TW200811138A - Pharmaceuticals - Google Patents

Abstract

The present invention relates to the use of a CCR5 antagonist in an HIV infected patient to enhance their immune reconstitution and so treat to HIV related opportunistic conditions resulting from the immunocompromised state of the HIV patient. The invention also allows treatment with a CCR5 antagonist of patients having a CXCR4 using viral population since such patients will also benefit from an increase in their CD4 and/or CD8 cell count.

Description

200811138 IX. Description of invention:

FIELD OF THE INVENTION The present invention relates to the use of a CCR5 modulator, particularly an antagonist, for the use of HIV (such as HIV-1) and gene-related retrovirus infections and acquired immunodeficiency syndrome ( Reconstruction of immunity in patients with AIDS). The invention further encompasses the use of a combination comprising a CCR5 antagonist for the treatment of HIV and AIDS patients. I: Prior Art 3 10 BACKGROUND OF THE INVENTION The name "π chemical hormone" is an abbreviation for "chemotactic cytokines." Chemical hormones include a large family of proteins having a common important structural configuration and having the ability to attract white blood cells. White blood cell chemotaxis factor, a chemical hormone that plays an indispensable role in attracting white blood cells to different tissues of the body, 15 attracts the necessary processes for inflammation and body-to-infection reactions. Because chemical hormones and their receptors are The pathophysiology center of inflammatory and infectious diseases, which is effective in regulating (preferably antagonizing) the activity of chemical hormones and their receptors, is useful in the therapeutic treatment of this inflammatory and infectious disease. Chemical hormone receptor CCR5 It is particularly important in the context of the treatment of inflammatory and infectious diseases. CCR5 is a chemical hormone (especially the giant sputum cell inflammatory protein (ΜΙΡ) (labeled as ΜΙΡ_丨ΜΙΡ_丨ρ) and regulates activity and is expressed by normal tau cells. And the protein of the secreted protein (RANTES). The mountainous neonatal deficiency syndrome (fine S) will make the body immune system gradually dissolve and central and week Progressive deterioration of the nervous system. Because it began to understand in the early 1980s and early 1980s, AIDS has rapidly expanded and now reaches the proportion of infections within relatively limited populations. Intensive research has led to the discovery of reactive agents, Human T lymphatic gland retroviral virus III (HTLV-III) (now more commonly referred to as human immunodeficiency virus or .5 HIV is a member of a virus class well known as a retrovirus. The genome of a retrovirus is composed of RNA, It can be converted into 〇1^8 by reverse transcription. Then, the DNA of the retrovirus is stably bound to the chromosome of the host cell, and the replication process of the host cell is used to generate new retrovirus particles and progressive infection. Other cells. HIV has a special affinity for human Τ4 lymphocytes (CD4) 10 and CD8 cells, which play an important role in the body's immune system. HIV infection of white blood cells can deplete this white blood cell population. Ultimately, the immune system Become inactive and have no effect on a variety of HIV-related opportunistic symptoms such as pneumocystitis carini, Kaposi (Kaposi's) sarcoma and lymphatic system cancer. 15 CD4 cells have both CCR5 and CXCR4 co-receptors on their surface, and these are thought to be used by HIV to gain access to the cells. However, there are different viral populations and It is classified according to co-receptors (CCR5 or CXCR4, which are normally used as cell inlets). Thereafter, the viral population including the substantially CCR5 virus is classified as pro-CCR5 (CCR5 20 tr〇pic), including substantially CXCR4 virus. The viral population is classified as pro-CXCR4tropic (CXCR4tropic); the viral population containing both CCR5 and CXCR4 viruses is classified as mixed tropic; meanwhile, the dual tropic virus can be via CCR5 or CXCR4 co-receptors Enter the CD4 cells. 6 200811138 Thereafter, a population of viruses comprising certain CXCR4 viruses (preferably more than 2% CXCR4 virus, more preferably 5% cXcR4 virus, optimally more than 1% CXCR4 virus) is classified as using cXcr4 Virus population. Patients with sputum IV who have not received any prior ΗIV medication are classified as single-pure patients and are generally afflicted with CCR5 virus, while those who have received treatment for certain HIV medications are classified as treated patients. Over time, 'treated patients tend to develop resistance to many HIV drugs, and perhaps coincidentally, the CXCR4 virus appears to be increasing. Ultimately, when the immune system is no longer sustainable, the treated patients will develop into 10 AIDS ° Koot et al. (Ann. Intern. Med. 1993, 118: 681_688) for almost two and a half years. Reported after a study of mv patients who received treatment with a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI). Two patients have been identified: those infected with fusion cell induction (SI) (CXCR4 form) and those without SI virus (i.e., 15 groups of pro-CCR5 patients). The authors report that patients with SI virus develop 70.8% chance of developing AIDS. However, the rate of developing AIDS in patients without SI virus is 15.8%. In addition, the exposure of the SI variant may indicate a prognosis for a rapid decline in cd4 cell count. Thus, the CXCR4 virus has been thought to have greater damage to CD4 cells 20 and may accelerate the onset of AIDS, such as by a decrease in CD4 cells. Therefore, it has been concerned that only drugs that inhibit the entry of CD4 cells of the pro-CCR5 virus will indeed harm patients infected with a viral population using CXCR4. That is to say, selective inhibition of the pro-CCR5 virus can accelerate CD4 cell infection by allowing the pro-CXCR4 virus to have additional cellular targets, thus increasing viral load 7 200811138 and decreasing CD4 count. This in turn may accelerate the onset of AIDS and HIV-related opportunistic symptoms. Therefore, tests have been developed to measure the tropism of infected HIV populations in HIV patients, thus providing appropriate treatment. 5 Maraviroc (chemical name N- {(1 S)-3-[3-isopropyl-5-methyl_4H-1,2,4-triazole_4_yl]- -8-吖 bicyclo[3.2.1]oct-8-yl}small phenylpropyl)-4,4-difluorocyclohexane-decomposed decylamine, disclosed in w〇01/90106 (for reference And in this article) are chemical hormone receptor antagonists that inhibit HIV entry via the CCR5 co-receptor (ie, 10 CCR5 antagonists in Malawilock) and have been indicated for the treatment of patients with pro-CCR5 HIV 0 The PhenosenseTM test (other known as the TrofileTM test, Monogram Bi〇sciences in California, USA) can be used to measure patients with HIv 15 No is pro-CCR5, and if so, then Maraviroc can be administered. Malawilock does not indicate use for non-pro-CCR5 (i.e., pro-CXCR4, dual/mixed affinity), and that Maraviroc or any other CCR5 antagonist would not be expected to have therapeutic benefit for these HIV patients. C SUMMARY OF THE INVENTION 3 20 SUMMARY OF THE INVENTION We have now found that the use of a CCR5 antagonist in a patient infected with a viral population using CXCR4 causes a significant increase in the cell count bed of CD4, or CD8, or CD4 and CD8. This increase in cell count indicates that the use of CCR5 antagonists can improve the immune reconstitution of HIV patients in 2008-11138 regardless of their viral tropism. Improved immune reconstitution means that the patient's immune function can be restored to the extent that it can be used to treat HIV-related opportunistic symptoms. Thus, a CCR5 antagonist can beneficially treat all mv patients and can give 5 drugs without first determining the viral tropism. The HIV-related opportunistic symptoms are those in which patients with HIV infection are more susceptible due to their immune deficiencies. "Treatment" is intended to include a reduction in the risk of developing HIV-related opportunistic symptoms and an improvement in the patient's ability to counteract the presence of HIV-related opportunistic symptoms. Thus, 10 treatments include both treatment and prevention of HIV-related opportunistic symptoms. An increase in the cell count