL) | 6.21 (46.9) | 10.2 (19.0) | 1.65 |
| AUC(0-∞) * (μg h/mL) | 7.97 (46.7) | 12.5 (17.4) | 1.57 |
| C max * (μg/mL) | 0.423 (37.1) | 0.955 (26.1) | 2.26 |
| t max(h) + | 5.00 (2.00-6.00) | 4.00 (2.00-6.00) | NA |
| T 1/2(h) | 16.5 (14.1-22.4) | 15.4 (12.6-18.6) | 0.935 |
*=geometric average (variable % geometrical factor)
+=intermediate value (minimum-maximum)
NA=is inapplicable
=harmonic-mean (minimum-maximum)
The absorption of Compound I activity form is slow relatively, between 4 to 5 hours after wherein maximum observes the time of plasma concentration occur in the Compound I administration.As being apparent that from table 1, food is being arranged and do not having under the condition of food, after the administration Compound I, the time of maximum observation plasma concentration is similar.In addition, food is being arranged and do not having under the condition of food, determining that behind drug administration the half-life of Compound I activity form is similar.
But several pharmacokinetic parameters are subjected in the influence that administration Compound I under the condition of food is arranged.These comprise: AUC
0-tz, AUC
0-∞And C
Max, when comparing, high by 65% respectively when the administration Compound I is arranged under the food condition, 57% and 126% with administration Compound I under the fasting state.When the geometric average plasma concentration of Compound I activity form was plotted in Fig. 1 neutralization and is plotted among Fig. 2 with the semilog form with linear forms, these raisings were remarkably tangible.
When administration medicine is compared under fasted conditions, when under the condition that food is being arranged during the administration Compound I the observed raising of pharmacokinetic parameter show the raising of the bioavailability of pharmaceutically active form.
Embodiment 2
In the research of design, differentiate the influence that food absorbs the Compound I activity form in the male patient of Caucasia, relatively food to be arranged and do not having under the condition of food, the CETP activity after the oral administration 900mg Compound I.
Administration, dosage and sampling schedule are substantially similar to those described in the embodiment 1.
Determine that the active program of CETP is substantially similar in Tollefson etc., Methods Enzymol., 129,797-816 (1986) and Kato etc., J.Biol.Chem., 264, the program described in the 4082-4087 (1989).
Measure the active variation that reaches from datum line (before the administration) of CETP, and measurement result is summarized in the table 2 as the variation percentage ratio from datum line.The mean change from datum line (administration before) of CETP activity along with the time is given in the curve chart of Fig. 3.
Average (S.D.) from datum line (before the administration) in the table 2-CETP activity changes
| The treatment draft | Variation percentage ratio (standard deviation) before the administration | |||||||
| Before the administration | 1h | 2h | 4h | 6h | 8h | 24h | Research back (all experimenters) | |
| Feed | 96 (17.0) | -1 (2.3) | -16 (13.2) | -44 (14.0) | -59 (11.1) | -58 (11.1) | -34 (7.5) | 96 (17.4) |
| Fasting | 91 (16.0) | 1 (2.2) | 2 (2.4) | -4 (2.2) | -10 (3.1) | -15 (4.7) | -10 (3.8) | |
When under the condition that is being with or without food during the administration Compound I, observe the active significant difference of CETP.Compare with fasting treatment draft, treat on the feed in the draft, the active inhibition of CETP is more remarkable.For example, after the administration between 4 to 24 hours, compare with fasting state, the CETP activity under the feed condition has significant reduction.The active reduction of this CETP shows: when comparing with administration medicine under the condition that does not have food, the bioavailability of pharmaceutically active form is improved during administration under food condition is arranged.
The relation that the plasma concentration of Compound I activity form and CETP are active on the feed and under the fasting state between suppressing is respectively by the curve chart diagram of Figure 4 and 5.Along with the plasma concentration of Compound I activity form increases, the inhibition effect of CETP is also increased (that is, CETP is active reduces).
Embodiment 3
With embodiment 2 described similar researchs in, in the research of design, differentiate the influence that food absorbs the Compound I activity form in Japanese male patient, relatively food to be arranged and do not having under the condition of food, the relative CETP activity after the oral administration 600mg Compound I.
Administration, those described in dosage and sampling schedule and embodiment 1 and 2 are suitable.But, having and do not having under the situation of food, patient's administration 600mg (rather than 900mg) Compound I.To two tablets of tablets of patient's administration, every 300mg.According to embodiment 1 described preparation tablet.
