CN101336107A

CN101336107A - Methods for improving the pharmacokinetics of HIV integrase inhibitors

Info

Publication number: CN101336107A
Application number: CNA2006800520141A
Authority: CN
Inventors: B·P·卡尼; A·凯基; 川口功
Original assignee: Japan Tobacco Inc; Gilead Sciences Inc
Current assignee: Japan Tobacco Inc; Gilead Sciences Inc
Priority date: 2005-12-30
Filing date: 2006-12-29
Publication date: 2008-12-31
Also published as: ZA200806222B; UA101141C2; UA108605C2

Abstract

The invention provides methods for improving the pharmacokinetics of an HIV integrase inhibiting compound by administering food and/or ritonavir or a pharmaceutically acceptable salt thereof with the HIV integrase inhibitor.

Description

Improve the method for the pharmacokinetics of hiv integrase inhibitor

The priority of invention

The U.S. Provisional Patent Application 60/755,039 of the application's request December in 2005 submission on the 30th; 60/756,631 of submission on January 6th, 2006; With 60/763,901 the priority of submitting on February 1st, 2006.

Background technology

The retroviral infection that is called human immunodeficiency virus (HIV) continues to become serious health problem.The method that treatment HIV infects comprises the medicament that suppresses the essential viral enzyme activity of viral life cycle.

Ritonavir ((2S; 3S; 5S)-5-(N-(((N-methyl-N-((2-isopropyl-4-thiazolyl) methyl) amino)-carbonyl)-L-is valyl for N-) amino)-2-(N-((5-thiazolyl) methoxycarbonyl group) amino)-1; 6-diphenyl-3-hydroxyl hexane) be the hiv protease inhibitor, it can be synthetic by disclosed method in International Patent Application Publication No. WO 1994/14436 and the U.S. Patent number 5567823.As protease inhibitor, ritonavir can suppress human body HIV effectively to be infected.Also show ritonavir be relate to many drug metabolisms by way of the inhibitor of metabolic enzyme cytochrome P 450 monooxygenases, particularly 3A4 isotype (CYP 3A4).Referring to United States Patent (USP) the 5541206th, 5635523,5648497,5674882,5846987 and No. 5886036.

Protease inhibitor is by the cytochrome P 450 monooxygenases metabolism, thereby causes bad pharmacokinetics and need be than required more frequent and higher dosage.The medication combined pharmacokinetics that gives to improve medicine of the metabolic medicament of cytochrome P 450 monooxygenases and this class (for example half-life and reach the prolongation of peak plasma concentration required time, and blood drug level increases) will be suppressed.

Ritonavir can be used to improve the pharmacokinetics of metabolic some the hiv protease inhibitor of cytochrome P 450 monooxygenases.Referring to United States Patent (USP) the 6th, 037,157 and 6,703, No. 403.Give ritonavir and cytochrome P 450 monooxygenases jointly, especially the metabolic medicine of P450 3A4 isotype (isozyme) may cause the pharmacokinetics of this class medicine to be improved.More particularly, giving ritonavir jointly may cause the pharmacokinetics of hiv protease inhibitor to be improved with another kind of by the metabolic hiv protease inhibitor of cytochrome P 450 monooxygenases.In this class conjoint therapy, ritonavir can be used inferior therapeutic dose, promptly be lower than the dosage that free burial ground for the destitute intentionally suppresses virus replication and use, use but also can be as high as the dosage that is enough to the pharmacokinetics that suppresses cytochrome P 450 monooxygenases and strengthen other hiv protease inhibitor.

, comprise chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl with a series of 4-Oxoquinoline classes]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid is accredited as anti human immune deficiency virus (HIV) medicament.Referring to the serial number of submitting on November 20th, 2003 is 10/492,833 U.S. Patent application, and it is announced with U.S. Patent Application Publication No. 2005/0239819.Especially, with 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid is described as that the integrase protein of HIV is had the activity of inhibition.Document is the same.HIV belongs to retrovirus family and is the pathogen of acquired immune deficiency syndrome (AIDS) (AIDS).Therefore, reduce body inner virus load, AIDS can effectively be treated or prevent to the medical substance that viral genome or HIV duplicate.

At present, to can be used for improving integrase inhibitor, such as 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1, there are demand in the bioavailability of 4-dihydroquinoline-3-formic acid or absorption with medicament and the method that increases its therapeutical effect in the patient.Especially, to the pharmacokinetics of improving this class integrase inhibitor so that can have demand by medicament and the method that administration once a day obtains acceptable therapeutical effect.Also ubiquity can be used for treating the demand of the pharmacokinetics of the medicine (for example integrase inhibitor) that HIV infects to improvement.

Summary of the invention

The present invention relates to improve the method for the pharmacokinetics of 4-Oxoquinoline compounds.The invention further relates to the method for inhibition retrovirus integrase, particularly HIV inhibiting (HIV) intergrase and suppress the method that retroviral infection, particularly HIV infect.

The present invention provides in one embodiment and can be used for improving integrase inhibitor, such as 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1, the bioavailability of 4-dihydroquinoline-3-formic acid (chemical compound 1) or absorption are so that increase the medicament and the method for its therapeutical effect in the patient:

The present invention provides in one embodiment by giving described integrase inhibitor and ritonavir to the patient or its pharmaceutically acceptable salt improves integrase inhibitor, such as the method for the pharmacokinetics of chemical compound 1.

The present invention provides the method for the pharmacokinetics of improving hiv integrase inhibitor in one embodiment, it comprises that the patient to this inhibitor of needs gives ritonavir or its pharmaceutically acceptable salt of effective reinforcement amount, makes this inhibitor have than not adding more efficient drug dynamics under the ritonavir situation.

The present invention provides the method for the pharmacokinetics of the 4-Oxoquinoline compounds that is used for shown in the improvement formula (I) in another embodiment:

Wherein

Ring Cy is C _3-10Carbocylic radical or heterocyclic radical, each group is optional to be replaced by 1-5 substituent group that is selected from group A;

Described heterocyclic radical is to comprise the heteroatomic saturated or unsaturated heterocycle that at least one is selected from nitrogen, oxygen and sulfur;

Group A is a cyano group, phenyl, nitro, halogen, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1Or-NR ^A2COOR ^A3

R ^A1And R ^A2Identical or different, and the H that respectively does for oneself, C _1-4Alkyl or benzyl;

R ^A3Be C _1-4Alkyl;

R ¹Be selected from group B or be the optional C that is replaced by the individual substituent group that is selected from halogen or group B of 1-3 _1-10Alkyl;

Group B is:

Optional by 1-5 C that is selected from the substituent group replacement of group A _3-10Carbocyclic ring;

Optional by 1-5 heterocyclic radical that is selected from the substituent group replacement of group A;

-OR ^a4；

-SR ^a4；

-NR ^a4R ^a5；

-CONR ^a4R ^a5；

-SO ₂NR ^a4R ^a5；

-COR ^a6；

-NR ^a4COR ^a6；

-SO ₂R ^a6；

-NR ^a4SO ₂R ^a6；

-COOR ^A4Or

-NR ^a5COOR ^a6；

R ^A4And R ^A5Identical or different, and respectively do for oneself:

H；

C _1-4Alkyl;

Optional by 1-5 C that is selected from the substituent group replacement of group A _3-10Carbocylic radical; Or

R ^A6For:

C _1-4Alkyl;

R ²Be H or C _1-4Alkyl;

R ³¹Be H, cyano group, hydroxyl, amino, nitro, halogen, C _1-4Alkyl, C _1-4Alkoxyl, C _1-4Alkyl alkylthio base, halo C _1-4Alkyl or halo C _1-4Alkoxyl;

X is C-R ³²Or N;

Y is C-R ³³Or N;

R ³²And R ³³Identical or different, and respectively do for oneself:

H；

Cyano group;

Nitro;

Halogen;

Optional by 1-5 C that is selected from the substituent group replacement of group A _3-10Carbocylic radical;

Optional by 1-5 heterocyclic radical that is selected from the substituent group replacement of group A; Optional by 1-3 C that is selected from the substituent group replacement of halogen or group B _1-10Alkyl;

-OR ^a7；

-SR ^a7；

-NR ^a7R ^a8；

-NR ^a7COR ^a9；

-COOR ^A10Or

-N＝CH-NR ^a10R ^a11；

R ^A7And R ^A8Identical or different and be selected from H separately, group B or the optional C that is replaced by 1-3 substituent group that is selected from halogen or group B _1-10Alkyl;

R ^A9Be C _1-4Alkyl; And

R ^A10And R ^A11Identical or different, and respectively do for oneself H or C _1-4Alkyl;

This method comprises the chemical compound of patient's giving construction (I) that these needs are arranged or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt.

The present invention provides the method for pharmacokinetics of the chemical compound of improvement formula (I) in one embodiment, and it comprises that the patient to this chemical compound of needs or its pharmaceutically acceptable salt gives ritonavir or its pharmaceutically acceptable salt of effective dose.

The present invention provides the patient's of the chemical compound of raising use formula (I) or the treatment of its pharmaceutically acceptable salt the method for blood drug level of this chemical compound in one embodiment, and it comprises that the patient to this chemical compound of needs or its pharmaceutically acceptable salt gives ritonavir or its pharmaceutically acceptable salt of effective dose.

The present invention provides the method that suppresses hiv integrase in the patient of this class treatment of needs in one embodiment, and it comprises the chemical compound of giving construction (I) or ritonavir or its pharmaceutically acceptable salt of its pharmaceutically acceptable salt and effective dose.

The present invention provides the method that improves the bioavailability of chemical compound 1 among the patient in one embodiment.This method comprises treats the chemical compound 1 of effective dose to described patient with food.If can observe the raising of chemical compound bioavailability by with not giving the increase that described chemical compound compares maximal plasma concentration or the increase of the area (AUC) under the plasma concentration time graph with food.

The present invention provides raising chemical compound 1 in the systemic method of patient's body in one embodiment, and it comprises treats the chemical compound 1 of effective dose to this patient with food.Can be by absorption at this chemical compound of concentration determination that gives in blood flow, to obtain behind the described chemical compound.If can observe the raising that absorbs according to not giving the increase that described chemical compound compares maximal plasma concentration or the increase of the area (AUC) under the plasma concentration time graph with food.

The present invention provides in one embodiment and has been used to suppress the active method of patient's retrovirus integrase, comprises this patient is treated the chemical compound 1 of effective dose with food.

The present invention provides the method that is used for the treatment of or prevents patient's retroviral infection in one embodiment, comprises this patient is treated the chemical compound 1 of effective dose with food.

The present invention provides kit in one embodiment, and it comprises: the pharmaceutical composition of (1) inclusion compound 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier; The information of (2) prescribing; (3) container.The information of prescribing comprises the patient is related to suggestion sincere advice or the explanation that gives chemical compound 1 with food.

The present invention provides kit in another embodiment, and it comprises integrase inhibitor, such as chemical compound 1, and information of prescribing and container, the information of wherein prescribing comprises about giving described chemical compound so that improve the information of its bioavailability.

The present invention provides in one embodiment by the patient being given integrase inhibitor and ritonavir or its pharmaceutically acceptable salt and food, improves this integrase inhibitor, such as the method for the pharmacokinetics of chemical compound 1.

The present invention provides in one embodiment and has improved the method for chemical compound 1 in the intravital bioavailability of patient, and it comprises the chemical compound 1 and ritonavir and food of this patient being treated effective dose.

The present invention provides the method that improves the absorption of chemical compound 1 in the patient in one embodiment, and it comprises the chemical compound 1 and ritonavir and food of this patient being treated effective dose.

The present invention provides in one embodiment and has been used for suppressing the active method of patient's retrovirus integrase, and it comprises the chemical compound 1 and ritonavir and food of this patient being treated effective dose.

The present invention provides the method that is used for the treatment of or prevents retroviral infection among the patient in one embodiment, and it comprises the chemical compound 1 and ritonavir and food of this patient being treated effective dose.

The present invention provides ritonavir or its pharmaceutically acceptable salt to be used for improving hiv integrase inhibitor (for example chemical compound of formula (I)) or the purposes of its pharmaceutically acceptable salt in the medicament of patient's bioavailability in preparation in one embodiment.

The present invention provides the chemical compound of ritonavir or its pharmaceutically acceptable salt and formula (I) or its pharmaceutically acceptable salt to be used for suppressing purposes in the medicament of patient's hiv integrase in preparation in one embodiment.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for improving the purposes of the medicament of this chemical compound bioavailability in preparation, and it comprises described chemical compound or its pharmaceutically acceptable salt that the patient is given effective dose in the treatment that food gives.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for improving the application of this chemical compound at the systemic medicament of patient's body in preparation, and it comprises described chemical compound or its pharmaceutically acceptable salt that this patient is given effective dose in the treatment that food gives.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for suppressing purposes in the active medicament of patient's retrovirus integrase in preparation, and it comprises described chemical compound or its pharmaceutically acceptable salt that this patient is given effective dose in the treatment that food gives.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S in one embodiment]-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for the treatment of or prevent purposes in the medicament of retroviral infection among the patient in preparation, and it comprises described chemical compound or its pharmaceutically acceptable salt that this patient is given effective dose in the treatment that food gives.

