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Details for Patent: 8,088,770

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Details for Patent: 8,088,770

Title:Modulators of pharmacokinetic properties of therapeutics
Abstract: The present application provides for a compound of Formula IV: ##STR00001## 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.
Inventor(s): Desai; Manoj C. (Pleasant Hill, CA), Hui; Hon C. (San Mateo, CA), Liu; Hongtao (Cupertino, CA), Sun; Jianyu (San Mateo, CA), Xu; Lianhong (Palo Alto, CA)
Assignee: Gilead Sciences, Inc. (Foster City, CA)
Filing Date:Jul 03, 2008
Application Number:12/217,496
Claims:1. A compound of Formula IV: ##STR00248## or a pharmaceutically acceptable salt, and/or ester thereof, wherein: each A is independently aryl or heterocyclyl; Z.sup.1 and Z.sup.2 are each independently --O-- or --N(R.sup.7)--; X and Y are each independently aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl; R.sup.1, R.sup.3, and R.sup.5 are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; each R.sup.7 is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; R.sup.8 and R.sup.9 are each one or more substituents independently selected from the group consisting of H, alkyl, halogen, aryl, heterocyclyl, and CN; and R.sup.24 is selected from the group consisting of -alkylene-NR.sup.5--C(O)--R.sup.25, -alkylene-C(O)--NR.sup.5--R.sup.26, -alkylene-N(R.sup.27).sub.2, --CH.sub.2-heterocyclyl, and substituted --CH.sub.2-heterocyclyl; R.sup.25 is alkyl, heterocyclylalkyl, or substituted heterocyclylalkyl; R.sup.26 is a substituted or unsubstituted heterocyclyl; or R.sup.5 and R.sup.26 together with the nitrogen atom to which they are both shown attached, form a substituted or unsubstituted bicyclic heterocyclyl; each R.sup.27 is independently a substituted alkyl which may be the same or different; or each R.sup.27, together with the nitrogen atom to which they are both shown attached, form a substituted or unsubstituted bicyclic heterocyclyl; with the following provisos: (i) when X and Y are both thiazolylmethyl, Z.sup.1 is --N(R.sup.7)--, Z.sup.2 is --O--, each A is phenyl, and R.sup.24 is --CH.sub.2CH.sub.2--NR.sup.5--C(O)-alkyl, then each R.sup.8 and R.sup.9 are H; and (ii) when X and Y are both thiazolylmethyl, Z.sup.1 is --N(R.sup.7)--, Z.sup.2 is --O--, each A is phenyl, and R.sup.24 is --CH.sub.2--C(O)--NR.sup.5-pyridyl or --CH.sub.2--C(O)--NR.sup.5-pyrrolidinyl, then R.sup.5 is alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl; and (iii) when X and Y are both thiazolylmethyl, Z.sup.1 is --N(R.sup.7)--, Z.sup.2 is --O--, each A is phenyl, and R.sup.24 is substituted or unsubstituted --CH.sub.2-heterocyclyl, then said substituted or unsubstituted --CH.sub.2-heterocyclyl is not pyridylmethyl, pyrazolylmethyl, imidazolidine-2,4-dione-5-yl-methyl, imidazolylmethyl, or morpholinylmethyl.

2. The compound of claim 1, wherein R.sup.24 is --(CH.sub.2).sub.1-4NHC(O)--R.sup.25, --(CH.sub.2).sub.1-4C(O)NR.sup.5R.sup.26, --(CH.sub.2).sub.1-4N(R.sup.27).sub.2, or --CH.sub.2-heteroaryl.

3. The compound of claim 1, wherein each A is aryl.

4. The compound of claim 3, wherein each A is unsubstituted phenyl.

5. The compound of claim 1, wherein R.sup.1, R.sup.3, and R.sup.5 are H.

6. The compound of claim 1, wherein X and Y are heterocyclylalkyl.

7. The compound of claim 1, having the formula: ##STR00249##

8. The compound of claim 7, having the formula: ##STR00250##

9. The compound of claim 7, having the formula: ##STR00251##

10. The compound of claim 7, wherein R.sup.24 is --(CH.sub.2).sub.2NHC(O)-alkyl.

11. The compound of claim 7, wherein R.sup.24 is --CH.sub.2C(O)NR.sup.5R.sup.26.

12. The compound of claim 7, wherein R.sup.24 is --(CH.sub.2).sub.2N(R.sup.27).sub.2.

13. The compound of claim 7, wherein R.sup.24 is substituted or unsubstituted --(CH.sub.2)-- heteroaryl.

14. A compound selected from the group consisting of: ##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256## pharmaceutically acceptable salts, esters, and/or stereoisomers thereof.

15. A compound having the following structure: ##STR00257## or pharmaceutically acceptable salts, and/or esters thereof.

16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, and/or ester thereof, and a pharmaceutically acceptable carrier or exipient.

17. The pharmaceutical composition of claim 16, further comprising at least one therapeutic agent.

18. The pharmaceutical composition of claim 17, wherein said at least one therapeutic agent is metabolized by cytochrome P450 monooxygenase.