Measure relative CETP activity (being calculated as the active percentage ratio of benchmark CETP) and standard deviation (SD), and the data that obtain are summarized in the table 3.
The relative CETP activity of table 3-
| The treatment draft | With respect to the CETP activity (standard deviation) before the administration | |||||||
| Before the administration | 1h | 2h | 4h | 6h | 8h | 24h | Research back (all experimenters) | |
| Feed | 100 (0.0) | 100.4 (1.9) | 87.8 (9.2) | 52.6 (13.4) | 37.6 (6.6) | 39.1 (8.3) | 65.5 (5.7) | 102.9 (7.3) |
| Fasting | 100 (0.0) | 102.1 (3.6) | 99.6 (2.1) | 96.5 (3.1) | 89.5 (2.0) | 87.8 (4.6) | 92.6 (3.0) | 100.4 (2.8) |
When having and not having under the condition of food the administration Compound I, observe the significant difference of CETP relative activity, this with embodiment 2 in the result that discusses be consistent.Compare with fasting treatment draft, treat in the draft more remarkable on the feed the active inhibition of CETP.For example, after the administration between 4 to 24 hours, with respect to fasting state, the CETP under the feed condition is active significantly to descend.Particularly, having under the condition of food, reaching its peak value, and had CETP activity in 6 hours that the CETP after the administration Compound I is active after being suppressed at administration with respect to benchmark 37.6%.On the contrary, do not having under the condition of food, reaching its peak value, and had CETP activity in 8 hours that the CETP after the administration Compound I is active after being suppressed at administration with respect to benchmark 87.8%.This under the condition of food is arranged the active reduction of relative CETP after the administration Compound I show: compare the raising of pharmaceutically active form bioavailability during administration under food condition is arranged with administration medicine under the condition that does not have food.
Embodiment 4
With embodiment 1 described similar research in, in the research of design, differentiate the influence that food absorbs the Compound I activity form among the patient, relatively food to be arranged and do not having under the condition of food, to the bioavailability of Japanese male volunteers oral administration 600mg Compound I.
Administration, those described in dosage and sampling schedule and the embodiment 1 are suitable.But, having and do not having under the situation of food, patient's administration 600mg (rather than 900mg) S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] and 2-methyl-prop thioester.To two tablets of tablets of patient's administration, every 300mg.According to embodiment 1 described preparation tablet.
As viewed among the embodiment 1, pharmacokinetic parameter is as maximum observation plasma concentration (C
Max) and from the area (AUC of zero-time to infinitely-great plasma concentration-time graph
0-∞) be subjected in the influence that administration Compound I under the food condition is arranged.Under food condition is being arranged during administration, the C after the administration 600mg Compound I
Max(on average) value is 1.029 μ g/mL, and only is 0.316 μ g/mL during administration under not having the condition of food.Under food condition is being arranged during administration, the AUC after the administration 600mg Compound I
0-∞(on average) value is 10.458 μ g h/mL, and only is 5.395 μ g h/mL during administration under not having the condition of food.Therefore, and compare under the condition that does not have food, under food condition is arranged during to patient's administration medicine, C
MaxAnd AUC
0-∞Be respectively about 3 times and 2 times high.
When under the condition that food is being arranged during the administration Compound I raising of observed pharmacokinetic parameter show: when administration was being arranged under the condition of food, during as administration after dining, the pharmaceutically active form is easier to be absorbed.Thereby, when comparing, there is being administration Compound I under the condition of food to cause the raising of the bioavailability of this pharmaceutically active form with administration medicine under fasted conditions.
All lists of references of wherein quoting comprise publication, patent application and patent, are combined in this by reference, reach as each piece list of references to be combined in this separately and particularly by reference and as its same degree of listing in full.
Context of the present invention (particularly in the content of accompanying Claim book) is being described, use term " ", " a kind of " and " described " and similarly explain to be intended to comprise odd number and plural number, unless explanation is wherein arranged in addition or clearly represent opposite meaning by content.Term " comprises ", " having ", " comprising " and " containing " are intended to be expressed as open term (that is, expression " including but not limited to "), unless explanation is wherein arranged in addition.Wherein quoting of numerical range only wanted as relating to the method for writing a Chinese character in simplified form of each the independent numerical value in this scope individually, unless explanation is wherein arranged in addition, and each independent numerical value is combined in the description, as quoting separately therein.Wherein said method can be carried out with any suitable order, unless explanation is wherein arranged in addition, or clearly represent opposite meaning by content.Any and all embodiment that wherein provide, or exemplary language (for example, " as ") only want to illustrate better the present invention and scope of the present invention is not applied restriction, unless opinion is arranged in addition.Language in description should not be considered to the key element of conduct to any non-requirement of the essence of the present invention's practice.