The present invention provides kit in one embodiment, it comprises: (1) pharmaceutical composition, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier; The information of (2) prescribing; (3) container; The information of wherein prescribing comprises about give 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl with food]-7-methoxyl group-4-oxo-1, the suggestion of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt.In one embodiment, this kit can be chosen wantonly and further comprise ritonavir or its pharmaceutically acceptable salt.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt purposes in the preparation medicament, this medicament is used for improving chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl when giving together with ritonavir or its pharmaceutically acceptable salt and food]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid is in the intravital bioavailability of patient.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1, the application in the preparation medicament of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament is used for improving chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl when giving together with ritonavir or its pharmaceutically acceptable salt and food]-7-methoxyl group-4-oxo-1, the 4-dihydroquinoline-absorption of 3-formic acid in the patient.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt purposes in the preparation medicament, this medicament is used for suppressing the activity of retrovirus integrase among the patient when giving together with ritonavir or its pharmaceutically acceptable salt and food.

The present invention provides chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl in one embodiment]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt be in the purposes of preparation in the medicament, and this medicament is used for treatment or prevention patient retroviral infection when giving together with ritonavir or its pharmaceutically acceptable salt and food.

The present invention provides pharmaceutical composition in one embodiment, and it comprises and is used to improve ritonavir or its pharmaceutically acceptable salt of hiv integrase inhibitor in the intravital pharmacokinetics of patient.

The present invention provides pharmaceutical composition in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition is used to improve the bioavailability of described chemical compound with food.

The present invention provides pharmaceutical composition in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition is used to improve described chemical compound in the intravital absorption of patient with food.

The present invention provides pharmaceutical composition in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition is used for suppressing the activity of patient's retrovirus integrase with food.

The present invention provides pharmaceutical composition in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition are used for the treatment of with food or prevent retroviral infection among the patient.

The present invention provides the antiretroviral agent agent in one embodiment, and it comprises and is used to improve ritonavir or its pharmaceutically acceptable salt of hiv integrase inhibitor in the intravital pharmacokinetics of patient.

The present invention provides antiretroviral agent agent compositions in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament composition is used to improve the bioavailability of this chemical compound with food.

The present invention provides the antiretroviral agent agent in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament is used to improve described chemical compound in the intravital absorption of patient with food.

The present invention provides the antiretroviral agent agent in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament is used for suppressing the activity of patient's retrovirus integrase with food.

The present invention provides the antiretroviral agent agent in one embodiment, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament are used for the treatment of with food or prevent retroviral infection among the patient.

The present invention provides integrase inhibitor or the purposes of its pharmaceutically acceptable salt in the preparation medicament in one embodiment, this medicament is used to improve this integrase inhibitor or the bioavailability of its pharmaceutically acceptable salt in the reactive illness of treatment intergrase (for example retroviral infection infects or AIDS such as HIV) with the food orally give.

The present invention provides the integrase inhibitor (chemical compound of formula (I) for example in one embodiment, such as chemical compound 1) or the purposes of its pharmaceutically acceptable salt in the preparation medicament, this medicament is used to improve this integrase inhibitor or the absorption of its pharmaceutically acceptable salt in the reactive illness of treatment intergrase (for example retroviral infection infects or AIDS such as HIV) with the food orally give.

The present invention provides the integrase inhibitor (chemical compound of formula (I) for example in one embodiment, such as chemical compound 1) or the purposes of its pharmaceutically acceptable salt in the preparation medicament, this medicament is with ritonavir or its pharmaceutically acceptable salt administration, be used for the treatment of the reactive illness of intergrase (for example retroviral infection infects or AIDS such as HIV).

The present invention provides ritonavir or the purposes of its pharmaceutically acceptable salt in the preparation medicament in one embodiment, this medicament and the integrase inhibitor (chemical compound of formula (I) for example, such as chemical compound 1) or the administration together of its pharmaceutically acceptable salt, be used for the treatment of the reactive illness of intergrase (for example retroviral infection infects or AIDS such as HIV).

The present invention provides the integrase inhibitor (chemical compound of formula (I) for example in one embodiment, such as chemical compound 1) or its pharmaceutically acceptable salt and ritonavir or the purposes of its pharmaceutically acceptable salt in the preparation medicament, this medicament is used for the treatment of the reactive illness of intergrase (for example retroviral infection infects or AIDS such as HIV).

The present invention provides the integrase inhibitor (chemical compound of formula (I) for example in one embodiment, such as chemical compound 1) or the purposes of its pharmaceutically acceptable salt in the preparation medicament, this medicament gives with ritonavir or its pharmaceutically acceptable salt and food, be used for the treatment of the reactive illness of intergrase (for example retroviral infection infects or AIDS such as HIV).

The present invention provides ritonavir or the purposes of its pharmaceutically acceptable salt in the preparation medicament in one embodiment, this medicament and the integrase inhibitor (chemical compound of formula (I) for example, such as chemical compound 1) or its pharmaceutically acceptable salt and food give together, be used for the treatment of the reactive illness of intergrase (for example retroviral infection infects or AIDS such as HIV).

Description of the invention provided herein has obviously embodied these and other advantage of the present invention and additional inventive features.

The accompanying drawing summary

Fig. 1 is independent chemical compound 1 and chemical compound 1 and the plasma concentration of ritonavir coupling and the sketch map of time relationship.

Fig. 2 is with 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1, the sketch map that 4-dihydroquinoline-3-formic acid (chemical compound 1) is drawn in the lineal scale of its plasma concentration after administration under fasting and the feeding state.

Fig. 3 is the diagram of the data of embodiment 3.

Fig. 4 is the data diagram of embodiment 3.

Fig. 5 is the data diagram of embodiment 3.

Detailed Description Of The Invention

The Ritonavir effect

The compound of formula (I) is hiv integrase inhibitor. The compound of formula (II) is the compound of specific one group of formula (I):

Wherein:

R ⁴And R⁶Identical or different and be selected from separately group A;

R ⁵Be selected from H or group A;

Or R⁴And R⁵Consist of together the ring that condenses with their phenyl ring of bonding;

M is 0-3; And

R ¹，R ³¹，R ³²And R³³Identical in definition separately and the formula (I);

Condition is when m is 2 or 3, the R of each m⁶Optional identical or different.

The compound of preferred formula (I) is compound 1:

U.S. Patent Application Publication US has described the compound of formula (I) for No. 2005/0239819, and this paper intactly introduces this application. Can find compound 1 among the embodiment 4-32 on the 76th page of this document. The preparation and application of this compound and formula (I) and other compound (II) has also been described in this document.

According to one embodiment of the invention, disclose a kind ofly by give Ritonavir or its pharmaceutically acceptable salt with medicine, improve the method for the pharmacokinetics of this medicine (or its pharmaceutically acceptable salt). This medicine is preferably hiv integrase inhibitor. In addition, this medicine is preferably by the cytochrome P 450 monooxygenases metabolism. When administration, two kinds of preparations can be mixed with independent composition, their maybe can be mixed with them single composition and administration simultaneously or in different time (for example simultaneously, continuously or successively) administration.

United States Patent (USP) the 6th, 037,157 and 6,703, described for No. 403 by the cytochrome P 450 monooxygenases metabolism and can have benefited from some hiv protease inhibitor with the Ritonavir administration, these documents intactly are incorporated herein by reference. Described in these patents can with preparation and the dosage regimen of Ritonavir coupling.

In U.S. Patent Application Publication US2004/0167124 number, can find preparation and the dosage regimen of hiv integrase inhibitor, the document intactly is incorporated herein by reference. Such scheme can be applied to the present invention as herein described. With regard to conjoint therapy, for example, can every day will about 20mg to formula (I) or the compound (II) of about 500mg, such as compound 1, with about 10mg Ritonavir administering drug combinations of about 1200mg extremely. In a specific embodiment of the present invention, can every day will about 20mg to formula (I) or the compound (II) of about 500mg, such as compound 1, with about 10mg Ritonavir administering drug combinations of about 600mg extremely. In one embodiment of the invention, the suitable dosage of compound 1 is about 20mg, 50mg, and 75mg, 85mg, 100mg, 125mg, 150mg, 175mg or 200mg are more particularly about 85 mg, about 125mg or about 150mg. In one embodiment of the invention, the suitable dosage of Ritonavir is that about 20mg is to about 200mg, particularly about 50mg to about 125mg, more particularly about 100mg. But, every kind of medicament higher and more low dosage may be effective.

In an embodiment of administration every day, the preferable amount of compound 1 and Ritonavir is to keep the blood concentration of compound 1 at IC during 24 hours₉₅On (be the external IC that protein bound is regulated₉₅Dosage 100nM).

In an embodiment of administration every day, the preferable amount of compound 1 and Ritonavir is for keeping the blood concentration of compound 1 at EC during 24 hours₉₀On the dosage of (being about 170ng/ml in the Emax model).

In one embodiment, the preferable amount of compound 1 be give the patient can make average drop-out value as the HIV RNA of anti-HIV activity greater than 1.5log₁₀Copy/ml, preferred 2.0log₁₀Dosage.

It is a kind of by giving or jointly give Ritonavir or its pharmaceutically acceptable salt and hiv integrase inhibitor (or its pharmaceutically acceptable salt) that the present invention provides in a specific embodiment, especially by cytochrome P 450 monooxygenases, more especially by the hiv integrase inhibitor of isotype CYP 3A4 metabolism, in the patient of this treatment of needs, improve the method for the pharmacokinetics of this integrase inhibitor. This class Ritonavir or its pharmaceutically acceptable salt be can be used for suppressing patient's hiv integrase by the drug combination of the hiv integrase inhibitor of cytochrome P 450 monooxygenases metabolism or its pharmaceutically acceptable salt and can be used for suppressing, treat or prevent patient's HIV infection or AIDS (acquired immunodeficiency syndrome).

The patient comprises any biology, particularly mammal (for example people).

One aspect of the present invention provides the Ritonavir of effective dose to strengthen the purposes of the pharmacokinetics of hiv integrase inhibitor. The effective dose of Ritonavir is namely strengthened the required consumption of hiv integrase inhibitor its characteristic for independent use the time and is compared, and improves the essential consumption of pharmacokinetic properties of hiv integrase inhibitor. Compare with not adding Ritonavir, this inhibitor has better active drug dynamics. Consumption that be used for to strengthen the Ritonavir of integrase inhibitor can be curative for the Asia (for example being lower than the dosage of the Ritonavir consumption that being used for the treatment of property of routine treatment patient HIV infects). The booster of Ritonavir is inferior curative for treatment HIV infects, but height is regulated formula (I) and compound metabolism (II) to being enough to realization, so that by improving bioavilability, increase blood concentration, increase the half-life, increase the time reach peak plasma concentrations, increase/faster suppress hiv integrase, and/or reduction systemic clearance and strengthen the contact of described compound in the patient.

Compound 1 is by cytochrome P 450 monooxygenases, particularly the hiv integrase inhibitor of isotype CYP 3A metabolism. Have been found that at present Ritonavir can be used for the compound of heavier-duty (I) and the pharmacokinetics of other hiv integrase inhibitor. Ritonavir is specially adapted to strengthen by the effect of the integrase inhibitor of cytochrome P 450 monooxygenases (for example isotype CYP 3A) metabolism. The degree of this class booster action is obvious unexpectedly. Ritonavir can limit the first pass effect of these compounds. Ritonavir can also limit time excessively (whole body or hepatic metabolism/removing) effect of these compounds.

According to method of the present invention, can also with integrase inhibitor (or compound of formula (I)) or its pharmaceutically acceptable salt and one or more other can be used for treating virus infections medicament unite and give, such as stavudine, emtricitabine, tenofovir, emtricitabine, Abacavir, Lamivudine, Zidovudine, Didanosine is pricked his shore of former times, phosphazide (phosphazide), efavirenz, NVP, delavirdine, tipranavir, inverase, indinavir, atazanavir, Nai Fennawei, APV, samprenavir, that Wei of furan mountain, Lopinavir, Ritonavir, T-20, fozivudine tidoxil, Aovudine, right Ai Fuxita shore, A Lita shore (Apricitabine), amdoxovir, Ai Fuxita shore (ACH126443), La Xiwei (Racivir) (racemic FTC, PSI-5004), MIV-210, KP-1461, the phosphorus husband decides ester (fosalvudine tidoxil) (HDP 99.0003), AVX756, dioxolanes thymidine (DOT), TMC-254072, INK-20,4 '-Ed4T, TMC-125 (etravirine), capravirine, TMC-278 (rilpivirine), GW-695634, Calanolide A, BILR 355 BS and VRX 840773 or its pharmaceutically acceptable salt. Although above-mentioned catalogue comprises the trade name of several compounds, it should be understood that the trade name that relates to also comprises activity chemistry agent wherein, irrelevant with the source. Kit of the present invention can also be chosen wantonly and comprise that further one or more are selected from other medicament of above-mentioned catalogue.