of both CD4, or CD8, or both CD4 and CD8 may also delay the onset of AIDS in HIV patients. Therefore, in the first aspect of the present invention, there has been provided a use of a CCR5 antagonist which is used in a preparation of a medicament to enhance the immune reconstitution of a patient infected with HIV. According to a first aspect of the invention, the improvement in immune reconstitution is measured by recovery of CD4 cell counts. The increase in CD4 cell count will vary depending on the individual patient, and a higher degree of CD4 cell count can be obtained from patients who are gradually benefiting from immune reconstitution. For example, a patient with a very low CD4 cell count (also 20, say 10 cells/microliter) will still benefit clinically and increase to about 50 cells/microliter. In a second aspect of the invention, there is provided a use of a CCR5 antagonist for use in a formulation of an agent to increase the cell count of both CD4, or CD8, or both CD4 and CD8 in a patient infected with HIV. 9 200811138 In a third aspect of the invention, there is provided a use of a CCR5 antagonist for use as an immunopotentiator in a formulation of a medicament for use in a patient infected with HIV, such as a viral population using CXCR4. In a fourth aspect of the invention, there is provided a CCR5 antagonist for use in the formulation of a medicament for the treatment of HIV-associated opportunistic symptoms. The following specific examples and all combinations thereof, in addition to the other aspects, are further described in terms of the first, second, and third aspects of the present invention. In a specific embodiment of the first to third aspects of the invention, the 10 agent is provided to an HIV patient for treating HIV-associated opportunistic symptoms. In a further embodiment, the patient's CD4 count (i.e., baseline CD4 count) prior to administration of the CCR5 antagonist is 4 cells/microliter. In a still further embodiment, the baseline CD4 count is 200 cells per microliter. In still further embodiments, the baseline CD4 count is 50 cells per microliter. In a still further embodiment, the patient's CD4 count after treatment with a CCR5 antagonist is increased to more than 5 cells per microliter. In still further embodiments, the patient's CD4 count after treatment with a CCR5 antagonist is increased to more than 100 cells per microliter. In still further embodiments, the patient's CD4 count after treatment with a CCR5 antagonist is increased to more than 200 20 cells/μl. In still further embodiments, the patient's CD4 count after treatment with a CCR5 antagonist is increased to more than 350 cells per microliter. In a still further embodiment, the patient's CD4 count after treatment with a CCR5 antagonist is increased to more than 600 cells per microliter. In still further embodiments, CD4, 200811138, after treatment with a CCR5 antagonist, is a cell. The tens of increases exceeded the baseline cell count by more than (6)%. In a further step, the CD4 fine material was added over 100% of the baseline cell count. In a further advanced embodiment, the CD4 cell count increased by more than 200 〇/Q of the baseline cell count. 5 The increase in the number of cells # themselves is revealed in the circulating blood of HIV patients', but the amount of fines added here can also be in other parts of the body (eg, lymph nodes). In still further embodiments, the patient has been treated (but not a CCR5 antagonist). In a still further embodiment of the invention, a patient infected with a pro-CCR5 viral population has been treated (but not receiving a CCR5 antagonist) and has a low viral load (eg, the patient has virologically responded and has a large Part of the virus load under control). According to the present invention, a CCR5 antagonist can now be provided to a patient with a further agent (added to treatment) to increase the CD4 cell count, thereby increasing its immune reconstitution. In still further embodiments, HIV patients have an HIV viral load of more than 5000 replicas per milliliter. In still further embodiments, HIV patients have an HIV viral load of more than 1000 replicas per milliliter. In still further embodiments, HIV patients have an HIV viral load of less than 5000 copies of 20 cells/ml. In still further embodiments, HIV patients have an HIV viral load of less than 400 replicas per milliliter. In still further embodiments, HIV patients have an HIV viral load of less than 200 replicas per milliliter. In still further embodiments, the HIV patient has an HIV viral load of less than 50 copies/ml. 11 200811138 In a still further embodiment of the invention, the HIV patient is infected with a population of viruses that use CXCR4. These patients will normally be under existing HIV drug treatment and will not receive CCR5 antagonists. However, in accordance with the present invention, a CCR5 antagonist can be further provided to an existing HIV drug therapy 5 (added to therapy). In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 2% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 5% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of HIV patients comprises more than 10% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of HIV patients comprises more than 15% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 20% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of HIV patients comprises more than 25% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 30% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 35% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 40% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 45% of the CXCR4 virus. In a still further embodiment of the invention, the viral population of the HIV patient comprises more than 50% of the CXCR4 virus. In a still further embodiment of the invention, the HIV patient is infected with a pro-CCR5 viral population. 12 200811138 HIV-related opportunity symptoms include opportunistic infections and malignancy. Examples of HIV-related opportunistic symptoms include pneumocystitis camii, venom protozoa, isopodasis, cryptosporidiosis, cadidiasis, cryptococcosis 5 ( Cryptococcosis), histoplasmosis, coccidioidomycosis, Myc〇bacterium tuberculosis, non-tuberculous mycobacterial infection, salmonella, cytomegalovirus, herpes simplex virus, recurrent or persistent Upper respiratory tract infection, sinmisitis, otitis media, bacterial meningitis, pneumonia, septicemia, oropharyngis candidaiasis, diarrhea, hepatitis, herpes zoster, leiomyosarcoma, lymphatic Interstitial pneumonia, soil nocardiosis, systemic varicella and brain venom protozoa, progressive multifocal leukoencephalopathy, Kaposi's sarcoma, lymphoma, cervical cancer , mv dementia and mv consumptive 15 syndrome. More particularly, examples of HIV-related opportunistic infections include Pneumocystis carinii, venom protozoa, isosporosis, cryptosporidiosis, candidiasis, cryptococcal disease, histoplasmosis, and ball Sporozoosis, Mycobacterium tuberculosis, non-tuberculous mycobacterial infection, Salmonella, cytomegalovirus, herpes simplex virus 20, progressive multifocal leukoencephalopathy, recurrent or persistent upper respiratory tract infection, sinusitis, otitis media , bacterial meningitis, pneumonia, septicemia, oropharyngeal candidiasis, diarrhea, hepatitis, herpes zoster, leiomyosarcoma, lymphatic interstitial pneumonia, soil filariasis, systemic varicella and venom protozoa Sick brain. 