Modulators of pharmacokinetic properties of therapeutics

Abstract

The present application provides for a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.

1 - 20 . (canceled) 
     
     
         21 : A method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with the drug a therapeutically effective amount of a compound of formula IB 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein, 
         L 2  is a covalent bond, —C(R 6 ) 2 — or —C(O)—; 
         Z 1  is —O— or —N(R 7 )—; 
         R 6  is selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; 
         R 7  is selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; and 
         R 8  and R 9  are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN. 
       
     
     
         22 : The method of  claim 21 , wherein Z 1  is —N(R 7 )—. 
     
     
         23 : The method of  claim 21 , wherein R 7  is H. 
     
     
         24 : The method of  claim 21 , wherein R 7  is alkyl. 
     
     
         25 : The method of  claim 21 , wherein R 7  is heteroalkyl. 
     
     
         26 : The method of  claim 21 , wherein R 7  is substituted or unsubstituted carbocyclyl. 
     
     
         27 : The method of  claim 21 , wherein R 7  is substituted or unsubstituted heterocyclyl. 
     
     
         28 : The method of  claim 21 , wherein Z 1  is —O—. 
     
     
         29 : The method of  claim 21 , wherein L 2  is —C(R 6 ) 2 —, wherein each R 6  is H. 
     
     
         30 : The method of  claim 21 , wherein L 2  is —C(R 6 ) 2 —, wherein each R 6  is independently H or alkyl. 
     
     
         31 : The method of  claim 21 , wherein L 2  is —C(R 6 ) 2 —, wherein one R 6  is H and the other R 6  is alkyl. 
     
     
         32 : The method of  claim 21 , wherein R 8  and R 9  are both H. 
     
     
         33 : The method of  claim 21 , wherein R 8  and R 9  are independently selected from H and alkyl. 
     
     
         34 : The method of  claim 21 , wherein the compound of formula IB is 
       
         
           
           
               
               
           
         
       
     
     
         35 : The method of  claim 21 , wherein a therapeutically effective amount of a combination comprising the drug and the compound of Formula IB or the pharmaceutically acceptable salt of the compound of Formula IB is administered to the patient. 
     
     
         36 : The method of  claim 21 , wherein the drug metabolized by cytochrome P450 is an HIV protease inhibiting compound, HIV non-nucleoside inhibitor of reverse transcriptase, HIV nucleoside inhibitor of reverse transcriptase, HIV nucleotide inhibitor of reverse transcriptase, HIV integrase inhibitor, gp41 inhibitor, CXCR4 inhibitor, gp120 inhibitor, CCR5 inhibitor, capsid polymerization inhibitor, other drug for treating HIV, interferon, ribavirin, taribavirin, NS3 protease inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, non-nucleoside inhibitor of HCV, NS5a inhibitor, NS5b polymerase inhibitor, other drug for treating HCV, or a mixture thereof. 
     
     
         37 : The method of  claim 36 , wherein
 (1) said HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;   (2) said HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806;   (3) said HIV nucleoside inhibitors of reverse transcriptase are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003);   (4) said HIV nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir and adefovir;   (5) said HIV integrase inhibitors are selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011;   (6) said gp41 inhibitor are selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;   (7) said CXCR4 inhibitor is AMD-070;   (8) said entry inhibitor is SP01A;   (9) said gp120 inhibitor is BMS-488043 or BlockAide/CR;   (10) said G6PD and NADH-oxidase inhibitor is immunitin;   (11) said CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;   (12) said other drugs for treating HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040);   (13) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta;   (14) said ribavirin analogs are selected from the group consisting of rebetol, copegus, and viramidine (taribavirin);   (15) said NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;   (16) said NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191;   (17) said alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;   (18) said hepatoprotectants are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ;   (19) said non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and   (20) said other drugs for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).