In one embodiment of the invention, method of the present invention further comprises one or more other medicaments that are selected from as lower: tenofovir DF (TDF), emtricitabine (FTC), Zidovudine (AZT), Didanosine (ddI), stavudine (d4T), Abacavir (ABC), atazanavir (ATV), Lopinavir (LPV), inverase (SQV), tipranavir (TPV), that Wei of furan mountain (FosAPV) and efavirenz (EFV). Kit of the present invention can also further be chosen wantonly and comprise one or more other medicaments that are selected from above-mentioned catalogue.

The present invention also provides kit, and it comprises: (i) integrase inhibitor (for example compound 1) or its pharmaceutically acceptable salt; (ii) Ritonavir or its pharmaceutically acceptable salt; The information of (iii) prescribing; (iii) one or more containers. The information of prescribing can provide with the inventive method and/or such as the consistent information of prescribing of the other side of this paper discussion. In one embodiment of the invention, the information of prescribing comprises with Ritonavir and gives integrase inhibitor or its pharmaceutically acceptable salt in order to improve the pharmacokinetics of this integrase inhibitor.

Now illustrate the effect of ritonavir to the bioavailability of representational integrase inhibitor by following non-limiting examples.

Embodiment 1. ritonavirs are to the booster action of the pharmacokinetics of chemical compound 1

Measured and given the effect of 100mg ritonavir (RTV) jointly the stable state pharmacokinetics of chemical compound 1.The single dose and the multiple dose pharmacokinetics of chemical compound 1 have also been measured.Also measured give separately and with the multiple dose safety of the common administered compound 1 of RTV.

Method

This research is for using 12 open labellings that the experimenter carries out, permanent order, intersection pharmacokinetic study.The experimenter is healthy male and the non-pregnancy non-lactogenic women of age in 18-45 year (containing end value).

The research time limit is 20 days, and wherein the 1st to the 10th day was the 1st phase, and the 11st to the 20th day was the 2nd phase, followed up a case by regular visits to contact at the 27th day.

Twice of every day is at orally give chemical compound 1 (100mg) and RTV (100mg at once after the meal.Twice of every day is at orally give chemical compound 1 (100mg) at once after the meal.

Evaluation criterion

Pharmacokinetics: the following parameters of computerized compound 1 (if possible, and metabolite) in blood plasma: C _Max, T _Max, C _Finally, T _Finally, C _Tau, λ _z, AUC _{0-is final}, AUC _{Infinitely great}, %AUC _Exp, AUC _Tau, T _1/2, V _z/ F and CL/F.

Safety: in this research process, by estimating clinical laboratory tests at baseline and different time points; Regular Physical Examination comprise vital sign; Assess safety with whole research process record adverse events.

Statistical method

Pharmacokinetics: the pharmacokinetics of using descriptive statistics generalization compound 1 and RTV.In addition, parameter (standard theory) variance analysis (ANOVA) that use is suitable for the fixed-effect model of cross-over design fits to chemical compound 1 pharmacokinetic parameter (AUC and C _Max) natural logrithm transform.Use multiple dose that 90% confidence interval of the right geometrical mean ratio of each treatment carries out chemical compound 1 and single dose of drug kinetics and chemical compound 1 with and not with the multiple dose pharmacokinetics comparison of RTV co-administered.

Safety: in this pharmacokinetic study, data of safety is not carried out statistical inference.

The result

Pharmacokinetics result: do not having RTV or having as single dose (100mg, the 11st day) or multiple dose (100mg, twice of every day, the 20th day) there is single orally give chemical compound 1 (100mg down in the RTV of oral administration, the 1st day) and orally give chemical compound 1 (100mg repeatedly, at twice, the 10 day every day) average (%CV) drug plasma kinetic parameter of back chemical compound 1 and RTV is as follows.

A with regard to chemical compound 1, the AUC when AUC represents the 1st day _{Infinitely great}AUC with the 10th, 11 and 20 day _Tau

B C _TauConcentration when representing the 1st, 10,11 and 20 days dosing interval end.

The c median (min, max)

D with regard to ritonavir, the AUC when AUC represents the 11st day _{Infinitely great}AUC with the 20th day _Tau

In the process that gives chemical compound 1 separately, with the average steady state exposure (AUC of chemical compound 1 (the 10th day) _Tau) than the average exposure (AUC behind the single dose (the 1st day) _{Infinitely great}) low about 20%, shown chemical compound 1 metabolic auto-induction.Give RTV jointly and cause chemical compound 1 metabolic clean inhibition, as exposing by stable state and relative long meta eliminates the half-life that (9.5 contrast 3.5 hours, under stable state) confirmed greater than prediction.The increase of chemical compound 1 exposure may be that the oral administration biaavailability that reason causes in the first pass metabolism minimizing improves due to the combination that descends with systemic clearance, as passing through observed T after giving RTV jointly _1/2Change shown.

In a word, these data support RTV (for example low dosage RTV) to allow to as the pharmacokinetics stiffener of chemical compound 1, for example realize the purposes of the dosing interval of higher paddy concentration and lower frequency.

Safety results: to 4 (33% among 12 experimenters, 5 incidents) reported and given separately in chemical compound 1 process and the adverse events (AEs) of 7 among 12 experimenters (58%, 44 incident) treatment emergency in giving chemical compound 1+RTV process.In the process that gives chemical compound 1 separately, do not report the single AE that surpasses 1 experimenter.In the process that gives chemical compound 1+RTV, the AE of the treatment emergency of frequent report is feel sick (33%) that 4 experimenters are taken place.The AEs of most of treatment emergency is slight (1 grade) aspect seriousness and need not therapy and can recover voluntarily.

Among 12 experimenters after giving chemical compound 1 separately 2 (17%, 2 incidents) reported research worker in 5 (42%, 21 incident) and after giving chemical compound 1+RTV among 12 experimenters and thought the AEs of the treatment emergency relevant with the research medicine.Be not reported in and give chemical compound 1 back separately above the AE relevant among 1 experimenter with treatment.The AEs relevant with treatment that reports among 1 experimenter surpassing after giving chemical compound 1+RTV is for feeling sick (3 experimenters) vomiting (2 experimenters), headache (2 experimenters) and pruritus (2 experimenters).

No serious adverse events takes place in this research, and no experimenter is interrupted because of adverse events, and does not have the gestation generation.No experimenter studies medicine because of clinical laboratory stops using unusually, and does not have clinical laboratory to be reported to AE unusually.

Conclusion

Give RTV jointly and cause chemical compound 1 metabolic clean inhibition and systemic exposure, particularly paddy concentration significantly increases.These data have been supported the application of low dosage RTV as the Booster of chemical compound 1.

Continue in the research experimenter, to have obtained abundant tolerance up to the oral administration (100mg, twice of every day) of 20 days chemical compound 1.After giving chemical compound 1 separately, all adverse events are slight and of short duration.Continue up to 10 days chemical compound 1 (100mg, twice of every day) and RTV in the time of (100mg, twice of every day) oral administration studying among the experimenter and generally speaking obtained abundant tolerance.After giving chemical compound 1+RTV, most of adverse events of report is slight with of short duration and generally speaking with consistent to those of RTV report.

Embodiment 2. is the safety of chemical compound 1 behind the oral administration in the experimenter who has infected HIV-1,

Pharmacokinetics and antiviral activity

Studied among the experimenter of the long-term infected by HIV-1 of not accepting antiretroviral therapy at present safety, toleration and antiviral activity (twice of 1,2 and 4 group every day as the chemical compound 1 of continuous 10 oral dose administrations every day; 3 and 5 groups once a day).The pharmacokinetics and the pharmacodynamics of chemical compound 1 have also been investigated.

Method

Research is the double blinding among the adult who tests or take place HIV-at the antiretroviral of not accepting at present antiretroviral therapy first and infect, randomization, and placebo, preface takes group, and 1/2 phase of chemical compound 1 therapy that dosage is sorted out is studied.In when screening, the experimenter should have 〉=and 10, the blood plasma HIV-1RNA carrying capacity of 000-≤300,000 a copy/mL and 〉=200 cell/mm ³The CD4+ cell counting.

The experimenter's (6 experimenters use activating agent and 2 use placebo) who began with 8 uniquenesses of 5 continuous groups in research medicine or the placebo treatment feeding state at the 1st day connects treatment 10 days.After the monitoring administration to the 21st day safety, toleration, pharmacokinetics and effect.Activating agent treatment in 5 groups is as follows: the 1st group, 400mg chemical compound 1, twice of every day; The 2nd group, 800mg chemical compound 1, twice of every day; The 3rd group, 800mg chemical compound 1, once a day; The 4th group, 200mg chemical compound 1, twice of every day; The 5th group, 50mg chemical compound 1+100mg RTV (RTV), each is once a day.Placebo group in the 5th group is also accepted 100mg RTV.

Registration has 8 experimenters in each group, and 2 are used placebo and 6 use activating agent (randomizations; 48,40 of administrations).Estimate the safety of 8 experimenters of every group (2 are used placebo, and 6 are used activating agent), amount to 40 experimenters.Estimate 28 experimenters' pharmacokinetics at the 1st day, estimated 30 experimenters at the 10th day.Estimate 30 experimenters' pharmacokinetics and estimate 40 experimenters' HIV-1 RNA.Measure the effect of 8 experimenters of every group (2 are used placebo, and 6 are used activating agent), amount to 40 experimenters.

The experimenter is the masculinity and femininity in 18-60 year (containing end value), they have all infected HIV-1 for a long time, and do not accept antiretroviral therapy at present, and wherein examination blood plasma HIV-1 RNA is 〉=10,000-≤300,000 a copy/mL and examination CD4+ cell counting are 〉=200 cell/mm ³The experimenter has carried out antiretroviral therapy or has accepted antiretroviral therapy first, but should not accept antiviral drugs at 90 days in baseline (the 0th day).

This research time limit is 21 days, wherein treats and follows up a case by regular visits in 11 days in 10 days.Orally give 50mg or 200mg chemical compound 1 tablet under feeding state.The placebo of orally give coupling under feeding state.Only with regard to the 5th group, the oral 100mgRTV capsule that gives jointly under feeding state.

Evaluation criterion

Effect: main effect terminal point is from 11 days maximum HIV-1 RNA drop-out value (log of baseline to the ₁₀Copy number/mL).For the maximum drop-out value of individual subjects is the maximum drop-out value from baseline changes between the 2nd day to the 11st day.

Pharmacokinetics: the following drug plasma kinetic parameter of computerized compound 1: C _Max, T _Max, C _Finally, T _Finally, C _Tau, λ _z, T _1/2, AUC _{0-is final}, AUC _{Infinitely great}, %AUC _Exp, AUC _Tau, V _z/ F and CL/F.Measure chemical compound 1 in peripheral mononuclear cells (PBMC) concentration and detect the pharmacokinetics of chemical compound 1 in PBMCs.

Safety: adverse events has been estimated in safety, vital sign, electrocardiogram, ophthalmologic examination and clinical laboratory tests.

Statistical method

Effect: use Wilcoxon sum of ranks Precision Test to carry out paired comparison, each level (6 experimenters under each dosage level) in the dosage level of placebo group (each is from 2 experimenters of the 1-4 group that merges) and 5 chemical compounds 1 relatively, and carry out each paired comparison at 5 chemical compound 1 dosage levels.2 experimenters that accept placebo+100mg RTV are handled as independent group.(the HIV-1 RNA value note of 50 copies/mL) is made 49 copy/mL to be lower than detectability.

Pharmacokinetics: use the pharmacokinetic parameter of descriptive statistics generalization compound 1 in blood plasma or peripheral blood lymphocytes.In addition, for each chemical compound 1 dosage level, to pharmacokinetic parameter (AUC and C _Max) carry out variance analysis so that check dosage proportionality and stable state pharmacokinetics.If suitable, in analyzing, these are included in the chemical compound 1 paddy level of measuring in the 2nd, 4,7,10 and 11 days.

Safety: by treatment, system's organ type and the adverse events that preferably is used for the treatment of emergency, adverse events, the serious adverse events relevant and cause the inactive term summary of studying the adverse events of medicine to have experimenter's ratio of adverse events with treatment.Use MedicalDictionary for Regulatory Activities (Med

) 8.1 editions coding adverse events.The extra general introduction of adverse events is by highest ranking, and research worker pair is showed with the relation assessment of research medicine with to the influence of the research medicine of stopping using.Represent laboratory result according to original measurement yardstick and toxic grade.Be summarised in the quantitative experiment chamber test change by visit from baseline.