13 200811138 Examples of malignancy include progressive Kaposi's sarcoma, lymphoma and cervical cancer. In still further embodiments, the CCR5 antagonist has an IC5 黏 less than ΙμΜ for CCR5 binding (as measured by the MIP-Ιβ assay, Combadiere et al, J. Leukoc Biol., 60) , 147-152 (1996)). In a still further embodiment of the invention, the CCR5 antagonist is selected from the group consisting of Malawilock, NCB-9471, PRO-140, CCR5mAb004, TAK-779 (WO 99/32468), ZM-688523, 4-Chlorine _6_Fluorosulphonamide, TAK-220 (WO 01/25200), TAK-652 (which is disclosed in WO 03014105 1 及 and has the chemical name 8-[4-(2-butoxyethoxy)benzene Base]_1_isobutyl hydrazone-[4_[[(1·propyl·1Η-口米口坐-5-yl)methyl] 石石基]phenyl]-i,2,3,4_ tetrahydrogen ·1·Benzacocine-5-decylamine), SC_351125, ancriviroc (formerly known as SCH-C), vicroviroc (which has a chemical name ( 4,6-Dimethylpyrimidin-5-15-yl){4-[(3S)-4-{(lR)-2_methoxyoxy[4-(trifluoromethyl)phenyl]ethyl} -3-methyl travel and -1-yl]-4-methyl brigade. D-l-yl} ketone), promo, apliviroc (formerly known as GW-873140, Ono- 4128, AK-602), AMD-887, INC_B9471, CMPD-167 (which has the chemical name N-methyl-N-((lR,3S,4S)-3-[4-(3-benzyl small ethyl) 20 ·1Η·pyrazole _5-yl) piperidine-1·ylmethyl H_[3_fluorophenyl Cyclopentanyl-fluorenyl]-D-proline ()-, 1-endo-{8-[(3S)-3-(ethenylamino)_3_(3-fluorophenyl)propyl]-8 -吖Bicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7·tetrahydro-1H_imidazo[4,5-c]pyridine-5-carboxylic acid methyl ester , 3-内_{8-[(38)-3-(ethylamino)-3-(3_fluorophenyl)propyl]-8-indole bicyclo[3.2.1]oct-3-yl 2-methyl-4,5,6,7-tetrahydro 14 200811138 -3H-imidazole [4,5-c]pyridine-5-carboxylic acid methyl ester, 1_内_{8_[(33)_3_(B Mercaptoamino)-3-(3-fluorophenyl)propyl]-8-indole bicyclo[3.2.1]oct-3-yl}-2-methyl_4,5,6,7_four Hydrogen-1H-imidazo[4,5-c]pyridine-5-carboxylic acid ethyl ester and N-{(lS)-3-[3-endo-(5-isobutylindenyl-2-methyl-4,5,6 ,7_tetrahydro-1H_imidazole 5 [4,5-c]° pyridine-1·yl)_8_ 吖 bicyclo[3.2.1]oct-8-yl]-1-(3_fluorophenyl)propene And pharmaceutically acceptable salts, solvates or derivatives thereof. The last four compounds are disclosed in WO 03/084954 and WO 05/033107. In a still further embodiment, the CCR5 antagonist is selected from the group consisting of Mara 10 Veloc, Vicriviroc, NCB-9471 , PRO-140, CCR5mAb004, 8·[4-(2-butoxyethoxy)phenyl]isoisobutyl good [4_[[(1_propyl-1Η-imidazole-5-yl)methyl]) Sulfone]phenyl]-indole, 2,3,4_tetrahydro-1-benzene-cocaine-5-formamide, 1-endo-{8-[(3S)-3-(ethenylamino) -3-(3-fluorophenyl)propyl]·8_吖bicyclo[3.2.1]oct-3-yl}-2-methyl 15 _4,5,6,7_tetrahydro-1H- Rice mouth sitting [4,5-c] mouth is more than -5 - tartare agglutination, 3-end • {8-[(3S)-3-(acetamido)-3-(3-fluoro Phenyl)propyl]-8-indole bicyclo[3.2.1] oct-3-yl}-2-methyl-4,5,6,7-tetrahydro_3Η·口米唾[4,5- c]° than 唆-5-carboxylic acid methyl ester, 1-endo{8-[(3S)_3-(ethoxymethylamino)-3_(3-fluorophenyl)propyl]-8-anthracene Ring [3.2.1]oct-3-yl}_2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c] 2〇pyridine-5-carboxylic acid ethyl ester and N-{(1 S)-3-[3-endo-(5-isobutylmethyl-2.methyl-4,5,6,7·tetrahydro-1H-imidazole [4,5-c]° pyridine -1-yl)-8-fluorene bicyclo[3.2.1]oct-8- ] -1- (3-fluorophenyl) propyl} as acetamide), and the above-described pharmaceutically acceptable salts, solvates or derivatives thereof. In still further embodiments, the CCR5 antagonist is Maraviro 15 200811138 grams. It will be appreciated that the present invention encompasses all combinations of the specific embodiments as described herein. Patients with H-oral therapy will receive 5 HIV treatments of one of the many existing HIV drugs to control their viral load. Examples of mv drug treatment include, but are not limited to, HIV protein negative enzyme inhibitors (pis), non-nuclear reverse transcriptase inhibitors (NNRTIs), nuclear correction (tetra) acid reverse transcriptase inhibitors (nrtIs), inhibition 卯 (10) I4CD4 Interacting agents, other agents that inhibit mv entry into target cells (such as fusion inhibitors), HIV ligase inhibitors, RNase_formulations, 10 prenylation inhibitors, maturation inhibitors (which interfere with mv coat proteins) The role of manufacturing). It will be appreciated by those skilled in the art that the mv therapeutic combination as indicated above may comprise two or more compounds having the same or different mechanisms of action. Thus, for purposes of illustration only, a combination may comprise a CCR5 antagonist and one or more 15 NRTIs; one or more NRTIs and PI; or a plurality of nrtIs and another CCR5 antagonist; PI; PI and NNRTI; NNRTI and the like. The recommended treatment for HIV is a combination of medications known as sputum active anti-retroviral therapy or H A ART. H A ART combines three or more HI V drugs. In a still further embodiment of the invention, the treated patient receives HAART therapy therapy comprising three or more HIV drugs, has a low viral load and a CCR5 antagonist is administered with a further agent to increase the patient's immunity reconstruction. Typically, HAART treatment is selected from the following drug classes: Ηΐν蛋16 200811138 White shell enzyme inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (LIRTIS), nuclear bud/nucleotide reverse transcriptase inhibitors ( NRTIs) and fusion inhibitors.

Examples of Pis include, but are not limited to, amprenavir (141W94), CGP-73547, CGP-61755, 5 DMP_45〇 (mozenavir), nefenavir (neifinavir), Ritonavir, saquinavir, lopinavir, TMC-126, atazanavir, palinavir, GS-3333, KNI-413 , KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 10 178392, U-140690, ABT-378, DMP-450, AG-1776, MK_944, VX-478, Indinavir, tipranavir, TMC-114, DPC-681, DPC-684, fosamprenavir calcium, benzoic acid derivatives (disclosed in WO 03/053435 Medium), R-944, Ro-03-34649, VX-385, GS-224338, 15 OPT-TL3, PL-100, PPL-100, SM-309515, AG-148, DG-35-VIII, DMP- 850, GW-5950X, ΚΝΙ·1039, L-756423, LB-71262, LP-130, RS-344, SE-063, UIC-94-003, Vb-19038, A-77003, BMS-182193, BMS- 186318, SM-309515, JE-2147, GS-9005. Examples of 20 NRTIs include, but are not limited to, abacavir (Obacavir), GS-840, lamivudine, adefovir dipivoxil, beta-fluoro-ddA, zalcitabine ( Zalcitabine), didanosine, stavudine, zidovudine, tenofovir disoproxil, anti-succinic acid, Andorsovir 17 200811138 (amdoxovir ) (DAPD), SPD_754, SPD-756, racivir, reverset (DPC-817), MIV-210 (FLG), PL-Fd4C (ACH-126443), MIV-310 (alovudine, FLT), dOTC, DAPD, entecavir, GS-7340, emtricitabine (FTC), Truvada (tenofovir and Emtricitabine). Examples of NNRTIs include, but are not limited to, efavirenz, HBY-097, nevirapine, TMC 120 (dapivirine), TMC-125, etravirine , delavirdine 10, DPC-083, DPC-961, capraavirine, rilpivirine, TMC-278, Epzicom (abacavir) And lamivudine), Trizivir (Zidovudine and Lamivudine and Abacavir), Combivir (Zidovudine and Lamivudine), 5- {[3,5-Diethyl-1-(2-hydroxyethyl)-1 Η-pyrazole-4-yl]oxy} 15-diphthalonitrile or a pharmaceutically acceptable salt, solvate or derivative thereof GW-678248, GW-695634, MIV-150, calanolide and tricyclic pyrimidinone derivatives (as disclosed in WO 03/062238). Examples of agents that inhibit gp 120 and fusion inhibitors include, but are not limited to, BMS-806, BMS-488043, 5_{(lS)-2_[(2R)-4_benzylidene-2-20 methylperazine- 1·yl]-1-methyl-2-oxoethoxy} methoxy-pyridine-2-carboxylic acid methyl decylamine and 4-{(lS)-2-[(2R)- 4-benzylindenyl-2-methyl-piperidin-1_yl]-1-methyl-2-oxo-ethoxy}-3-methoxy-N-methyl-benzoic acid amine, Enfu Enfuvirtide (T-20), sifuvirtide, SP-01A, T1249, PRO 542, TNX-355, 2F5, 2G12, BMS-378806, 18 200811138 BMS-488043, PRO-2000, DEBIO-025, PS-Ons, D5, TR-290999, TR-291144, AMD-3100, soluble CD4, a compound disclosed in JP 2003171381 and a compound disclosed in JP 2003119137. 5 Examples of inhibitors of HIV ligase include, but are not limited to, 1^-000870810, 0\¥-81078, 1,5-naphthyridin-3-carbamide derivatives (disclosed in WO 03/062204), revealing Compounds in WO 03/047564, compounds disclosed in WO 03/049690 and 5-hydroxypyrimidine-4-carbimemine derivatives (disclosed in WO 03/035076), MK-0518 and 10 GS-9137 ( JTK-303), a compound disclosed in PCT/IB2006/002735, (5-( 1,1 -«one oxygen-1,2-°Koukoujingkou-2_base)-N-(4-gas Alkyl)-8-transyl-1,6-naphthyridin-7-carbamamine (disclosed in WO 03016315), GSK-364735. Examples of prenylation inhibitors include, but are not limited to, HMG CoA Reductase inhibitors, such as statins (e.g., atorvastatin). Examples of mature inhibitors include 3-0-(3 ',3 '-dimethylammonium) white birch Fatty acid (other known as PA-457) and aHGA. Other therapeutic agents used to enhance the treatment of opportunistic symptoms defined by HIV in combination with CCR 5 antagonists according to any of the present invention include: 20 - Anti-infectives (including antibacterial agents and Mold agents. Examples of antibacterial agents include, but are not limited to, atazava t (at〇vaqU〇ne), azithromycin, ciarithr〇mycin, trimethoprim, Trafloxacin (tn>vafloxacin), pyrimidine, daunorubicin, clindamycin and primaquine, fluconazole, 19 200811138 pastill, Ornidyl, eflornithine etoluene, rifabutin, spiramycin, intraconazole-R51211, trimetrexate, mucor , recombinant human erythropoietin, recombinant human growth hormone, alpha progesterone acetate, testerone and total enteral nutrition. Examples of antifungal agents include, but are not limited to, aniduffungin , C31G, caspofungin, DB-289, fluconazaole, itraconazole, ketoconazole, micafungin, posaconazole (posaconazole) and voriconazole 10 (voriconazole) 〇 - in the treatment of hepatitis Useful agents such as interferon, pegylated interferon (eg, peginterferon a-2a and peg interferon a-2b), long acting interferon (eg , albumin-interferon a), lamivudine, ribavirin, emtricita 15, viramidine, ceig0Sivir, valoritabine Valopicitabine), HCV-086, HCV-796, EMZ702, BILN 2061, IDN6566, NM283, SCH 6 and VX-950; a serine inhibitor, as disclosed in WO 05/007681; aryl thiourea derivatives, as disclosed In WO 05/007601; purine nucleoside analogs, as disclosed in w〇20 05/009418; imidazole derivatives, as disclosed in w〇05/012288; macrocyclic derivatives based on oxime peptides, As disclosed in WO 05/010029. - Agents useful in the treatment of AIDS-related Kaposi's sarcoma, such as interferon, daunorubicin, doxorubicin, paclitaxel, metalloproteinase, alpha·007, bevacant伯20 200811138 (bevacizumab), BMS-275291, halofuginone, leukocyte interstitial-12, rituximab, porfimer sodium, rebimastat, COL-3. - Agents useful in the treatment of cytomegalovirus (CMV), such as fomivirsen, oxetanocin G, cidofovir, cytomegalovirus immunoglobulin, foscarnet (foscarnet) sodium, Isis 2922, valacyclovir, valganciclovir, ganciclovir. - Agents useful in the treatment of herpes simplex virus (HSV), such as acyclovir, penciclovir, famciclovir, ME-609, are also included within the scope of the invention. The CCR5 antagonist of the invention is in combination with one or more other therapeutic agents each independently selected from the group consisting of: 15 - a proliferation inhibitor, such as hydroxyurea. Immunomodulators such as AD-439, AD_519, interferon alpha, AS-101, bropirimine, acemannan, CL246, 738, ELIO, FP-21399, gamma interferon Granulocyte megaloblastic cell community stimulating factor (eg, sargramostim), IL-2, immunoglobulin intravenous, IMREG-1, IMREG-2, imuthiol II Dithiocarbamate, alpha 2 interferon, methionine enkephalin, ΜΤΡ-ΡΕ, remune, rCD4, recombinant soluble human CD4, interferon alpha 2, SK& F106528, soluble thymopentin, tumor necrosis 21 200811138 factor (TNF), tUCaresol, recombinant human interferon beta, interferon alpha η_3. - tachykinin receptor modulators (e.g., ΝΚ1 antagonists) and different forms of interferon or interferon derivatives. 5 - Other chemical hormone receptor agonists/antagonists, such as CXCR4 antagonists (e.g., AMD070 and AMD3100) or CD4 antagonists (e.g., ΤΝΧ-355). An agent that substantially inhibits, interrupts, or reduces viral transcription or RNA replication, such as a tat (transcriptional anti-activator) 4nef (negative control factor) inhibitor. 10 - An agent that substantially inhibits, interrupts, or reduces translation of one or more proteins (other than reverse transcriptase) expressed by a virus (including, but not limited to, down-regulating protein expression or antagonizing one or more proteins), such as Tat*Nef. An agent that interferes with cell activation or cell cycle, such as rapamycin 〇15. Other therapeutic agents can be used with CCR 5 antagonists according to all aspects of the present invention, for example, to provide further immunostimulation or to be accompanied by treatment. Pain and inflammation of the initial and underlying HIV infection. Further combinations for use with CCR5 antagonists according to all aspects of the present invention include beta adrenergic receptor co-agents such as salmeterol 20; corticosteroid co-agents such as fluticasone C Acid salt; LTD4 antagonists, such as metrodukast; muscarinic antagonists such as 粍〇br〇pimn bromide; PDE4 inhibitors such as cilostazol 〇milast) or roflmnilast; COX_2 inhibitors such as 希克考昔柏 (cd(10)心), 22 200811138 valdecoxib or rofecoxib; α_2-δ酉 , , such as gabapentin or pregabalin; β, interferon, such as REBIF; TNF receptor modulators, such as TNF-α inhibitors (eg, adalimumab) . 5 In the combination described above, the CCR5 antagonist and other treatments may be administered separately or in combination with each other in the form of a dosage form, and may be administered simultaneously or sequentially in terms of administration time. Thus, administration of a component agent can be carried out prior to, concurrently with, or subsequent to the administration of the other component agents. The pharmaceutically acceptable salts of the C C R 5 antagonists listed herein include 10 acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples thereof include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphor, and screw Citric acid, cyclamate, ethanedisulfonate, esylate, formate, fumarate, glucoheptonate, gluconate, glucosaldehyde Acid salt, hexafluorophosphate, hibenzate, hydrochloric acid/chloride, hydrogen desert acid/evolution, hydroquinone/enide, isethionate, lactate, malate , maleate, malonate, methyrin, methyl sulfate, naphthylate, 2-2 guanidine naphthalate, nicotinic acid, nitrate, whey Acid salt, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroguanamine, saccharide, stearate, succinate, Tannin, tartrate, toluene, trifluoroacetate and phthalofoate. Suitable base salts are formed from bases which form non-toxic salts. Examples include 23 200811138 aluminum, arginine, benzathine, calcium, choline amine, diethylamine, glycolamine, glycine, lysine, magnesium, glucosamine, ethanolamine, potassium, sodium, slow-blood Acid amine and zinc salt. It is also possible to form half salts of acids and bases, for example, hemisulfate and hemicalcium salts. 5 For a review of the appropriate salt, see Stahl and Weng (W Jane). The Handbook of Medicines and the use of f Wiley-VCH, 2002) The method of reference is also included in this article. The CCR5 antagonist can be administered alone or in combination with one or more other therapeutic compounds. Generally, they will be administered in a formulation in association with one or more pharmaceutically acceptable excipients. As used herein, the term "excipient" is used to describe any ingredient other than the compound of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the formulation. Pharmaceutical compositions suitable for delivery of CCR5 antagonists and combinations thereof, and methods for their preparation, will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995, which is incorporated herein by reference). Suitable modes of administration include oral, parenteral, topical, inhalation/intranasal, rectal/vaginal and ocular/ear administration. This CCR5 antagonist and combinations thereof can be administered orally. Oral administration can include swallowing. To allow the compound to enter the gastrointestinal tract; and/or buccal, lingual or sublingual administration by allowing the compound to pass directly into the bloodstream from the mouth. 24 200811138 Formulations suitable for oral administration include solid, semi-solid and liquid Department, first class n 'package a lot or nano particles, soft or hard capsules of liquid or powder, line agent (including those filled with liquid); chewing agent; gel; fast dispersing form; film; Small body; spray 5 (mucoadhesive) patch and buccal/mucosal adhesion liquid formulations including suspensions, solutions, sugar aggregation and liquid contact. This formulation can be used in soft or hard capsules (for example, from (4) based on methyl cellulose (as a filler), and typically includes a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil; and one or more 10 emulsifiers and / Or a suspending agent. The liquid formulation can also be prepared by reconstituting a solid (for example, from a sachet). The CCR5 antagonist and combinations thereof can also be rapidly dissolved and rapidly disintegrated to form a 'such as by Liang (Liang) Chen describes those in the Expert Opinion in Therapeutic Patents (jJ_(6) > 15 981-986, (2001), which is incorporated herein by reference). In terms of dosage form, the drug may constitute from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to the drug, the tablet usually Examples include disintegrants. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, carboxymethyl cellulose 20 13⁄4 salt, cross-linked croscarmellose sodium, cross-linked poly- _ ( Crospovidone), polyethylene ° pirone, methyl cellulose, Microcrystalline cellulose, short chain alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant contained will be 1% by weight of the dosage form to 25% by weight, preferably 5% to 20% by weight. 