Wherein describe the preferred embodiments of the invention, comprised the known enforcement of inventor best mode of the present invention.Those of ordinary skill in the art is by the explanation above reading, and the variant of those preferred embodiments can be obvious.The inventor expects that the technical staff adopts these variants when suitable, and except wherein specifically described those, the inventor wants the present invention to want real feasible.Thereby, present invention resides in all variants of the theme of being quoted in this additional claim and be equal to replacement, as being allowed by applicable law.And the combination of key element recited above in its all possible variant is also included among the present invention, unless explanation is wherein arranged in addition, or clearly represent opposite meaning by content.
Claims (53)
1. one kind to accepting S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] patient of 2-methyl-prop thioester treatment improves S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method of the bioavailability of 2-methyl-prop thioester activity form, this method is included under the condition of food, to S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of the treatment effective dose of described patient's oral administration in pharmaceutical composition] 2-methyl-prop thioester.
2. the described method of claim 1, wherein treating effective dose is that about 100mg is to about 1800mg.
3. the described method of claim 2, wherein treating effective dose is that about 300mg is to about 900mg.
4. any one described method of claim 1-3 wherein occurred in before the feed food about 1 hour to the food of taking food about 2 hours to patient's administration.
5. the described method of claim 4 is wherein carried out with feed food basically simultaneously to patient's administration.
6. the described method of claim 4, wherein on the feed after the food to the food at most on the feed about 1 hour immediately, to patient's administration.
7. any one described method of claim 1-6, wherein said pharmaceutical composition is the tablet of unit dosage forms.
8. the described method of claim 7, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 100mg to about 1800mg] 2-methyl-prop thioester.
9. the described method of claim 8, wherein said tablet comprises S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 300mg] 2-methyl-prop thioester, and described treatment effective dose is that about 300mg is to about 900mg.
10. any one described method of claim 1-9, wherein with do not having administration S-[2-under the condition of food ([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester compares, described administration causes S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] increase of 2-methyl-prop thioester activity form maximal plasma concentration.
11. any one described method of claim 1-10, wherein said pharmaceutical composition offers the patient with prescription information in container, and described prescription information is informed the patient: the described pharmaceutical composition of administration is being arranged under the condition of food.
12. the method for claim 11, wherein prescription information is also informed the patient: with administration S-[2-under the fasted conditions ([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] 2-methyl-prop thioester compares, S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of administration in pharmaceutical composition arranged under the condition of food] 2-methyl-prop thioester causes S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] increase of the maximal plasma concentration of 2-methyl-prop thioester activity form.
13. the method for claim 11 or 12, wherein said prescription information is also informed the patient: before the food about 1 hour to the food of taking food about 2 hours on the feed, and the described pharmaceutical composition of administration.
14. the method for claim 13, described prescription information is also informed the patient: basically on the feed food the time, and the described pharmaceutical composition of administration.
15. the method for claim 13, described prescription information is also informed the patient: after the food to the food at most on the feed about 1 hour immediately on the feed, and the described pharmaceutical composition of administration.
16. one kind is improved S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl] method of 2-methyl-prop thioester activity form trap, described trap is that the measurement of concetration by the activity form that obtains in blood flow as time goes by in the patient of its therapeutic effect of needs obtains, this method comprises: having under the condition of food, to S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of the treatment effective dose of described patient's oral administration in pharmaceutical composition] 2-methyl-prop thioester.
17. the described method of claim 16, wherein treating effective dose is that about 100mg is to about 1800mg.
18. the described method of claim 17, wherein treating effective dose is that about 300mg is to about 900mg.
19. any one described method of claim 16-18 wherein occurs in before the feed food about 1 hour to the food of taking food about 2 hours to patient's administration.
20. the described method of claim 19 is wherein carried out with feed food basically simultaneously to patient's administration.