The result

Effect, pharmacokinetics and pharmacodynamic result.With individually dosed (twice of 200mg every day, 400mg every day twice, twice of 800mg every day or 800mg are once a day) or 50mg during once a day with 100mg RTV co-administered the stable state pharmacokinetic parameter (meansigma methods [%CV]) and the antiviral activity of chemical compound 1 be listed in the following table:

A. the maximum drop-out value with HIV-1 RNA is defined as with log ₁₀Copy number/mL meter between the 2nd to the 11st day from the maximum drop-out value of baseline.(the HIV-1 RNA value of 50 copies/mL) is imported with 49 copy/mL to be lower than quantitative limit.With respect to placebo group, compare 5 chemical compound 1 dosage levels and placebo+RTV group.

B. based on bilateral Wilcoxon sum of ranks Precision Test continuous data is matched and check gained p-value, chemical compound 1 each dosage level and the correlated p=0.0007 of placebo.

C. based on what calculate continuous data is matched the p value of check by bilateral Wilcoxon sum of ranks Precision Test, to 800mg chemical compound 1 once a day with the p=0.0152 of 800mg chemical compound two doses level 1 every day and 400mg chemical compound twice gained, 1 every day.

D.50mg chemical compound 1+RTV dosage level contrasts p=0.0714 with placebo+RTV once a day; With twice contrast 200mg every day, p=0.1797; With twice contrast 400mg every day, p=0.9372; Contrast p=0.0022 once a day with 800mg; With twice contrast 800mg every day, p=0.8182.

E. percentage ratio is based on the experimenter of all randomizations and treatment.

12-and 24-hour pharmacokinetics sample that the dosing interval (tau) that f. will be equivalent to gather in the 10th day (twice administration every day) or 11 days (administration once a day) respectively stops are appointed as 12 or 24 hours nominal time.

Chemical compound 1 monotherapy under all dosage all than the remarkable HIV-1 rna level (p＜0.0007) that reduced of placebo.In continuous 10 days administration processes, twice of 400mg every day, twice of 800mg every day or 50mg and 100mg the RTV dosage of common administered compound 1 once a day cause HIV-1 RNA to descend from the maximum of baseline being respectively-1.94 ± 0.52 ,-1.91 ± 0.60 and-1.99 ± 0.38log ₁₀Copy number/mL (mean+SD).After using 10 days monotherapies of chemical compound 1, no experimenter be equivalent in external selection experiment observed chemical compound 1 resistant mutation or using other experiment integrase inhibitor select under HIV-1 intergrase of sudden change of generation suddenly change.

Along with dosage rises (200,400 and 800mg every day twice), chemical compound 1 does not show pharmacokinetics and increase dose ratio, and shows dose dependent metabolism auto-induction.The chemical compound 1+100mg RTV that gives 50mg dosage once a day jointly causes the metabolic clean inhibition of CYP3A-mediation and height system to expose, particularly paddy concentration.Pharmacokinetics in PBMCs is found consistent with the drug plasma dynamics data.Use the C of chemical compound 1 _TauValue authenticating compound 1 exposure-reaction relation, the C of described chemical compound 1 _TauValue fully is suitable for having EC ₅₀For 14.4ng/mL compares decline 2.32log with having with baseline ₁₀The E of copy number/mL _MaxWith observed average C _TauExternal IC divided by the protein bound adjusting ₅₀7.17ng/mL the estimation inhibition index of calculating gained chemical compound 1 is in 400mg every day twice, twice of 800mg every day and 50mg+RTV are respectively 5.9,6.7 and 18.8 under the dosage level once a day.The paddy concentration of chemical compound 1 under these dosage has also surpassed the external IC that protein bound is adjusted at whole dosing interval ₉₅44.9ng/mL (100nM).

Treatment emergency adverse events takes place in the safety results most subjects, but headache and diarrhoea are for surpassing only adverse events of 2 experimenter's reports in group.It is similar or be lower than incidence rate in the placebo group to treat the incidence rate of emergency adverse events and the incidence rate in the placebo group the experimenter who accepts chemical compound 1, and the class types of adverse events seemingly.In group, do not have to be studied personnel and be considered as the adverse events relevant with studying medicine above 2 experimenters' experience, and only 3 kinds of adverse events that treatment is relevant of following preferred term take place in 2 experimenters in group: diarrhoea (placebo), feel sick (placebo and 200mg chemical compound 1 every day twice) and fatigue (200mg chemical compound 1 every day twice).

All 40 experimenters that accept the research medicine have all finished this research.No dosage interrupts, drug withdrawal or serious adverse events.5 experimenters, promptly in the placebo group 2 experimenters and placebo+RTV once a day, twice of 1 every day of 400mg chemical compound and 50mg chemical compound 1+RTV organize each 1 experimenter once a day and have treatment emergency 3 or 4 grades of laboratory abnormalities.One of 3 grades of laboratory abnormalities in placebo group, the high triglyceride that does not promptly use therapy to solve are studied personnel and are considered as and study the irrelevant adverse events of medicine.Use 2 experimenters with 3 grades of laboratory abnormalities (the triglyceride of fasting does not raise or the serum amylase rising) of chemical compound 1 treatment also to have exceptional value at baseline.Hematology and urinalysis in this research process, do not occur and find vital sign, the relevant clinically change of body weight or electrocardiogram and ophthalmologic examination.

Conclusion

Effect: 200,400 or twice of 800mg every day; 800mg once a day or 50mg+100mg RTV once a day dosage down 10 days the monotherapy of experimenter's successive administration that infects of the viral first Application of antagonism or experience HIV-compare the remarkable HIV-1 RNA that reduced with the placebo under all dosage levels.400mg every day twice, twice of 800mg every day and 50mg+100mg RTV chemical compound 1 dosage once a day cause being respectively-1.94 from the average drop-out value of baseline ,-1.91 and-1.99log ₁₀Copy number/mL.All do not detect chemical compound 1 resistant mutation up to the 21st day in the integrase gene any experimenter.

Pharmacokinetics/pharmacodynamics: chemical compound 1 shows supports twice of every day individually dosed or once a day with the pharmacokinetics of (100mg) RTV administration of low dosage.Use and fully be suitable for simple E _MaxThe C of the chemical compound 1 of model _TauValue authenticating compound 1 exposure-reaction relation.The external IC that adopts protein bound to regulate ₅₀7.17ng/mL the estimation inhibition index of the chemical compound 1 that calculates is in 400mg every day twice, twice of 800mg every day and 50mg+RTV are respectively 5.9,6.7 and 18.8 under the dosage level once a day.The paddy concentration of chemical compound 1 under these dosage levels has surpassed the external IC that protein bound is adjusted with regard to whole dosing interval ₉₅44.9ng/mL.

Safety: generally speaking chemical compound 1 is fully to tolerate under all dosage levels, does not wherein have dosage and interrupts, drug withdrawal or serious adverse events.Most of adverse events is slight and untreated can be recovered voluntarily.The adverse events of modal treatment emergency is headache, and the modal adverse events relevant with treatment is for feeling sick.The type of adverse events, frequency and seriousness and laboratory abnormalities are similar between activating agent and placebo group.

Embodiment 3. ritonavir dosage are to the influence of the pharmacokinetics of chemical compound 1

Estimated of the influence of ritonavir (RTV) dosage (20,50,100 and 200mg once a day) of certain limit to the pharmacokinetics of chemical compound 1.Also use CYP3 A substrate to estimate the RTV dosage of certain limit (20,50,100 and 200mg once a day) to the active influence of liver cell pigment P450 3A (CYP3A).The RTV dosage of certain limit and the safety and the toleration of chemical compound 1 coupling have also been estimated.

Method

To the age in 18-45 year (containing end value), the non-lactogenic female subjects of healthy male that is evenly distributed basically and non-gestation carries out randomization, open labelling, single center, 2 group of 1 phase research (24 experimenter (can assess for 16) in 2 groups of multiple dose; 12 (can assess for 8) experimenters in every group).

Qualified experimenter carries out male and the non-lactogenic women of non-gestation that screening and assessing is determined for being no more than 28 days before the first administration according to plan by research worker, the scope of experimenter's body weight index (BMI) is 19≤BMI≤30, and no major disease history and general health are in order.The creatinine clearance of estimating by Cockroft-Gault (use ABW) is＞80mL/ minute.

Use following compounds 1/r research treatment:

Treatment A: chemical compound 1,1 * 125mg sheet+RTV 20mg (with giving 20mg dosage behind the 80mg/ml solution dilution) QD (two kinds of medicines are all in administration in the morning).

Treatment B: chemical compound 1,1 * 125mg sheet+RTV 50mg (with giving 50mg dosage behind the 80mg/ml solution dilution) QD (two kinds of medicines are all in administration in the morning).

Treatment C: chemical compound 1,1 * 125mg sheet+RTV 100mg (giving 10mg dosage) QD (two kinds of medicines are all in administration in the morning) with 80mg/ml solution.

Treatment D: chemical compound 1,1 * 125mg sheet+RTV 200mg (giving 200mg dosage) QD (two kinds of medicines are all in administration in the morning) with 80mg/ml solution.

In each research treatment, at first give RTV, give chemical compound 1 subsequently at once.

Give the slow IV of midazolam to every experimenter in 6 hours at the 1st day 14:00 and after giving chemical compound 1/r on the 11st and 21 day and inject (MDZ; 1mg during 1 minute), as the active probe of CYP3A.

After examination program and baseline are estimated, as described below qualified experimenter is divided into two treatment groups at random:

All chemical compound 1/r dosage all eat up breakfast the experimenter, give at once after finishing off 240mL water.At the 11st and 21 day, be used for the serial blood sample that chemical compound 1 and RTV plasma concentration are analyzed by the time point collection after the following chemical compound 1/r administration: 0 (before the administration), after the administration 0.5,1,1.5,2,3,3.5,4,4.5,5,5.5,6,8,10,12,14,16,18 and 24 hours.At the 1st, 11 and 21 day, be used for the serial blood sample that the MDZ plasma concentration is analyzed: 0 (before the administration), after the MDZ administration 5 minutes, 10 minutes, 15 minutes, 30 minutes and 1,2,4,6,8,10,12 and 18 hours by the time point collection after the following MDZ administration.Assessment chemical compound 1, the pharmacokinetic parameter of RTV and MDZ.

When examination, carry out the ECG assessment.In examination, carry out clinical laboratory inspection, physical examination and vital sign inspection (body temperature, blood pressure, heart rate and breathing rate) when baseline and the 10th and 20 day.Also after the 1st, 11 and 21 day 0 hour (before the midazolam administration) and midazolam administration, carried out vital sign inspection (body temperature, blood pressure, heart rate and breathing rate) in 0.5,1.0,1.5 and 2.0 hours.

Test products, dosage and administering mode:

1. chemical compound 1,1 * 125mg sheet+RTV 20mg QD (administration in the morning)

2. chemical compound 1,1 * 125mg sheet+RTV 50mg QD (administration in the morning)

3. chemical compound 1,1 * 125mg sheet+RTV 200mg QD (administration in the morning)

After finishing the standardization meals, the experimenter gives all chemical compound 1/r dosage at once.

Reference therapy, dosage and administering mode

Chemical compound 1,1 * 125mg sheet+RTV 100mg QD (administration in the morning)

Evaluation criterion

Estimate clinical laboratory inspection by different time points in this research process, ECG, periodic physical examination comprises the vital sign inspection and comes evaluate safety by the record adverse events.

Calculate following drug plasma kinetic parameter: with regard to chemical compound 1 and RTV: C _Max, T _Max, C _Finally, T _Finally, C _Tau, λ _z, AUC _Tau, T _1/2, CL/F and V _z/ F.

With regard to MDZ: AUC _{0-is final}, AUC _{Infinitely great}, %AUC _Exp, C _Finally, T _Finally, λ _z, T _1/2, CL/F and V _z

Statistical method: use descriptive statistics, according to experimenter and RTV dosage level generalization compound 1, the safety of RTV and MDZ and pharmacokinetic parameter.Use is from chemical compound 1 pharmacokinetic parameter (AUC, the C of all treatments _MaxAnd C _Tau) capability of fitting model and/or ANOVA model (if suitable).Estimate colony's G-bar according to corresponding 90%CI.This research is carried out according to the guideline of good Good Clinical Practice (GCPs).

The result: the result of this research is shown in following 3 table 3A-3C and Fig. 3-5.