25 200811138 A binder is generally used to impart a cohesive quality to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, poly Ethylene glycol, natural and synthetic resins, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablet may also include a diluent such as lactose (monohydrate, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol. , microcrystalline cellulose, starch and binary calcium phosphate dihydrate. The tablet may also optionally include a surfactant such as sodium lauryl sulfate and polysorbate 80; and a glidant such as ceria and talc. When present, the surfactant may comprise from 0.2% to 5% by weight of the tablet, and the flow aid may comprise from 0.2% to 1% by weight of the tablet. The lozenge also typically includes a lubricant such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant to be contained is usually from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight, of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents. Typical lozenges comprise up to about 80% of the drug, from about 10% to about 20% by weight of the binding agent, from about 0% to about 85% by weight of the diluent, from about 2% to about 10% by weight % of a disintegrant and from about 0.25 wt% to about 10 wt% of a lubricant. The tablet mixture can be directly compressed or can be formed into a tablet by a roller. Alternatively, the mixture or portion of the mixture may be granulated, melt frozen or extruded by 26 200811138 prior to bond making, dry or melt. The final formulation may comprise one or more layers and may be coated or uncoated, which may even be encapsulated. Rotating agent formulations are discussed in the following literature: H. Lieberman 5 and [• Lachman's pharmaceutical agent Gangbin: Lozenges, Volume 1 (Marcel Dekker) ), New York, 1980), which is incorporated herein by reference. A consumable oral film for human or veterinary use is typically a soft, water-soluble or water-swellable film form which dissolves quickly or adheres to the mucosa, and the formula 10 comprises a compound of the formula (1), a film-forming polymer, a binder, a solvent. , Diffuse, plasticizer, stabilizer or emulsifier, viscosity modifier and solvent. Certain components of this formulation may perform more than one function. The compound of formula (1) is soluble or insoluble in water. The water-soluble compound contained is typically from 1% by weight to 80% by weight of the solute, more typically from 20% by weight to 50% by weight. The less soluble compound may comprise a greater proportion of the composition, typically up to 88% by weight of the solute. Further, the compound of the formula (1) may be in the form of multiparticulate beads. The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids, and is typically present in the range of from 0.01 to 99% by weight, more typically in the range of from 30 to 8 % by weight. Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, coolants, cosolvents (including oils), emollients, bulking agents, anti-foaming agents, interfacial activity Agents and Taste Masking Agents 0 27 200811138 Films in accordance with the present invention are typically prepared by evaporative drying of an aqueous film that has been applied to a peelable stent carrier or paper.

Vacuum is done. . This can be formulated into an immediate and/or modified release in a dry oven or in a solid formulation for controlled release or oral administration. Modifiers released for modification include delayed, sustained, pulsed, controlled, and stylized release. Suitable modified release formulations for the purposes of the present invention are described in U.S. Patent No. 6,1, 6,864, the disclosure of which is incorporated herein by reference. Other details of suitable release techniques (such as high energy dispersions and infiltrated and coated particles) can be found in Verma et al. (Pharmaceutical Technology On2linel (25(2), 1_14, ( 2001), which is herein incorporated by reference. The use of chewing gum to achieve controlled release is described in WO 00/35298 (which is incorporated herein by reference). Administration into the bloodstream, into the muscles or into the internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracoronary, Intramuscular, intrasynovial, and subcutaneous administration. Devices suitable for parenteral administration 20 include needle (including microneedle) syringes, needleless syringes, and infusion techniques. Parenteral formulations typically have aqueous solutions, which may include Excipients such as salts, carbohydrates and buffers (preferably from pH 3 to 9); however, for some applications they may be more suitably formulated as sterile non-aqueous solutions or 28 200811138 dry form With suitable media For example, if the sterile non-pyrogenic water is combined with the parenteral formulation, the preparation of the Helmet is known by those skilled in the art, and the preparation method can be used to obtain m, * quasi-medical technology. (For example, the rotation of a compound of formula (I) used by cold non-intestinal injections is increased by ship technology (such as incorporation of solubility enhancers). 10 float or solid, semi-solid or The thixotropic liquid non-enteral type (4) of the touch material can be immediately and/or modified release type. The modified release type formulation includes delay, duration, pulse, control, target and stylized crane. Therefore, the present invention The compound can be formulated as a suspension to provide an implanted drug delivery for the modified release of the active compound. Examples of such formulations include a drug coated stent and a drug-loaded poly(dl-lactic-co-glycol) a semi-solid and suspension of acid (pGLA) microspheres. 15 The formulation of this CCR5 antagonist may also be administered topically, dermally (by the skin to the skin or mucous membranes. Typical formulations for this purpose include gels, Hydrogel, lotion, solution, cream, ointment, body powder, Materials, soaking, film, skin patches, flakes, implants, sea rotation, fibers, end bands and microemulsions. Lipids can also be used. Typical carriers include alcohol, water, mineral oil, 20 liquid petrolatum. , white soft paraffin, glycerin, polyethylene glycol and propylene glycol. Can be incorporated into penetration enhancers' see, for example, Finnin and Morgan (M〇rgan) J Pharm Sci 'legs 10) '955-958 (1999 1 month), which is incorporated herein by reference. Other methods of topical administration include electroporation, iontophoresis 29 200811138, phonophoresis, and ultrasonic transfection (s〇 N〇ph〇resis) and microneedle or needleless (eg, powder P〇wderjectTM, BiojectTM, etc.) are delivered for delivery. Formulations for topical administration may be formulated for immediate and/or modified release type 5. Modification release formulations include delay, duration, pulse, control, target, and stylized release. The CCR5 antagonist and combinations thereof may also be administered intranasally or by inhalation, typically in dry powder form (alone, in a mixture (for example, in a dry mixture with lactose), or as a mixed component particle (eg, with Linseed (such as printing grease) 10 mixed)) from dry powder inhaler, aerosol from pressurized container, pump, sprayer, atomizer (using electric body mechanics to produce a fine spray of fog Preferably (or better) or sprayer (with or without the use of a suitable propellant, such as 1,1,1,2_tetrafluoroethane or 1,1,1,2,3,3,3_heptafluoropropane Burn) spray, or as a nose drop. For intranasal use, the powder may comprise a bioadhesive, for example, 15 polycarboside or cyclodextrin. The pressurized container, pump, nebulizer, nebulizer or sprinkler comprises a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol or another agent suitable for dispersing, solubilizing or providing release activity, A propellant (as a solvent) and an optional surfactant (such as trioleic acid dehydrated 20 sorbitol ester, oleic acid or oligolactic acid). The pharmaceutical ingredient is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) prior to use as a dry powder or suspension formulation. This can be accomplished by any suitable milling method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticle, high pressure 30 200811138 homogenization or spray drying. Capsules (e.g., made from gelatin or hydroxypropyl methylcellulose), blister packs, and sachets for use in an inhaler or insufflator can be formulated to include a compound of the invention, a suitable powder base (such as , a powder mixture of a lactose or starch) and a performance modifier such as L-leucine, mannitol or magnesium stearate. The lactose may be anhydrous or monohydrate, and the latter is preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and sucrose. 