21. the described method of claim 19, wherein on the feed after the food to the food at most on the feed about 1 hour immediately, to patient's administration.
22. any one described method of claim 16-21, wherein said pharmaceutical composition is the tablet of unit dosage forms.
23. the described method of claim 22, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 100mg to about 1800mg] 2-methyl-prop thioester.
24. the described method of claim 23, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 300mg] 2-methyl-prop thioester, and described treatment effective dose is that about 300mg is to about 900mg.
25. active method of cholesterol ester transfer protein (CETP) that reduces among the patient, this method comprises: having under the condition of food, to S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of the treatment effective dose of described patient's oral administration in pharmaceutical composition] 2-methyl-prop thioester.
26. the described method of claim 25, wherein treating effective dose is that about 100mg is to about 1800mg.
27. the described method of claim 26, wherein treating effective dose is that about 300mg is to about 900mg.
28. any one described method of claim 25-27 wherein occurs in before the feed food about 1 hour to the food of taking food about 2 hours to patient's administration.
29. the described method of claim 28 is wherein carried out with feed food basically simultaneously to patient's administration.
30. the described method of claim 28, wherein on the feed after the food to the food at most on the feed about 1 hour immediately, to patient's administration.
31. any one described method of claim 25-30, wherein said pharmaceutical composition is the tablet of unit dosage forms.
32. the described method of claim 31, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 100mg to about 1800mg] 2-methyl-prop thioester.
33. the described method of claim 32, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 300mg] 2-methyl-prop thioester, and described treatment effective dose is that about 300mg is to about 900mg.
34. method for the treatment of or preventing patient's cardiovascular disease, this method comprises the phenyl to patient's administration S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino)] 2-methyl-prop thioester, described method is included under the condition of food, to S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of the treatment effective dose of described patient's oral administration in pharmaceutical composition] 2-methyl-prop thioester.
35. the described method of claim 34, wherein said cardiovascular disease is selected from the group of being made up of cardiovascular diseases, coronary heart disease, coronary artery disease, Hypoalphalipoproteinemia, hypercholesterolemia and atherosclerosis.
36. claim 34 or 35 described methods, wherein treating effective dose is that about 100mg is to about 1800mg.
37. the described method of claim 36, wherein treating effective dose is that about 300mg is to about 900mg.
38. any one described method of claim 34-37 wherein occurs in before the feed food about 1 hour to the food of taking food about 2 hours to patient's administration.
39. the described method of claim 38 is wherein carried out with feed food basically simultaneously to patient's administration.
40. the described method of claim 38, wherein on the feed after the food to the food at most on the feed about 1 hour immediately, to patient's administration.
41. any one described method of claim 34-40, wherein said pharmaceutical composition is the tablet of unit dosage forms.
42. the described method of claim 41, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 100mg to about 1800mg] 2-methyl-prop thioester.
43. the described method of claim 42, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 300mg] 2-methyl-prop thioester, and described treatment effective dose is that about 300mg is to about 900mg.
44. test kit that comprises pharmaceutical composition, prescription information and container, described pharmaceutical composition comprises S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl for the treatment of effective dose] 2-methyl-prop thioester and pharmaceutical carrier, wherein said prescription information comprise offer the patient about S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of administration in pharmaceutical composition arranged under the condition of food] suggestion of 2-methyl-prop thioester.
45. the described test kit of claim 44, wherein said prescription information shows: administration S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl is being arranged under the condition of food] 2-methyl-prop thioester raising bioavailability.
46. claim 44 or 45 described test kits, wherein treating effective dose is that about 100mg is to about 1800mg.
47. the described test kit of claim 46, wherein treating effective dose is that about 300mg is to about 900mg.
48. any one described test kit of claim 44-47 wherein occurs in before the feed food about 1 hour to the food of taking food about 2 hours to patient's administration.
49. the described test kit of claim 48 wherein carries out with feed food basically simultaneously to patient's administration.
50. the described test kit of claim 48, wherein on the feed after the food to the present at most feed foods about 1 hour immediately, to patient's administration.
51. any one described test kit of claim 44-50, wherein said pharmaceutical composition is the tablet of unit dosage forms.
52. the described test kit of claim 51, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 100mg to about 1800mg] 2-methyl-prop thioester.