Table 3A: average (CV%) MDZ PK parameter

The PK parameter	Independent MDZ	+20mg RTV	+50mg RTV	+100mg RTV	+200mg RTV
The PK parameter	Independent MDZ	+20mg RTV	+50mg RTV	+100mg RTV	+200mg RTV	AUC _{Infinitely great} (ng.hr/ml)	31.0(30.9)	101(28.7)	145(36.1)	219(49.0)	146(22.6)
C _Finally(ng/ml)	0.20(40.6)	1.53(42.4)	2.51(26.7)	3.34(23.1)	2.58(24.8)	AUC _{Infinitely great} (ng.hr/ml)	31.0(30.9)	101(28.7)	145(36.1)	219(49.0)	146(22.6)
C _Finally(ng/ml)	0.20(40.6)	1.53(42.4)	2.51(26.7)	3.34(23.1)	2.58(24.8)	Half-life (hr)	3.97(34.4)	7.83(38.9)	14.4(70.4)	22.4(70.7)	15.2(31.6)
CL(1/hr/kg)	0.447(27.9)	0.143(26.5) ¹	0.090(25.2) ^1，2	0.072(33.6) ^1，2	0.087(22.0) ^1，2	Half-life (hr)	3.97(34.4)	7.83(38.9)	14.4(70.4)	22.4(70.7)	15.2(31.6)

¹All+RTV dosage is different from independent MDZ (p＜0.05)

^1,2Compare p＜0.05 with 20mg, compare p=ns each other

Table 3B; Average (CV%) chemical compound 1 parameter

Parameter	Chemical compound 1+ 20mg RTV	Chemical compound 1+ 50mg RTV ¹	Chemical compound 1+ 100mg RTV ¹	Chemical compound 1+ 200mg RTV ¹
Parameter	Chemical compound 1+ 20mg RTV	Chemical compound 1+ 50mg RTV ¹	Chemical compound 1+ 100mg RTV ¹	Chemical compound 1+ 200mg RTV ¹	AUC _tau(ng.hr/ml)	10200 (36.3)	15800(24.4)	20300(24.8) ²	20600(24.3) ²
C _tau(ng/ml)	73.8 (60.2)	251(27.7)	380(39.9)	410(26.0)	AUC _tau(ng.hr/ml)	10200 (36.3)	15800(24.4)	20300(24.8) ²	20600(24.3) ²
C _tau(ng/ml)	73.8 (60.2)	251(27.7)	380(39.9)	410(26.0)	C _max(ng/ml)	1370 (43.0)	1560(36.4)	1830(20.1)	2030(37.4)
Half-life (hr)	4.34(34.1)	9.52(27.5)	11.5(28.8)	14.3(27.6) ²	C _max(ng/ml)	1370 (43.0)	1560(36.4)	1830(20.1)	2030(37.4)
Half-life (hr)	4.34(34.1)	9.52(27.5)	11.5(28.8)	14.3(27.6) ²	IQ	10.3	35.0	53.0	57.2
IC ₉₅Multiple	1.65	5.60	8.48	9.15	IQ	10.3	35.0	53.0	57.2

IQ and IC ₉₅The IC that multiple is adjusted based on the protein bound in PBMCs ₅₀And IC ₉₅

¹With regard to all PK parameters, RTV 50,100 and 200mg are different from 20mg

²Compare P＜0.05 with 50mg

Table 3C: average (CV%) RTV PK parameter

The PK parameter	Chemical compound 1+ 20mg RTV	Chemical compound 1+ 50mg RTV	Chemical compound 1+ 100mg RTV	Chemical compound 1+ 200mg RTV
The PK parameter	Chemical compound 1+ 20mg RTV	Chemical compound 1+ 50mg RTV	Chemical compound 1+ 100mg RTV	Chemical compound 1+ 200mg RTV	AUC _tau(ng.hr/ml)	135(54.9)	1120(61.4)	6550(26.9)	16000(43.9)
C _tau(ng/ml)	0.718(98.8)	11.6(66.2)	53.8(41.6)	78.5(36.7)	AUC _tau(ng.hr/ml)	135(54.9)	1120(61.4)	6550(26.9)	16000(43.9)
C _tau(ng/ml)	0.718(98.8)	11.6(66.2)	53.8(41.6)	78.5(36.7)	C _max(ng/ml)	19.5(56.7)	130(61.3)	807(29.5)	2460(50.5)
Half-life (hr)	4.74(34.3)	6.54(32.6)	6.34(18.4)	5.71(15.9)	C _max(ng/ml)	19.5(56.7)	130(61.3)	807(29.5)	2460(50.5)

-in some experimenter during by 16 hours RTV to expose as dose proportional, under 20mg and BLQ concentration, expose extremely low (＜0.5ng/ml)

-T _1/2Has dose dependent with MDZ clearance rate Notes of Key Data RTV first pass effect

-CV% is higher under dosage＜100mg

The co-administered of the chemical compound 1 of embodiment 4 emtricitabines/fumaric acid tenofovir ester and ritonavir-reinforcement

Give chemical compound 1 once a day and not only significantly strengthen exposing but also suppressing only metabolism (10-16 times) with low dose ritonavir.In addition, the chemical compound 1 of ritonavir-reinforcement has once a day reached high paddy concentration, thereby causes the inhibition index (IC that uses protein bound to adjust ₅₀) be chemical compound 1 do not strengthen more than 3 times of dosage regimen, allow late administration or not administration thus to a certain extent, be patient's dosage regimen that facilitates.Chemical compound 1 conduct of ritonavir-reinforcement is from having potent short-term activity, the simple new medicament of the new treatment type of dosage regimen once a day of favourable security feature and the scheme of support compliance, be treatment HIV, comprise the polytype patient of treatment experience, great potential is provided.

The fixed dosage of emtricitabine/fumaric acid tenofovir ester (FTC/TDF) is combined as advantages of simplicity and high efficiency NRTI drug combination, it has the security feature that is better than the thymidine analog, and is recommended as preferred nucleoside (nucleotide) principal agent of receiving treatment first and living through the adult and teenager HIV patient of treatment by U.S. Department of Health and Human Service (United States Department of Health andHuman Services).Carry out this study portion and be in order to estimate the interactional probability when its co-administered of related drugs-medicine clinically.

Interact for estimating pharmacokinetics (PK), this research is used the health volunteer to remove the potential Confounding Factor relevant with background scheme and has been avoided the short-term of therapeutic scheme in HIV patient to change.

Therefore, checked the probability of drug-drug interactions relevant clinically between the chemical compound 1 (chemical compound 1/r) of emtricitabine/fumaric acid tenofovir ester (FTC/TDF) and hiv integrase inhibitor ritonavir-reinforcement.

Give FTC/TDF (200mg/300mg to normal adults; 7 days once a day), under feeding state, accept chemical compound 1/r (50mg/100mg at random successively subsequently with interleaved mode; Once a day) and chemical compound 1/r+FTC/TDF 10 days.In the time of the 7th, 17 and 27 day, carry out pharmacokinetics (PK) blood draw.Will be to FTC, tenofovir (TFV) and chemical compound 1 no PK change are defined as the geometric average of main PK parameter 70-143% than (GMR; Co-administered; 90% confidence interval (CI) separately): observed maximal plasma concentration (C _Max), the area (AUC in the dosing interval under plasma concentration-time graph _Tau) and paddy concentration (C _Tau).

There are 24 among the experimenter of 26 registrations and finished this research, wherein do not have serious adverse events (seriousness AEs) or because of the AEs drug withdrawal.FTC, TFV and chemical compound 1PK are unaffected in the co-administered process, and all three kinds of major parameters all satisfy the definition of equivalence scheme and satisfy stricter bioequivalence standard (90%CI; 80-125%).FTC and TFV PK parameter are suitable with history value.

FTC/TDF and chemical compound 1/r do not have relevant clinically drug-drug interactions when its co-administered.

There is not relevant clinically drug-drug interactions between the hiv integrase inhibitor chemical compound 1/r of embodiment 5 ritonavir-reinforcements and the zidovudine (ZDV)

Zidovudine is the NRTI that is used for HIV patient.In randomised study, measured the probability of drug interaction between zidovudine and the chemical compound 1/r.Whether the pharmacokinetics of having estimated zidovudine or chemical compound 1 is compared with individually dosed behind zidovudine+chemical compound 1/r giving jointly, be affected.In addition, estimated the safety of the co-administered of zidovudine+chemical compound 1/r.

As described below, there is not relevant clinically pharmacokinetics drug-drug interactions between zidovudine and the chemical compound 1/r.The co-administered of zidovudine and chemical compound 1/r is safe and abundant tolerance.Chemical compound 1 shows the half-life of supporting administration once a day, and this administration once a day continues 48 hours after administration.

To study medicine (chemical compound 1/r 200/100mg QD, ZDV 300mg BID) gives together with meals (～400kcal, 13g fat).At 12 (ZDV) or carried out pharmacokinetics (PK) sampling in 24 hours during (chemical compound 1/r).After administration in the 27th day, measure 48 hours PK characteristics of chemical compound 1.Use the LC/MS/MS algoscopy of checking to measure ZDV, G-ZDV and chemical compound 1 blood plasma level.Use WinNonlin ^TM5.0.1 (Pharsight Corporation, Mountain View, CA, USA) assessment PK parameter.With regard to AUC _Tau, C _MaxAnd C _TauThe geometric average of (only chemical compound 1) is than (GMR), and the equivalence scope of 90% confidence interval (CI) is set in 70%-143% (co-administered; Separately).

The consensus data.Register 28 experimenters and 24 experimenters have finished this research (12 male, 12 women; Mean age; 31 years old (scope: 20 years old-42 years old); Average weight: 70.2kg (scope: 50.9kg-101kg); Race: 20 Spaniards, 4 Caucasians).

Safety.There are not 3/4 grade of adverse events (AEs) or serious adverse events.4 drug withdrawals are arranged; Gestation (1) withdraws from informed consent (1), vomiting (1; ZDV+ chemical compound 1/r organizes (arm)), abdominal distention (1; The ZDV group).Generally speaking separately and unite and give chemical compound 1/r and ZDV for abundant tolerance.Occur the most frequent AEs in the treatment group and be headache and pernicious.All AEs are light to moderate and are resolved when treatment.

Pharmacokinetics result.ZDV, G-ZDV and chemical compound 1AUC _Tau, C _MaxAnd C _Tau(only chemical compound 1) 90%CI is in predetermined PK equivalence scope, and wherein ZDV and G-ZDV PK and history value are similar.

Food effect

The present invention also provides and has been used to improve chemical compound 1 in the method to the pharmacokinetic properties after patient's administration.The present invention also provides and has been used to improve chemical compound 1 in treatment or prevent disease, the method for the treatment effectiveness in disease and the illness.

Disease, the example of disease or illness include, but are not limited to retroviral infection or the disease relevant with retroviral infection, disease or illness.Can also give chemical compound 1 so that suppress the activity of retrovirus integrase to the patient.In one embodiment of the invention, described retrovirus is HIV.

Do not estimate the pharmacokinetic study of food in the past to the influence of chemical compound 1 pharmacokinetics.Generally speaking, food has variable influence to the bioavailability and the absorption of activating agent.Medicine-food interacts and may cause the systemic drug availability to descend, and delays or increases.For example, referring to Welling, Clin.Pharmacokinet., 9; 404-434 (1984).

Have been found that in the method for the treatment effectiveness that in this class patient, improves chemical compound 1, can give the patient chemical compound 1.When with the food administration, chemical compound 1 shows the bioavailability and the absorption of raising in the patient.

Therefore, the invention provides and improve the bioavailability of chemical compound 1 in the patient and the method for absorption, it comprises the chemical compound 1 of this patient being treated effective dose with food.

It is 10/492 that chemical compound 1 is described in the serial number of submitting on November 20th, 2003, the serial number that 833 U.S. Patent application (U.S. Patent Application Publication No. is 2005/0239819) and on May 20th, 2005 submit to is 11/133, in 463 the U.S. Patent application (U.S. Patent Application Publication No. is 2005/0288326), these documents intactly are incorporated herein by reference.Chemical compound 1 exists with at least three kinds of different crystal forms.Crystal formation I, II and III are described in the international patent application that publication number is WO05/113508, also the document intactly are incorporated herein by reference.These three kinds of crystal formations can be distinguished by differential scanning heat meter (DSC) and x-ray powder diffraction instrument (XRD).Any in these crystal formations all can be used for the present invention.In one embodiment of the invention, give crystal form II or III or its mixed crystal to the patient.

Although the administration of chemical compound 1 is a specific embodiments of the present invention, the present invention also pays close attention to other chemical compound that produces chemical compound 1, for example administration of the prodrug of chemical compound 1.For example, this class prodrug can comprise having protecting group, but in patient's body (promptly in vivo) still cause the chemical compound that chemical compound 1 forms.The carboxylic acid protecting group comprises, for example alkyl esters and benzyl esters, and they can be respectively be removed by acid or alkali and hydrogenolysis.In addition, can dissociate in vivo according to method afford of the present invention and generate the chemical compound with any organic residue of chemical compound 1.Therefore, the present invention also pay close attention to chemical compound 1 ' administration (wherein R ' represents organic residue) so that obtain chemical compound 1

(chemical compound 1 ')

The present invention further pays close attention to the administration of the pharmaceutically acceptable salt of chemical compound 1.For example, can be by making chemical compound 1 and mineral acid, organic acid, inorganic base, the pharmaceutically acceptable salt of organic base or aminoacid reaction acquisition chemical compound 1, all example hydrochloric acids of described mineral acid, sulphuric acid, phosphoric acid, hydrobromic acid etc.; Described organic acid such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzyl sulfonic acid etc.; Described inorganic base is such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide etc.; Described organic base is such as methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, trihydroxymethylaminomethane, guanidine, choline, cinchonine etc.; Described aminoacid is such as lysine, arginine, alanine etc.The present invention also comprises the aqueous product and the solvate of chemical compound 1, such as administration of hydrate etc.