10 15 20 . . Suitable for use in the use of electrohydrodynamics to produce a fine spray of atomized liquid composition, each drive can comprise from 丨 micrograms to 2 () milligrams of the compound of the invention, and the county volume can vary by m microliters To (10) microliters. The formulation of the formula (4) may comprise a compound of the formula 1, propylene glycol, money water, and an additional solvent for the use of τ to replace the propylene glycol, including glycerin and poly, a suitable flavoring agent (such as a fat and a left (four) agent ( For example, saccharin 3 sweet sodium) added to those who are screaming for inhalation/intranas, and mouth stalks. For example, G=: drug release ^ shell release type. Modified release formulation includes performance In the example of pulse, control, target, late holding & inhaling aerosol, the dosage unit is supplied by the valve of the amount 1 , the buckle - the delivery is recognized, and the unit is typically arranged according to the present invention. ", or 剂s 1 microgram to 10 milligrams of the mouth of the invention, a mouthful of cigarettes." The typical range of the total dose per meal is in the range of 丨 micrograms to 31 200811138 200 mg. It can be administered in a single dose or more usually in divided doses throughout the day.This CCR5 antagonist and combination can be administered rectally or vaginally, for example, in the form of a test, pessary, vaginal ring, bactericide or enema. a suppository base for cocoa 5, but as appropriate Different substitutes are used. Formulations for rectal/vaginal administration may be formulated for immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, target, and stylized release. The CCR5 antagonist and combinations thereof may also be administered directly to the eye or ear, typically in the form of a micronized suspension or solution in an isotonic, pH-adjusted money salt solution. Suitable for the eye and Other U-week formulations for ear administration include implants, sheets, and biodegradable (eg, absorbable sponges, collagen) and non-biodegradable (eg, polyoxygenated) implants, sheets Lenses and microparticles or vesicle systems (such as large vesicles (niosom (9) or 15 lipid granules). Polymers (such as cross-linked polyacrylic acid, polyethylene glycol, hyaluronic acid), cellulosic polymers (for example, By propylmethylcellulose, ethylcellulose, mono- or thioglycolic cellulose, or heteropolysaccharide polymers (for example, gellan gum) and anti-corrosion (such as gasified thallium) - Incorporate into the mixture. This formulation can also be delivered by iontophoresis. Formulations for oedal administration can be formulated for immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, standard or private release. Agents and combinations thereof may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their use in any of the aforementioned administrations. Solubility, dissolution rate, masking taste, bioavailability and/or stability in mode. It has been found that the drug cyclodextrin complex is useful, for example, for most dosage forms and routes of administration. In addition to being directly mismatched with the drug 5, the cyclodextrin can be used as an auxiliary additive, i.e., as a carrier, diluent or solubilizing agent. The most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which are described in International Patent Application No. WO 91/11172, WO 94/02518 and WO 98/55148 (hereby incorporated by reference) And found in this article). 10 Included within the scope of the invention are two or more pharmaceutical compositions (at least one of which comprises a compound according to the invention), for the purpose of administering a combination of active compounds, for example for the purpose of treating a particular disease or condition. It is conveniently combined in a kit form suitable for co-administering the composition. Accordingly, the kit of the present invention comprises two or more individual pharmaceutical 15 compositions (at least one of which comprises a compound of formula (1) according to the invention), and means for retaining the edge composition, such as a container, respectively. Separate bottles or separate them into small packets. Examples of such kits are blister packs well known for use in packaging keying agents, capsules and the like. The kit of the present invention is particularly suitable for administering different dosage forms (e.g., oral and parenteral) for administering individual compositions at different dosage intervals, or for individual compositions to be titrated with one another. . To aid in capacity flexibility, this kit of formulations typically includes guidelines for administration and may provide so-called mnemonics. In a further aspect of the invention, there is provided a method of treating a patient in a patient infected with a population of viruses using CXCR4, comprising administering a beneficial amount of a CCR5 antagonist, wherein the viral population of the patient comprises More than 2 X) of the CXCR4 virus. In further specific embodiments, the patient's viral population includes more than 5%, 10%, 15%, 20〇/〇, 25%, 3〇〇/0, 35〇/〇, 4〇〇/0, 45 % or 50% of the CXCR4 virus. The patient may be treated alone or has been treated for 5 treatments. In a further embodiment, the CCR5 antagonist is Maraviroc. In a still further aspect of the invention, a method for increasing the count of both cD4, or CD8, or both CD4 and CD8 in HIV patients infected with a viral population using CXCR4 has been provided, which comprises administering a CCR5 antagonist. In a still further aspect of the invention, a method for increasing a CD4 count in an HIV patient infected with a viral population that causes 10 CXCR4 has been provided, comprising administering a beneficial amount of a CCR5 antagonist, wherein the patient's viral population Includes more than 2% CXCR4 virus. In a further embodiment, the viral population of the patient comprises more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of the CXCR4 virus. The patient may be treated alone or has been treated. In a further embodiment, the CCR5 antagonist is Malawilock. In a still further aspect of the invention, there is provided a method of increasing a CD8 count in an HIV patient infected with a viral population using CXCR4, comprising administering a beneficial amount of a CCR5 antagonist, wherein the patient's viral population 20 comprises More than 2% of the CXCR4 virus. In a further embodiment, the viral population of the patient comprises more than 5%, 10%, 15%, 20%, 25%, 3%, 35%, 40%, 45% or 50% of the CXCR4 virus. The patient may be treated alone or has been treated. In a further embodiment, the CCR5 antagonizes Qilan^ Malawilock. 34 200811138 In a still further aspect of the invention, there is provided a method of increasing CD4 and CD8 counts in HIV patients infected with a viral population using CXCR4, comprising administering a CCR5 antagonist, wherein the patient's viral population comprises More than 2% of the CXCR4 virus. In a further embodiment, the viral population of patient 5 comprises more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of the CXCR4 virus. The patient may be treated alone or has been treated. In a further embodiment, the CCR5 antagonist is Malawilock. In a still further aspect of the invention, there is provided a method of enhancing immune reconstitution in an HIV patient infected with a viral population comprising CXCR4 comprising administering to the patient a beneficial amount of a CCR5 antagonist. In further embodiments, the viral population of the patient comprises more than 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of the CXCR4 virus. The patient may be treated alone or has been treated. In a further embodiment, the CCR5 antagonist is Maraviroc. In a still further aspect of the invention, there is provided a method of treating HIV-associated opportunistic infection in a HIV patient infected with a viral population using CXCR4 comprising