53. the described test kit of claim 52, wherein said tablet comprise S-[2-([[1-(2-ethyl-butyl) cyclohexyl] carbonyl] amino) phenyl of about 300mg] 2-methyl-prop thioester, and described treatment effective dose is that about 300mg is to about 900mg.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45529303P | 2003-03-17 | 2003-03-17 | |
| US60/455,293 | 2003-03-17 | ||
| US60/460,521 | 2003-04-04 | ||
| US60/477,202 | 2003-06-10 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710096744 Division CN101036636A (en) | 2003-03-17 | 2004-03-17 | Method for increasing the oral bioavailability of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1761463A true CN1761463A (en) | 2006-04-19 |
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ID=36707296
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710096744 Pending CN101036636A (en) | 2003-03-17 | 2004-03-17 | Method for increasing the oral bioavailability of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate |
| CN200480007445.7A Expired - Fee Related CN1777419B (en) | 2003-03-17 | 2004-03-17 | Pharmaceutical compositions of CETP inhibitors |
| CN 200480007444 Pending CN1761463A (en) | 2003-03-17 | 2004-03-17 | Method for increasing the oral bioavailability of s-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710096744 Pending CN101036636A (en) | 2003-03-17 | 2004-03-17 | Method for increasing the oral bioavailability of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]-2-methylpropanethioate |
| CN200480007445.7A Expired - Fee Related CN1777419B (en) | 2003-03-17 | 2004-03-17 | Pharmaceutical compositions of CETP inhibitors |
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| ZA (2) | ZA200508159B (en) |
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| CN102471254A (en) * | 2009-07-01 | 2012-05-23 | 霍夫曼-拉罗奇有限公司 | Preparation and crystallisation of s-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]-2-methylthiopropionate |
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| CA2724048A1 (en) * | 2008-05-14 | 2009-11-19 | Agriculture Victoria Services Pty Ltd. | Oral preparation |
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| JP2894445B2 (en) * | 1997-02-12 | 1999-05-24 | 日本たばこ産業株式会社 | Compounds effective as CETP activity inhibitors |
| US6147089A (en) * | 1998-09-17 | 2000-11-14 | Pfizer Inc. | Annulated 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines |
| US6197786B1 (en) * | 1998-09-17 | 2001-03-06 | Pfizer Inc | 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines |
| US7115279B2 (en) * | 2000-08-03 | 2006-10-03 | Curatolo William J | Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors |
| EP1453544A2 (en) * | 2001-06-21 | 2004-09-08 | Pfizer Products Inc. | Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors |
| EP1269994A3 (en) * | 2001-06-22 | 2003-02-12 | Pfizer Products Inc. | Pharmaceutical compositions comprising drug and concentration-enhancing polymers |
| ES2333645T3 (en) * | 2001-06-22 | 2010-02-25 | Bend Research, Inc. | PHARMACEUTICAL COMPOSITIONS OF DISPERSIONS OF MEDICINES AND NEUTRAL POLYMERS. |
| AR038375A1 (en) * | 2002-02-01 | 2005-01-12 | Pfizer Prod Inc | PHARMACEUTICAL COMPOSITIONS OF INHIBITORS OF THE PROTEIN OF TRANSFER OF ESTERES DE COLESTERILO |
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- 2004-03-17 CN CN 200710096744 patent/CN101036636A/en active Pending
- 2004-03-17 CN CN200480007445.7A patent/CN1777419B/en not_active Expired - Fee Related
- 2004-03-17 ZA ZA200508159A patent/ZA200508159B/en unknown
- 2004-03-17 CN CN 200480007444 patent/CN1761463A/en active Pending
- 2004-03-17 ZA ZA200508160A patent/ZA200508160B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471254A (en) * | 2009-07-01 | 2012-05-23 | 霍夫曼-拉罗奇有限公司 | Preparation and crystallisation of s-[2-[1-(2-ethylbutyl)cyclohexylcarbonylamino]-phenyl]-2-methylthiopropionate |
| CN102471254B (en) * | 2009-07-01 | 2015-08-19 | 霍夫曼-拉罗奇有限公司 | The preparation of 2-methylpropanethioate S-[2-[1-(2-ethyl-butyl) cyclohexylcarbonylamino]-phenyl] ester and crystallization |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1777419A (en) | 2006-05-24 |
| CN1777419B (en) | 2010-04-28 |
| ZA200508159B (en) | 2007-03-28 |
| CN101036636A (en) | 2007-09-19 |
| ZA200508160B (en) | 2007-01-31 |
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