Therefore, " giving ... chemical compound 1 " used herein means any chemical compound 1 form that gives to provide in vivo chemical compound 1.

Term used herein " bioavailability " means that active component discharges and in site of action become available speed and degree from drug products.Referring to U.S.Code of FederalRegulations, Title 21, Part 320.1 (2001 ed.).With regard to peroral dosage form, bioavailability relates to active component from peroral dosage form, for example discharges in the tablet and moves to site of action, for example is absorbed into the process of systemic circulation.Therefore, term " absorption " means chemical compound 1 on its site of action, and for example blood flow or immunocyte are such as the existence in T cell or the macrophage.

The situation that consumes food the time limit process after term used herein " with food " or " ingesting " mean from the administration precontract of chemical compound 11 hour to the administration of chemical compound 1 about 2 hours.In another embodiment, " with food " or " ingesting " means from consuming food precontract 1 hour to consuming the situation that gives chemical compound 1 after the food the process about 2 hours." food " used herein means liquid and food.Food can also be low-fat diet, high fat diet, the food that is easy to digest or stodgy food.In one embodiment of the invention, food is the food that can not dissolve fast and absorb under one's belt with enough volumes and fat content.Food can be meals, such as breakfast, and Chinese meal or dinner.In addition, can give, for example, consume food involuntaryly by the patient by intravenous by machinery.Selectively, the patient can consume food voluntarily.

Any time that can the same day gives chemical compound 1 with food.Generally can consume food in the administration precontract of the chemical compound 11 hour any time during between about 2 hours after the administration of chemical compound 1.For example, can be at chemical compound 1 administration precontract 1 hour, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes or about 5 minute time period internal consumption food.Similarly, can be after chemical compound 1 administration 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, consumed food in about 1.75 hours or about 2 hours.In another embodiment, " with food " or " ingesting " means from consuming food precontract 1 hour to consuming the situation that gives chemical compound 1 after the food the time limit process about 2 hours.For example, can consume food precontract 1 hour, about 45 minutes, about 30 minutes, about 15 minutes, give chemical compound 1 in about 10 minutes or about 5 minutes time period.Similarly, can be after consuming food 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, give chemical compound 1 in about 1.75 hours or about 2 hours time period.In another embodiment of the invention, can (for example ingesting back about 1 minute in) at once after ingesting, the back gave chemical compound 1 in about 1 hour up to ingesting.Ideally, give chemical compound 1 simultaneously with food basically.

Term used herein " not with food " or " fasting " mean the situation that does not consume food in about 2 hours time period after chemical compound 1 administration chemical compound 1 administration precontract 1 hour.

Method of the present invention comprises the chemical compound 1 for the treatment of effective dose.With regard to give unification compound 1 with food with regard to, in the treatment of 1 pair of patient's administration of chemical compound the suitable dosage of effective dose at about 10mg to about 2000mg/ days.In one embodiment of the invention, suitably dosage was about 400mg to about 1600mg/ days.In another embodiment of the invention, suitably dosage was about 600mg to about 1200mg/ days.In another embodiment of the invention, suitably dosage is about about 800mg/ days.

If desired, can with chemical compound 1 effective every day dosage as twice, three time that in whole day, gives separately with appropriate intervals, four times, five times, the sub-doses more than six times or six times (sub-dose) is chosen administration in unit dosage forms wantonly.According to method of the present invention, can be with chemical compound 1 with food repeatedly or selectively to give once a day every day.In one embodiment of the invention, chemical compound 1 is given once or twice with food every day.

Term used herein " unit dosage forms " means the form to patient's administered compound 1.Unit dosage forms can for, for example pill, capsule or tablet.In one embodiment of the invention, unit dosage forms is a tablet.In one embodiment of the invention, unit dosage forms comprises the chemical compound 1 of about 10mg to about 2000mg.In one embodiment of the invention, unit dosage forms comprises the chemical compound 1 of about 50mg or 200mg and is tablet form.In another embodiment of the invention, unit dosage forms comprises the chemical compound 1 of about 125mg or 150mg and is tablet form.

In another embodiment of the invention, the purity of chemical compound is not less than 95%.More preferably, the purity of chemical compound 1 is not less than 98%.

Can with the concentration determination of chemical compound 1 in blood flow plasma concentration (ng/mL).The pharmacokinetic parameter that is used to measure plasma concentration includes, but are not limited to observed maximal plasma concentration (C _Max), from 0 o'clock to finally can quantitative time point (AUC _0-t) the plasma concentration time graph under area (AUC), from 0 o'clock to infinitely great (AUC _{The 0-infinity}) AUC, the time (t of observed maximal plasma concentration after the administration _Max) and the half-life (t of chemical compound 1 in blood plasma _1/2).

Value when not giving with food with chemical compound 1 is compared, and chemical compound 1 causes the C of chemical compound 1 with food _MaxAnd/or AUC _{The 0-infinity}Increase, this bioavailability that confirms chemical compound 1 improves.

Give the absorption that chemical compound 1 can also increase chemical compound 1 according to method of the present invention with food.Can be according to the absorption of the concentration determination chemical compound 1 in blood flow that after chemical compound 1 administration, obtains in time.Can also be according to the C that does not compare chemical compound 1 with chemical compound 1 with food _MaxAnd/or AUC _{0-is infinitely-great}Increase and confirm that chemical compound 1 increases with the absorption that food gives to be caused.

The present invention also provides treatment or prevent disease, the method for disease and illness.Disease, the example of disease or illness include, but are not limited to retroviral infection or the disease relevant with retroviral infection, disease or illness.Retrovirus is RNA viruses and generally is categorized into α retrovirus, β retrovirus, δ retrovirus, ε retrovirus, γ retrovirus, slow virus and Spumavirinae.Retroviral example includes, but are not limited to human immunodeficiency virus (HIV), people T-lymphocyte virus (HTLV), rous sarcoma virus (RSV) and avian leukosis viruses.Generally speaking, the reverse transcription virus gene group has the protein of three kinds of gene encoding mature viruses: the gag of promptly encode virus core and structural protein (group specificity antigen) gene; The coding viral enzyme comprises reverse transcriptase, the pol of protease and intergrase (polymerase) gene; Env (peplos) gene with the encoding hiv reverse transcriptase surface protein.

Retrovirus is by being released into the host cell adhesion such as the complex of RNA and pol product (except other material) and invading host cell.Reverse transcriptase produces double-stranded DNA by viral RNA subsequently.This double-stranded DNA is transfused to host cell nuclear and is integrated into the host cell gene group by the viral integrase enzyme.When integrating viral DNA and changed into mRNA and virus protease effect and produce virus and forms requisite protein, form newborn viral by dna integration by the host cell polymerase.Virion carries out budding and discharges and the ripe virus of formation from host cell.

One embodiment of the invention provide and have been used to suppress the active method of patient's retrovirus integrase, and it comprises treats the chemical compound 1 of effective dose to this patient with food.In a specific embodiment of the present invention, described retrovirus is HIV." inhibition " used herein means at least a and protein, active decline or termination that enzyme or any other chemical compound are relevant.

Another embodiment of the invention provides the method that is used for the treatment of or prevents retroviral infection, and it comprises treats the chemical compound 1 of effective dose to the patient with food.In a specific embodiment of the present invention, described retrovirus is HIV.

Can give chemical compound 1 with any usual manner.Although chemical compound 1 can be given as starting compound, preferably it be given as pharmaceutical composition." pharmaceutical composition of inclusion compound 1 " means the pharmaceutical composition of inclusion compound 1 or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient and optional other therapeutic agent and/or composition.Described salt, carrier or excipient must be acceptable, its implication for other component compatibility and harmless for its receiver.Be used for the carrier of oral administration or the example of excipient and comprise corn starch, lactose, magnesium stearate, Pulvis Talci, microcrystalline Cellulose, stearic acid, polyvidone, crospovidone, calcium hydrogen phosphate, sodium starch glycollate, hydroxypropyl cellulose (for example low hydroxypropyl cellulose that replaces), hydroxypropyl emthylcellulose (for example hydroxypropyl methylcellulose 2910) and sodium lauryl sulphate.

Can pass through the prepared by any suitable process pharmaceutical composition, such as those well-known methods of pharmaceutics field, for example, such as Remington ' sPharmaceutical Sciences (the 18th ed. that is described in Gennaro etc., Mack Publishing Co., 1990), the 8th part especially; Those methods among the Pharmaceutical Preparations and their Manufacture.These class methods comprise chemical compound 1 and carrier or excipient and choose any one kind of them or the blended step of multiple helper component.This class helper component comprises those components commonly used in this area, such as filler, binding agent, and diluent, disintegrating agent, lubricant, coloring agent, correctives and wetting agent.

Pharmaceutical composition can provide the controlled release of chemical compound 1 at certain hour in the time limit, slow release or lasting release.Compare with common dosage forms, the controlled release of chemical compound 1, slow release or lasting release can be kept chemical compound 1 longer time in patient's blood flow.Pharmaceutical composition includes, but are not limited to coated tablet, pill and capsule and the dispersion of chemical compound 1 in medium, described medium is insoluble to physiological fluid, or wherein treat chemical compound at pharmaceutical composition because of machinery, chemistry or enzymatic activity and the back of degrading discharges.

Pharmaceutical composition of the present invention can be, pill for example, capsule or tablet form, and chemical compound 1 of their each self-contained scheduled volumes and preferred coating are powder or particle form or solution or suspension form so that easy-to-swallow.In one embodiment of the invention, pharmaceutical composition is described in inclusion compound 1 and this paper embodiment and the tablet form of the composition that uses.

With regard to oral administration, fine powder or granule can comprise diluent, dispersant and surfactant and for example may reside in water or syrup in, be present in capsule or the sachet with drying regime, or be present in non-aqueous solution or the suspension, wherein can comprise suspending agent, or be present in the tablet, wherein can comprise binding agent and lubricant.Pharmaceutical composition can also comprise extra composition, such as sweeting agent, and correctives, antiseptic (for example anti-microbial preservative), suspending agent, thickening agent and/or emulsifying agent.

When with liquid solution or suspension form administration, preparation can inclusion compound 1 and pure water.Optional ingredients comprises suitable sweeting agent in liquid solution or suspension, correctives, and antiseptic (for example anti-microbial preservative), buffer agent, solvent, and composition thereof.The composition of preparation can have more than one functions.For example, suitable reducing also can be used as correctives and sweeting agent works.

Suitable sweeting agent comprises, for example saccharin sodium, sucrose and mannitol.Can use the mixture of two or more sweeting agents.Sweeting agent or its mixture generally exist with the amount that accounts for total composition weight about 0.001% to about 70%.Suitable correctives may reside in the pharmaceutical composition so that Fructus Pruni pseudocerasi fragrance is provided, and cotton sugared fragrance or other suitable fragrance are so that this pharmaceutical composition is easy to take in into the patient.Correctives or its mixture generally exist with the amount that accounts for total composition weight about 0.0001% to about 5%.

Suitable antiseptic comprises, for example methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate and benzalkonium chloride.Can use the mixture of two or more antiseptic.Antiseptic or its mixture generally exist with the amount that accounts for total composition weight about 0.0001% to about 2%.

Suitable reducing comprises, citric acid for example, sodium citrate, phosphoric acid, potassium phosphate and different other acid and salt.Can use the mixture of two or more buffer agents.Buffer agent or its mixture generally exist with the amount that accounts for total composition weight about 0.001% to about 4%.

The suitable solvent that is used for liquid solution or suspension comprises, for example sorbitol, glycerol, propylene glycol and water.Can use the mixture of two or more solvents.Solvent or solvent system generally exist with the amount that accounts for total composition weight about 1% to about 90%.

Pharmaceutical composition and auxiliary agent can be given jointly.For example, can be with nonionic surfactant, give or mix pharmaceutical composition jointly such as polyoxyethylene oleyl ether and n-hexadecyl polyvinylether and pharmaceutical composition, with artificial increase intestinal wall permeability.Enzyme inhibitor can also be given or mix pharmaceutical composition with pharmaceutical composition.

The present invention also provides kit (kit), and it comprises: (i) pharmaceutical composition of inclusion compound 1 or its pharmaceutically acceptable salt and its pharmaceutically acceptable carrier, the information of (ii) prescribing; (iii) container.The information of prescribing can provide the method for otherwise discussing with the inventive method and/or this paper the consistent information of prescribing.In one embodiment of the invention, the information of prescribing comprises with food orally give chemical compound 1, so that improve the bioavailability and the absorption of chemical compound 1.