administering to the patient a beneficial amount of a CCR5 antagonist. In a further embodiment, the viral population of the patient comprises more than 2%, 5%, 20 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of the CXCR4 virus. . The patient may be treated alone or has been treated. In a further embodiment, the CCR5 antagonist is Maraviroc. In a further aspect of the invention, there is provided a use of a CCR5 antagonist for increasing the cell count of both CD4, or CD8, or CD4 and CD8 in a patient infected with a viral population using CXCR4, 35 200811138, wherein The patient's viral population includes more than 2% of the CXCR4 virus. In a further aspect of the invention, there is provided a use of a CCR5 antagonist for enhancing immune reconstitution in a patient infected with a viral population using CXCR4, wherein the patient's viral population comprises more than 2% CXCR4 virus. It will be appreciated that in all of the above aspects and specific embodiments of the present invention, it has been defined that nCCR5 antagonists are used in the formulation of pharmaceutical agents, but that the "CCR5 antagonists are used in" are consistent with the viewpoints and specific examples. Within the scope of the invention 10. For example, in a further aspect of the invention, the use of a CCR5 antagonist for increasing the number of cells in CD4, or CD8, or both CD4 and CD8 in HIV patients infected with a viral population using CXCR4 has been provided. In a further embodiment, the viral population of the patient comprises more than 2%, 5%, 10%, 15 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of the CXCR4 virus . The patient may be treated alone or has been treated. In a further embodiment, the CCR5 antagonist is Maraviroc. The phenotypic test for HIV-1 is described in Antimicrobial Agents and Chemotherapy on pages 920-928. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 3 The present invention will now be described by way of example and with reference to the accompanying examples. Example 36 200811138 HIV-1 patients who have been treated and infected with a viral population using CXCR4 are selected according to the following method, and the first group with the best background treatment (OBT) alone with OBT plus one day Malawilock And OBT plus a comparison of Malawilock's group twice a day. 5 Patients registered in the quasi-beauty check: (a) aged 16 or over;

(b) Infection with non-pro-R5 (a population of viruses using CXCR4) as measured by the Monoglan Biosciences FennishTM test (WO 02/-99383; US 10 5837464); or with uncertain trends Sexual phenotype; (c) Stable antiviral drug regimen has been administered for at least 4 weeks prior to randomization: (d) Have HIV-1 RNA count of at least 5,0 〇〇 copies/ml, as by Luo Increased (Roche Amplicor) HIV 1 monitor (version 丨 5) to measure; 15 (e) (1) has an anti-retroviral experience of at least three months with at least one agent previously used, wherein the agent is derived from four anti-retroviral viruses Three types of drugs (NTRIs 'NNRTIs, proteinase inhibitors and fusion inhibitors) (ie, three cycles); or (ii) already documented against two species of four anti-retroviral drugs Sex (ie, two kinds of resistance). Experimental Treatment Qualified patients were randomly assigned to three groups based on the drug intake regimen they received. Group 1: Optimal background treatment (ΟΒΤ) (3-6 anti-retroviral drugs 37 200811138 [retardant ritonavir], at least one of which is active and no more than one For the NNRTI), add 150 mg of Malawilock and take it once a day (QD). Group 2 · Optimal background treatment (as described above) plus 150 mg of Malawi 5 Locks per oral intake (BID). Group 3 · · Best background treatment (as above) plus placebo. The best background treatment for patients who did not include a proteinase inhibitor (pl) or delavirdine (NNRTI) was randomized to receive a daily dose of 3 mg of Malawilov once or twice. 10 Patients were graded according to whether they had an HIV-1 RNA count of greater than or less than 100,000 copies/ml and whether they received enfuvirtide as part of their optimal background treatment. These patients were evenly distributed among the three patient groups. Several viral load (VL) and CD4 count measurements were performed on each of the 15 patients prior to any treatment with Maraviroc or placebo. The average of these measurements was used as the measurement baseline for each patient. The mean of the baseline measurements of viral load and CD4 counts for all patients is shown in Table 1. The midpoint viral load and CD4 counts (before starting treatment) were also shown in Table 1 for all patients. 20 After 24 weeks of treatment, the endpoint was measured (as discussed below). (a) Measurement of HIV-1 viral load and baseline changes for each patient (using log [base 10] scale). The average of these values (average change in viral load across all patients) is shown in Table 2. (8) Percentage of 38 200811138 patients with less than (i) 400 and (ii) 50 HIV_1 RNA copies/ml. (C) Percentage of patients with a viral load reduction of at least 0.5 or 1.0 log1 () replicates per milliliter (compared to baseline). (d) Measurement of CD4 and CD8 cell counts and baseline changes for each patient. The average of these values is shown in Table 2. Cell counts were measured using the fluorescence activated cell classification (F A C S), which is a standard technique. Table 1: 10 mean and midpoint CD4 cell counts and HIV-1 RNA mobility variables placebo + optimal drug delivery regimen per Malawilock + best drug delivery regimen per second Malawilock + Best drug regimen CD4 average (cells / microliters) 98.6 85.0 96.4 CD4 midpoint (cells / microliters) 41.5 39.5 43.1 Average VL (l〇gl (^ body / ml) 5.01 5.03 5.10 midpoint VL ( L〇gl(^体/毫升) 5.10 5.01 5.17 As can be seen from Table 1, all patient groups started to have similar numbers of CD4 cells. 39 15 200811138 Variable placebo + optimal drug delivery regimen at 24 weeks曰 雉 雉 雉 + + 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳 最佳1.20 treatment difference in VL reduction (l〇glG replica/ml), 97.5% confidence interval +0.06 (-0.53, +0.64) -0.23 (-0.83 9 +0.36) VL<400 count/ml 24.1% 24.6% ~ 30.8% ^ VL<50 count/ml 15.5% 21.0%^^ 26.9% ^ >0.5 log10VL reduced 39.7% 42.1% ~ 48.1%', >1 log 1()VL reduced by 36.2% 31.6% ' 44.2% ^ Average change in CD4 count +35.7 +59.6 +62.4 Average change in CD8 count + 150.0 +384.5 +338.8 Result 5, as can be seen from Table 1 Pre-treatment measurements were seen, for each treatment group, the median CD4 count was less than 45 cells/μl and the mean baseline viral load was greater than 5 [log1G] counts/ml. As shown in Table 2, once daily And twice per week, the Malawilock group (1). 2 lGgiQ) and placebo group logio) showed similar changes in viral load to baseline. Negative side effects due to side effects, clinical and laboratory events were discontinued, and at all Death in the three groups: the frequency of occurrence is similar. There is no lymphoma or adenocarcinoma. The CD4 and CD8 cell counts are clinically meaningful in those patients who received both once and twice daily Malawilock ( And statistically significant increase (as compared to placebo). As shown in the table, all of the three treatment groups had a baseline CD4 count of less than milliliters, and a Malawilock group at each time 40 200811138 Slightly (but not statistically) lower in the group (8 5 cells/ Microliters, as compared to the two daily Malawilock groups (96.4 cells/μl) and the placebo group (98.6 cells/μl). As shown in Table 2, the average CD4 change for the once and twice daily Malawilock group was greater: +59.6 cells/μl (5 times per sputum) and +62.2 cells/μl (per Twice a day), as compared to +35·4 cells/μl of placebo. The average CD8 cell change in the Malawilock group was also greater: +384.5 cells/μl (once a day) and +338.8 cells/μl (once once a day) as with placebo (+150.0 cells) / microliter) comparison. Therefore, there is a clinically meaningful numerical difference in the size increase of the two Malawilock groups, as compared to the placebo group. This shows that Malawilock can be provided to HIV patients infected with a viral population using CXCR4 in order to cause a clinically meaningful increase in the cell count of both CD4, or CD8, or both CD4 and CD8 (more than the best background treatment alone) ). This demonstrates the immune reconstitution of patients in Malawi Rocket, which can be used to treat or prevent the symptoms of HIV. [Simple description of the diagram] (None) [Description of main component symbols]