Chemical compound 1 can be offered the patient in being associated with the container of the information of prescribing, the described message advises patient who prescribes is with the Orally administered chemical compound 1 of food and can explain that administration like this will improve the bioavailability of chemical compound 1.Chemical compound 1 can also be offered the patient in being associated with the container of the information of prescribing, the described message advises patient who prescribes causes the absorption of chemical compound 1 to increase with food administered compound 1, gives than under fasting state as the maximal plasma concentration according to chemical compound 1 that this chemical compound increase reflected.

Illustrate the influence of food to the treatment effectiveness of the pharmacokinetic properties of chemical compound 1 and chemical compound 1 by the following example, these embodiment play the qualification effect never in any form.

Embodiment 6

For clinical research chemical compound 1, chemical compound 1 is made the unit dosage forms of 50mg and 200mg tablet.Chemical compound 1 is with crystal formation I, and crystal form II and crystal form II I exist.Crystal form II I is used for final preparation, but the mixed crystal of crystal form II or crystal form II and crystal form II I also is used for preparation research.

The preparation of the 200mg tablet of chemical compound 1The final composition of 200mg tablet is as shown in table 1.

Table 1

Composition	Function	Consumption in every
Composition	Function	Consumption in every	Chemical compound 1	Drug substance	200.0mg
The D-mannitol	Diluent	107.6mg	Chemical compound 1	Drug substance	200.0mg
The D-mannitol	Diluent	107.6mg	Light anhydrous silicic acid	Fluidizer	25.0mg
Sodium lauryl sulphate	Surfactant	10.0mg	Light anhydrous silicic acid	Fluidizer	25.0mg
Sodium lauryl sulphate	Surfactant	10.0mg	Crospovidone	Disintegrating agent	25.0mg
Hydroxypropyl methylcellulose 2910 (3mm ²/s)	Binding agent	20.0mg	Crospovidone	Disintegrating agent	25.0mg
Hydroxypropyl methylcellulose 2910 (3mm ²/s)	Binding agent	20.0mg	Pure water ^＊1	Binding agent	-
Cross-linking sodium carboxymethyl cellulose	Disintegrating agent	100.0mg	Pure water ^＊1	Binding agent	-
Cross-linking sodium carboxymethyl cellulose	Disintegrating agent	100.0mg	Magnesium stearate	Lubricant	2.4mg
Total sheet is heavy		490.0mg	Magnesium stearate	Lubricant	2.4mg

^{* 1}In the course of processing, remove pure water.

At first use jet mill to make chemical compound 1 micronization.With micronized compound and D-mannitol (Japanese Pharmacopoeia JP), and crospovidone (Japanese pharmaceutic adjuvant, JPE) and light anhydrous silicic acid (JP) mixes in polyethylene (PE) bag and make it pass through 500 μ m sieve three times then.By stirring separately with hydroxypropyl emthylcellulose (HPMC) 2910 (3mm ²/ s) (JP) be dissolved in pure water and add sodium lauryl sulphate (JP) and make it dissolving.D-mannitol/crospovidone/light anhydrous silicic acid/chemical compound 1 mixture is put into fluidised bed granulator and used the HPMC/ sodium dodecyl sulfate solution to granulate.After granulation, dry wet particle in identical granulator.Make dried granules pass through 500 μ m sieve.

Then the granule that sieves is mixed and adds magnesium stearate (JP) with cross-linking sodium carboxymethyl cellulose (JPE) in the PE bag in bag.Use rotary tablet machine that this granule is pressed into tablet.

20 are packaged in the vial that contains desiccant and course (PE sheet) and with the capping of polypropylene (PP) screw-cap.

The preparation of the 50mg tablet of chemical compound 1The final composition of 50mg tablet is as shown in table 2.

Table 2

Composition	Function	Consumption in every
Composition	Function	Consumption in every	Chemical compound 1	Drug substance	50.0mg
The D-mannitol	Diluent	26.9mg	Chemical compound 1	Drug substance	50.0mg
The D-mannitol	Diluent	26.9mg	Light anhydrous silicic acid	Fluidizer	6.25mg
Sodium lauryl sulphate	Surfactant	2.5mg	Light anhydrous silicic acid	Fluidizer	6.25mg
Sodium lauryl sulphate	Surfactant	2.5mg	Crospovidone	Disintegrating agent	6.25mg
Hydroxypropyl methylcellulose 2910 (3mm ²/s)	Binding agent	5.0mg	Crospovidone	Disintegrating agent	6.25mg
Hydroxypropyl methylcellulose 2910 (3mm ²/s)	Binding agent	5.0mg	Pure water ^＊1	Binding agent	-
The D-mannitol	Diluent	145.35mg	Pure water ^＊1	Binding agent	-
The D-mannitol	Diluent	145.35mg	Microcrystalline Cellulose	Diluent	145.35mg
Cross-linking sodium carboxymethyl cellulose	Disintegrating agent	100.0mg	Microcrystalline Cellulose	Diluent	145.35mg
Cross-linking sodium carboxymethyl cellulose	Disintegrating agent	100.0mg	Magnesium stearate	Lubricant	2.4mg
Total sheet is heavy		490.0mg	Magnesium stearate	Lubricant	2.4mg

^{* 1}In the course of processing, remove pure water.

The size of 50mg tablet is identical with the 200mg tablet with weight.In order to simplify preparation process, the granule that sieves by using the chemical compound 1 of preparation as mentioned above is as raw material and dilute this granule with direct compression excipients and carry out the 50mg tablet formulation.But cause and the compatibility of chemical compound 1 and the briquettability and the disintegration properties of tablet are elected to be the dilution excipient with D-mannitol and microcrystalline Cellulose.Table 3 has shown that the granule that uses chemical compound 1 to sieve forms as the tablet of raw material.

Table 3

Composition	Consumption in every
Composition	Consumption in every	Chemical compound 1 granule	96.9mg
The D-mannitol	145.35mg	Chemical compound 1 granule	96.9mg
The D-mannitol	145.35mg	Microcrystalline Cellulose	145.35mg
Cross-linking sodium carboxymethyl cellulose	100.0mg	Microcrystalline Cellulose	145.35mg
Cross-linking sodium carboxymethyl cellulose	100.0mg	Magnesium stearate	2.4mg
Total sheet is heavy	490.0mg	Magnesium stearate	2.4mg

With the sieve granule and the cross-linking sodium carboxymethyl cellulose (JPE) of above-mentioned preparation, D-mannitol (JP) and microcrystalline Cellulose (JP) mix in the PE bag, add magnesium stearate (JP) subsequently in bag.Use rotary tablet machine that granule is pressed into tablet then.

Embodiment 7

Blind at the list that 32 Japanese men's health volunteers are carried out, randomization, the single oral dose of placebo progressively rises and identifies the influence of food to the pharmacokinetic properties of chemical compound 1 in the research.

Use the experimenter of this research of following Standard Selection:

(1) age is the 20-35 healthy Japanese male in year;

(2) Body Mass Index (BMI) is 18.5-25.0, wherein BMI=[body weight (kg)/height (m)] ²With

(3) before participating in this research, obtain the experimenter of written informed consent.

As the ingredient of bigger research, 8 experimenters (6 are used activating agent and 2 use placebo) accept 400mg dosage under fasting and feeding state.Experimenter in 400mg fasting group accepts extra 400mg dosage in removing phase (generally after initial administration minimum 10 days) back with breakfast.10 days interval between 2 dosage is considered as being suitable for eliminating residual (carryover) effect of any experimenter inside.

Be the treatment time limit that the food action component of bigger research gives, dosage, administering mode and product are as shown in table 4.

Table 4

The experimenter was taken in medical institutions afternoon the same day (" the-1 day ") before administration.Gave chemical compound 1 or placebo the same day (" the 1st day ") after being in hospital.The same day after administration, (" the 2nd day ") allowed the experimenter leave hospital.Therefore, the experimenter amounts to and was in hospital 3 days.6-8 days (" 7-9 days ") are carried out safety and are followed up a case by regular visits to evaluation after administration.

Use 200mL mouth of a river clothes to give chemical compound 1 or placebo.Every experimenter is given the dosage of similar number of times in each treatment time limit.Fasting and fluid after (the-1 day) dinner on the same day of all experimenters before administration are up to the 1st day breakfast (for accept the experimenter of chemical compound 1 or placebo under feeding state) or till the 1st day lunchtime (for the experimenter under the fasting state).

When giving chemical compound 1 to the experimenter under feeding state, they accepted breakfast in 30 minutes in the administration precontract.Breakfast is made up of following material:

The 160mL Sucus Mali pumilae

Boiled egg (50g)

Roll (105g)

The 8g butter

The 14g strawberry jam

Total energy content: 574.6Kcal; Total lipid content: 21.4g (total caloric 33%); Total protein: 17.5g (total caloric 12%); Total carbohydrates: 79.0g (total caloric 55%).

Following time before administration and after administration is gathered the blood sample that is used for pharmacokinetic analysis: preceding 1.5 hours of administration, and after the administration 0.25,0.5,1,2,3,4,6,8,12 and 24 hours.

In each seminar, chemical compound 1 is calculated following pharmacokinetic parameter (ingesting and fasted conditions):

t _MaxThe time of observed maximal plasma concentration;

C _MaxObserved maximal plasma concentration;

T _{1/2 λ z}The elimination half-life in latter stage;

AUC _0-tzFrom 0 o'clock area (AUC) under finally can the plasma concentration-time graph of quantitative concentration (AUC (0-tz)); With

AUC _{The 0-infinity}From the infinitely-great AUC of 0-.

Measure the plasma concentration of chemical compound 1 by following algoscopy.Separated plasma sample from the health volunteer who gives chemical compound 1.By using Empore ^TMDisk Plate (C8SD) solid phase extractions is extracted plasma sample and is passed through high performance liquid chromatography/polyphone mass spectrography (LC/MS/MS) (HPLC 2795 type separation assemblies that Waters produces then; The API4000 type mass spectrograph that MDS SCIEX produces) measures.Use the cation detection of electrospray ionization and the monitoring of application multiple reaction to carry out ionization and detection respectively.At selectivity, linear, lower limit of quantitation (LLOQ), in the algoscopy and degree of accuracy and accuracy between algoscopy, standard solution stability, substrate stability, the preparation rear stability, this analytical method has been verified in recovery and dilution integrity aspect, and when using 50 μ L human plasmas, it is considered as being used to measure the abundant reasonable method of the chemical compound 1 in the 1-1000ng/mL concentration range.

To mixed 90% acetonitrile and 20mmol/L ammonium formate-formic acid buffer (pH 3.0)/acetonitrile (10: 90, v/v) add 10 μ L inner mark solutions separately in the 50 μ L plasma samples of each 10mL.Adding 200 μ L are dissolved in 0.1% formic acid in 10% acetonitrile in these samples.Then these solution were mixed 10 seconds and under 4 ℃ with 10, centrifugal 5 minutes of 000rpm.250 μ L supernatant aliquots are joined Empore ^TMAmong the Disk Plate (C8SD) (in this order, regulating) with 150 μ L acetonitriles and 200 μ L, 0.1% formic acid.Be dissolved in twice of 0.1% formic acid eluting (total) in 80% acetonitrile with 0.1% formic acid of 200 μ L in 20% acetonitrile with dull and stereotyped washed twice and with 100 μ L with 200 μ L.0.1% formic acid and the mixing that in eluent, add 200 μ L.Then, each solution with 10 μ L injects LC/MS/MS system and analysis.

According to the C behind orally give 400mg chemical compound 1 under fasting and the feeding state _MaxAnd AUC _{The 0-infinity}Estimate to have the geometric average of 90% confidence interval than (ingesting/fasting).

The time dependent mean plasma concentration in orally give 400mg chemical compound 1 back as shown in Figure 2 under fasting and feeding state.Will be under fasting and feeding state the pharmacokinetic parameter AUC of chemical compound 1 _{The 0-infinity}(ng-hr/mL), C _Max(ng/mL), T _{1/2 λ z}(hr) and t _Max(hr) average result of the test is summarised in the table 5 and makes table 6.

Table 5

Dosage: 400mg

Mean+SD (n=6)

Table 6

Dosage: 400mg

N=6 position experimenter/every group

Fig. 2, table 5 and table 6 demonstration, when under feeding state, giving chemical compound 1, the C of unaltered medicine _MaxAnd AUC _{The 0-infinity}3.30 and the 2.69-that are higher than those values under fasting state respectively are doubly.These results show, improve in bioavailability that chemical compound 1 in the presence of the food is arranged and absorption.

The increase of viewed pharmacokinetic parameter shows chemical compound 1 when giving with food when giving chemical compound 1 with food, such as being easier to absorb after the meal.Improve when therefore, chemical compound 1 causes this bioavailability of medicament than administration under fasted conditions with food.In addition, chemical compound 1 for safety and fully can tolerate, do not have serious adverse events.All adverse events are slight.Significantly electrocardiogram (ECG) change clinically not to be noted.

All lists of references with this paper citation comprise open source literature, and patent application and patent intactly are incorporated herein by reference.

Unless indication is arranged in this article in addition or obviously opposite explanation is arranged in context in addition, otherwise the term of in describing context of the present invention (claim below comprising), using " a kind of (a) " and " a kind of (an) " and " described (the) " and similarly refer to speech and should be interpreted as covering odd number and plural number.Unless otherwise stated, otherwise term " comprises ", and " having ", " comprising " and " containing " should be interpreted as open-ended term (promptly meaning " including, but are not limited to ").Unless otherwise stated, otherwise the citation scope of this paper numerical value is only as meaning the stenography that falls into each the single value in the described scope separately, and the numerical value that each is independent introduces this description, just as it is quoted from separately in this article.Unless otherwise stated or obviously opposite description is arranged in the context, otherwise can implement all methods as herein described with any suitable order.Unless otherwise stated, otherwise the application of any and all embodiment provided herein or exemplary language (for example, " such as ") only be intended for use to illustrate the present invention better, but do not constitute limitation of the scope of the invention.In this manual should be with any linguistic interpretation for not representing that any key element of not asking for protection is for implementing the present invention for requisite.

Embodiment in this description provides the illustrating of embodiment of the present invention, but should not be interpreted as limiting the scope of the invention.Those skilled in the art recognize that, comprise many other embodiments among the present invention who asks for protection, and plan only this description and embodiment to be considered as typically, exact range of the present invention and spirit are represented by following claim.

Claims

1. ritonavir or its pharmaceutically acceptable salt are used for improving HTV integrase inhibitor or the purposes of its pharmaceutically acceptable salt in the medicament of patient's pharmacokinetics in preparation.

2. the described purposes of claim 1, wherein said integrase inhibitor is chemical compound or its pharmaceutically acceptable salt of formula (I):

Wherein

Described heterocyclic radical is to comprise the heteroatomic saturated or unsaturated ring that at least one is selected from nitrogen, oxygen and sulfur;

R ^A1And R ^A2Identical or different and the H that respectively does for oneself, C _1-4Alkyl or benzyl;

R ^A3Be C _1-4Alkyl;

Group B is:

-OR ^a4；

-SR ^a4；

-NR ^a4R ^a5；

-CONR ^a4R ^a5；

-SO ₂NR ^a4R ^a5；

-COR ^a6；

-NR ^a4COR ^a6；

-SO ₂R ^a6；

-NR ^a4SO ₂R ^a6；

-COOR ^A4Or

-NR ^a5COOR ^a6；

R ^A4And R ^A5Identical or different and respectively do for oneself:

H；

C _1-4Alkyl;

R ^A6For:

C _1-4Alkyl;

R ²Be H or C _1-4Alkyl;

X is C-R ³²Or N;

Y is C-R ³³Or N;

R ³²And R ³³Identical or different and respectively do for oneself:

H；

Cyano group;

Nitro;

Halogen;

-OR ^a7；

-SR ^a7；

-NR ^a7R ^a8；

-NR ^a7COR ^a9；

-COOR ^A10Or

-N＝CH-NR ^a10R ^a11；

R ^A9Be C _1-4Alkyl; And

R ^A10And R ^A11Identical or different and respectively do for oneself H or C _1-4Alkyl.

3. the described purposes of claim 1, the blood concentration of wherein said integrase inhibitor or its pharmaceutically acceptable salt obtain increasing.

4. the chemical compound of ritonavir or its pharmaceutically acceptable salt and formula (I) or its pharmaceutically acceptable salt are used for suppressing purposes in the medicament of patient's hiv integrase in preparation,

Wherein

R ^A3Be C _1-4Alkyl;

Group B is:

-OR ^a4；

-SR ^a4；

-NR ^a4R ^a5；

-CONR ^a4R ^a5；

-SO ₂NR ^a4R ^a5；

-COR ^a6；

-NR ^a4COR ^a6；

-SO ₂R ^a6；

-NR ^a4SO ₂R ^a6；

-COOR ^A4Or

-NR ^a5COOR ^a6；

R ^A4And R ^A5Identical or different and respectively do for oneself:

H；

C _1-4Alkyl;

R ^A6For:

C _1-4Alkyl;

Optional by 1-5 C that is selected from the substituent group replacement of group A _3-10Carbocyclic ring; Or

R ²Be H or C _1-4Alkyl;

X is C-R ³²Or N;

Y is C-R ³³Or N;

R ³²And R ³³Identical or different and respectively do for oneself:

H；

Cyano group;

Nitro;

Halogen;

-OR ^a7；

-SR ^a7；

-NR ^a7R ^a8；

-NR ^a7COR ^a9；

-COOR ^A10Or

-N＝CH-NR ^a10R ^a11；

R ^A9Be C _1-4Alkyl; And

5. the described purposes of claim 4, the chemical compound of its Chinese style (I) or its pharmaceutically acceptable salt are hiv integrase inhibitor.

6. any described purposes among the claim 2-5, the chemical compound of its Chinese style (I) is 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid.

7. any described purposes among the claim 1-6, wherein with described chemical compound or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt as single compositions to patient's administration.

8. any described purposes among the claim 1-7 is wherein with described chemical compound or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt oral administration.

9. the described purposes of claim 8, wherein said oral administration is for once a day.

10. any described purposes among the claim 1-9, wherein said patient also accepts one or more medicines, it is selected from stavudine, emtricitabine, tenofovir, emtricitabine, Abacavir, lamivudine, zidovudine, didanosine, prick his shore of former times, phosphazide, efavirenz, nevirapine, dilazep Wei Ding, tipranavir, Saquinavir, indinavir, atazanavir, Nai Fennawei, ammonia Pune Wei, samprenavir, that Wei of furan mountain, Lopinavir, ritonavir, En Fuwei ground, fozivudine tidoxil, alovudine, right Ai Fuxita shore, the A Lita shore, the many Suo Wei of ammonia, Ai Fuxita shore (ACH126443), La Xiwei (raceme FTC, PSI-5004), MIV-210, KP-1461, the phosphorus husband decides ester (HDP 99.0003), AVX756, dioxolanes thymus pyrimidine (DOT), TMC-254072, INK-20,4 '-Ed4T, TMC-125 (according to bent Wei Lin), capravirine, TMC-278 (a sharp Wei Lin), GW-695634, the plain A of poon, BILR 355 BS and VRX 840773, and pharmaceutically acceptable salt.

11. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for increasing the purposes of medicament of the bioavailability of this chemical compound in preparation, it comprises this chemical compound or its pharmaceutically acceptable salt that the patient is given effective dose in the treatment that food gives.

12. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for increasing the purposes of this chemical compound in the medicament that the patient absorbs in preparation, and it comprises this chemical compound or its pharmaceutically acceptable salt that the patient is given effective dose in the treatment that food gives.

13. the maximal plasma concentration that claim 11 or 12 described purposes, wherein said administration cause described chemical compound is greater than in this chemical compound or its pharmaceutically acceptable salt maximal plasma concentration under the situation that food gives not.

14. claim 11 or 12 described purposes, wherein said administration cause this chemical compound from 0 o'clock area (AUC under the plasma concentration time graph the infinity _0-∝) greater than this chemical compound or its pharmaceutically acceptable salt not under the situation that food gives from 0 o'clock area (AUC under the plasma concentration time graph the infinity _0-∝).

15. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for suppressing purposes in the active medicament of patient's retrovirus integrase in preparation, and it comprises this chemical compound or its pharmaceutically acceptable salt that this patient is given effective dose in the treatment that food gives.

16. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt are used for the treatment of or prevent purposes in the medicament of retroviral infection among the patient in preparation, and it comprises this chemical compound or its pharmaceutically acceptable salt that this patient is given effective dose in the treatment that food gives.

17. claim 15 or 16 described purposes, wherein said retrovirus are human immunodeficiency virus (HIV).

18. any described purposes among the claim 11-17, effective dose is about 10mg to about 2000mg in the wherein said treatment.

19. any described purposes among the claim 11-19 wherein gives described chemical compound or its pharmaceutically acceptable salt between about 2 hours after consume food consuming food precontract 1 hour.

20. the described purposes of claim 19 wherein gives described chemical compound or its pharmaceutically acceptable salt basically simultaneously with consumption food.

21. the described purposes of claim 19 wherein gave described chemical compound or its pharmaceutically acceptable salt at once and after consuming food up to about 1 hour after consuming food.

22. any described purposes among the claim 11-21, wherein the form with pharmaceutical composition gives described chemical compound or its pharmaceutically acceptable salt.

23. the described purposes of claim 22, wherein said pharmaceutical composition are the unit dosage forms of tablet.

24. any described purposes, the wherein described chemical compound of orally give or its pharmaceutically acceptable salt among the claim 11-23.

25. kit, it comprises: (1) comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1, the pharmaceutical composition of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier; The information of (2) prescribing; (3) container; The information of wherein prescribing comprises about give 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl with food]-7-methoxyl group-4-oxo-1, the suggestion of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt.

26. the described kit of claim 25, the information of wherein prescribing is included in 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1, the description that the bioavailability of the bioavailability of 4-dihydroquinoline-when 3-formic acid gives with food when not giving with food improves.

27. the described kit of claim 25, the information of wherein prescribing comprise relevant give 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl between about 2 hours after consume food consuming food precontract 1 hour]-7-methoxyl group-4-oxo-1, the suggestion of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt.

28. the described kit of claim 25, the information of wherein prescribing comprises about giving 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl basically simultaneously with consumption food]-7-methoxyl group-4-oxo-1, the suggestion of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt.

29. the described kit of claim 25, the information of wherein prescribing comprises about gave 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl at once and after consuming food up to about 1 hour after consuming food]-7-methoxyl group-4-oxo-1, the suggestion of 4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt.

30. any described kit among the claim 25-29, wherein said pharmaceutical composition is the unit dosage forms of tablet.

31. any described purposes among the claim 1-10, wherein said medicament is used for food patient's administration.

32. any described purposes wherein is mixed with the unit dosage forms tablet with described medicament among the claim 1-10.

33. any described kit among the claim 25-29, it further comprises ritonavir or its pharmaceutically acceptable salt.

34. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt purposes in the preparation medicament, this medicament is used for this medicament being improved chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl during with the food that gives with ritonavir or its pharmaceutically acceptable salt administration together]-7-methoxyl group-4-oxo-1, the 4-dihydroquinoline-bioavailability of 3-formic acid in the patient.

35. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt purposes in the preparation medicament, this medicament is used for this medicament being increased chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl during with the food that gives with ritonavir or its pharmaceutically acceptable salt administration together]-7-methoxyl group-4-oxo-1, the 4-dihydroquinoline-absorption of 3-formic acid in the patient.

36. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt be in the purposes of preparation in the medicament, and this medicament is used in the activity that this medicament is suppressed patient's retrovirus integrase during with the food that gives with ritonavir or its pharmaceutically acceptable salt administration together.

37. chemical compound 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt be in the purposes of preparation in the medicament, and this medicament is used at treatment or prevention patient's the retroviral infection during with the food that gives with ritonavir or its pharmaceutically acceptable salt administration together with this medicament.

38. pharmaceutical composition, it comprises and is used for improving ritonavir or its pharmaceutically acceptable salt of hiv integrase inhibitor in patient's pharmacokinetics.

39. the described pharmaceutical composition of claim 38, it gives with food.

40. pharmaceutical composition, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition is used to improve the bioavailability of described chemical compound with food.

41. pharmaceutical composition, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition is used for improving the absorption of described chemical compound the patient with food.

42. pharmaceutical composition, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition is used for suppressing the activity of patient's retrovirus integrase with food.

43. pharmaceutical composition, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this pharmaceutical composition are used for the treatment of with food or prevent retroviral infection among the patient.

44. any described pharmaceutical composition among the claim 40-43, it gives with ritonavir or its pharmaceutically acceptable salt.

45. the antiretroviral agent agent, it comprises and is used for improving ritonavir or its pharmaceutically acceptable salt of hiv integrase inhibitor in patient's pharmacokinetics.

46. the described antiretroviral agent agent of claim 45 compositions, it gives with food.

47. antiretroviral agent agent compositions, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, said composition is used to improve the bioavailability of described chemical compound with food.

48. antiretroviral agent agent, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament is used for increasing the absorption of described chemical compound the patient with food.

49. antiretroviral agent agent, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament is used for suppressing the activity of patient's retrovirus integrase with food.

50. antiretroviral agent agent, it comprises 6-(3-chloro-2-luorobenzyl)-1-[(2S)-1-hydroxy-3-methyl fourth-2-yl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid or its pharmaceutically acceptable salt, this medicament are used for the treatment of with food or prevent retroviral infection among the patient.

51. any described antiretroviral agent agent compositions among the claim 47-50, it gives with ritonavir or its pharmaceutically acceptable salt.