Claims (1)

200811138 X. Patent application scope: 1. The use of a CCR5 antagonist in the preparation of a medicament for the reconstruction of immunity of a patient infected with HIV in the south. 2. Use of a CCR5 antagonist in a formulation of a medicament for increasing the cell count of CD4, or CD8, or CD4 and CD8 in a patient infected with HIV. 3. Use of a CCR5 antagonist in a formulation of a medicament for the treatment of HIV-associated opportunistic symptoms. 4. The use of a CCR5 antagonist according to claim 1 or 2 in a formulation of a medicament for the treatment of an HIV related opportunistic symptom. 5. The use of a CCR5 antagonist according to claim 3 or 4 in a preparation for a medicament, wherein the HIV-related opportunistic symptom is selected from the group consisting of Pneumocystis carinii, venom protozoa, etc. Insect, cryptosporidiosis, candidiasis, cryptococcal disease, histoplasmosis, coccidioidomycosis, Mycobacterium tuberculosis, non-tuberculous mycobacterial infection, Salmonella, cytomegalovirus, herpes simplex virus, progressive Multifocal leukoencephalopathy, Kaposi's sarcoma, lymphoma, cervical cancer, HIV dementia, HIV-consumable syndrome, recurrent or persistent upper respiratory tract infection, sinusitis, otitis media, bacterial meningitis, pneumonia, defeat Blood disease, oropharyngeal candidiasis, abdominal filling, hepatitis, herpes zoster, leiomyosarcoma, lymphatic interstitial pneumonia, soil filariasis, systemic varicella and venom protozoa brain. The use of a c c R 5 antagonist according to any one of the preceding claims, wherein the patient has a baseline CD4 count of less than 200 cells/μl prior to administration of the CCR5 antagonist. 42 200811138 7. Use of a CCR5 antagonist as claimed in claim 6 in a formulation of a medicament, wherein the patient has a baseline CD4 count of less than 50 cells/microliter. The use of a c C R 5 antagonist according to any one of the preceding claims, in the formulation of the agent 5, wherein the patient has a CD4 count of more than 50 cells/μl after treatment with the CCR5 antagonist. 9. The use of a CCR5 antagonist according to any one of the preceding claims in a formulation of a medicament, wherein the patient has a CD4 cell count of more than 1 cells per microliter after treatment with a CCR5 antagonist. The use of a c C R 5 antagonist according to any one of the preceding claims, in the preparation of a medicament, wherein the patient has a CD4 cell count of more than 2 cells per microliter after treatment with a CCR5 antagonist. 11. Use of a CCR5 antagonist according to any of the preceding claims in a formulation of a medicament, wherein the patient has a CD4 cell count of more than 350 cells/microliter after treatment with a CCR5 antagonist. 12. The use of a ccR5 antagonist according to any one of the patents of item 7 to 7, wherein the patient's (3) sputum count is increased by more than 6% after the &ccr5 antagonist treatment. 13. The use of an antagonist of any of the patents & a in the 20 (d) I dose, the CD4 count of the patient with the towel increased by more than 1 after treatment with the CCR5 antagonist. %. 14. The use of a CCR5 antagonist according to any one of claims 1 to 7 in a formulation of a medicament, wherein the patient's CD4 count is 2% after treatment with a CCR5 antagonist. 43 200811138 15. The use of any of the CCR5 antagonists of any of the scope of the patents in the preparation of a medicament, wherein the patient has been treated. 16. Use of a C C R 5 antagonist as claimed in claim 15 of the scope of the invention wherein the patient who has been treated has a viral load of less than 55,000 copies/ml. The use of a CCR5 antagonist according to item 15 of the Shenqing patent scope in the preparation of a medicament wherein the patient has a viral load of less than 400 replicas per milliliter. 18. Use of a C C R 5 antagonist as claimed in claim 15 in a formulation of a medicament, wherein the patient has a viral load of less than 50 replicas per milliliter. 9. The use of a CCR5 antagonist according to any one of claims 15 to 18, wherein the already treated HIV patient has a third or more HIV drugs. HAART treatment plan. 15 2〇 j. ^ • The use of a CCR5 antagonist of any of the scope of the patent application in the preparation of a medicament in which the patient is infected with a viral population using CXCR4. 21. Use of a C C R 5 antagonist as claimed in claim 20 in a formulation of a medicament wherein the viral population of the patient comprises more than 2% of the CXCR4 2 病毒 virus. 22. Use of a CCR5 antagonist as claimed in claim 20 in a formulation of a medicament wherein the viral population of the patient comprises more than 5% of the CXCR4 virus. 2 3 • The use of a CCR5 antagonist as claimed in claim 20 in a formulation of a medicament 44 200811138, wherein the patient's viral population comprises more than 10% of the CXCR4 virus. 24. Use of a CCR5 antagonist according to claim 20, wherein the viral population of the patient comprises more than 20% CXCR4 5 virus. 25. The use of a CCR5 antagonist according to claim 20, in the preparation of a medicament, wherein the patient's viral population comprises more than 50% of the CXCR4 virus. 26. The use of a CCR5 antagonist 10 according to any one of claims 1 to 19, in the preparation of a medicament, wherein the patient is infected with a pro-CCR5 sex virus population. The use of a CCR5 antagonist according to any one of claims 1 to 19, wherein the patient is infected with a pro-CCR5 viral population and wherein the patient has been treated and has a low viral load. And low CD4 cell counts, and in addition to existing HIV treatments, CCR5 antagonists are provided to increase their CD4 cell count. 28. Use of a CCR5 antagonist as claimed in claim 27, wherein the patient has a viral load of less than 400 replicas per milliliter and a CD4 cell count of less than 200 cells per microliter. The use of a CCR5 antagonist according to any one of the preceding claims, wherein the CCR5 antagonist is selected from the group consisting of: Malawilock, Vickers, and NCB-947 -140, butoxyethoxy)phenyl]isoisobutyl-N-[4-[[(l-propyl-s--5-yl)methyl] sulfoxide]phenyl]_1,2 , 3,4-tetrahydrobenzobenzene cocaine _5_ 45 200811138 Weisamine, u]H (3S)-H acetamino group called 3_ sharp phenyl) propyl H-Ren ring [3·2·! ]辛冬基卜L methyl _4,5,6,7_tetranitro-paw_flavored wow [4,5♦ than 唆_5_carboxylic acid 甲酉卜3also {8•[叫^乙胺胺基) O-gas phenyl) propyl] such as fluorene bicyclo [3 2 辛士基卜 2_methyl 5 · 4,5,6,7·tetrahydro-3Η·_[4,5〇^5__ψ_, υ {8- [(3S)_3·(Ethylamino)-3_(3-fluorophenyl)propyl]_8·Ren[3.2.1] oct-3-yl b 2·methyl_4,5,6, 7-tetrahydro-indole_mi saliva [4 5々 than bite-5-wei acid B) and N_{(ls) winter [3_内_(5_isobutydenyl-2-methyl-4,5, 6,7-tetrahydro-_ιΗ_imidazole [4,5-c]acridine small group)_8_吖bicyclo[3.2.1]-oct-8-yl]·1-(3-fluorophenyl)propene Ethylamine; and its pharmaceutically acceptable salts, soluble Or derivative thereof. The use of a CCR5 antagonist according to any one of the patent applications of the invention, wherein the CCR5 antagonist is Malawilock or a pharmaceutically acceptable salt or solvate thereof. 15 31. Use of a CCR5 antagonist in a formulation of a medicament for treating HIV infection in a patient, wherein the CCR5 antagonist has been indicated to be administrable without pre-measuring the patient's viral tropism. 32. A CCR5 antagonist for use in HIV patients infected with a viral population using CXCR4 to increase the cell count of both CD4, or CD8, or both CD4 and CD8. 33. Use of a CCR5 antagonist in a formulation of a medicament for enhancing the immune reconstitution of an HIV patient infected with a viral population using CXCR4. 34. Use of a CCR5 antagonist in a formulation of a medicament, which is used to increase the cell count of both CD4, or CD8, or CD4 and CD8 of an HIV patient infected with a viral population using CXCR4. 35. Use of a CCR5 antagonist in a formulation of a medicament for the treatment of an opportunistic symptom of HIV-associated 5 in an HIV patient infected with a viral population using CXCR4. 47 200811138 VII. Designated representative map: (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (none)