19. The pharmaceutical composition of claim 16, wherein the at least one therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, CCR8 inhibitors, RNase H inhibitors, maturation inhibitors, other drugs for treating HIV, interferons, ribavirin, taribavirin, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, other drugs for treating HCV, and mixtures thereof.

20. The pharmaceutical composition of claim 19, 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, DG17, GS-8374, MK-8122 (PPL-100), DG35, AG 1859, SPI-256, TMC 52390, PL-337, SM-322377, SM-309515, GRL-02031, CRS-074, CRS-075, KB-98, and A-790742; (2) said HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, calanolide B, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, MIV-160, TMC-120 (dapiravine), TMC-278 (rilpivirene), BILR 355 BS, VRX 840773, UK-453061, RDEA806, RDEA806, RDEA 427, RDEA 640, IDX 899, ANX-201, R-1206, LOC-dd, IQP-0410 (SJ-3366), YM-215389, YM-228855, CMX-052, and CMX-182; (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, .+-.-FTC, D-d4FC, phosphazide, fozivudine tidoxil, apricitibine (AVX754), GS-7340, KP-1461, OBP-601, dioxolane thymine, TMC-254072, INK-20, PPI-801, PPI-802, MIV-410, 4'-Ed4T, B-108, and fosalvudine tidoxil (formerly HDP 99.0003); (4) said HIV nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir disoproxil fumarate, and adefovir dipivoxil; (5) said HIV integrase inhibitors are selected from the group consisting of curcumin, chicoric acid, 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, caffeic acid phenethyl ester, tyrphostin, quercetin, S-1360, AR-177, L-870812, L-870810, MK-0518 (raltegravir), elvitegravir (GS-9137), GSK-349572 (S-349572), GSK-265744 (S-265744), GSK-247303 (S-247303), S-1360 (GW810871), 1,5-DCQA, INH-001, INT-349, V-165, RIN-25, BFX-1001, BFX-1002, BFX-1003, RSC-1838, BCH-33040BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011; (6) said gp41 inhibitors are selected from the group consisting of enfuvirtide, sifuvirtide, MPI-451936, FB006M, Z-329029, and TRI-1144; (7) said CXCR4 inhibitor is selected from the group consisting of AMD-070, KRH-3955 (CS-3955), AMD-9370, AMD-3451, RPI-MN, MSX-122, and POL-2438; (8) said entry inhibitor is selected from the group consisting of SP01A, PA-161, SPC3, TNX-355, DES6, SP-10, SP-03, CT-319, and CT-326; (9) said gp120 inhibitor is selected from the group consisting of BMS-488043, R-15-K, KPC-2, and MNLP62; (10) said CCR5 inhibitors are selected from the group consisting of aplaviroc, nifeviroc, vicriviroc (SCH-417690), maraviroc, PRO-140, PRO-542, INCB15050, INCB9471, PF-232798, SCH-532706, GSK-706769, TAK-652, TAK-220, ESN-196, RO-1752, ZM-688523, AMD-887, YM-370749, NIBR-1282, SCH-350634, ZM-688523, and CCR5 mAb004; (11) said CCR8 inhibitor is ZK-756326, (12) said RNase H inhibitor is ODN-93 or ODN-112, (13) said maturation inhibitors are selected from the group consisting of bevirimat (PA-457), PA-040, MPC-9055 (vicecon, MPI-49839), ACH-100703, and ACH-100706; (14) said other drugs for treating HIV are selected from the group consisting of REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), rintatolimod, HRG214, anti-leukocyte adhesion MAb, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, BIT-225, UBT-8147, ITI-367, AFX-400, BL-1050, GRN-139951, GRN-140665, AX-38679, RGB-340638, PPI-367, and ALG 889; (15) said interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, interferon alpha, interferon alfacon-1, interferon alpha-n1, interferon alpha-n3, interferon-beta, interferon-omega, albinterferon alpha-2b, IFN alpha-2b XL, BLX-883, DA-3021, glycosylated interferon alpha-2b, pegylatedinterferon alfacon-1, pegylated interferon lambda-1, and belerofon; (16) said HCV NS3 protease inhibitors are selected from the group consisting of boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, and ITMN-191, (17) said alpha-glucosidase 1 inhibitors are selected from the group consisting of celgosivir (MX-3253), miglitol, and UT-231B, (18) said hepatoprotectants are selected from the group consisting of IDN-6556, ME 3738, LB-84451, silibilin, and mitoquinone/mitoquinol, (19) said nucleoside or nucleotide inhibitors of HCV NSSB polymerase are selected from the group consisting of R1626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283), and MK-0608, (20) said non-nucleoside inhibitors of HCV NS5B polymerase are selected from the group consisting of PF-868554, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190, (21) said HCV NS5A inhibitors are selected from the group consisting of AZD-2836 (A-831) and A-689, (22) said TLR-7 agonists are selected from the group consisting of ANA-975 and SM-360320 (23) said cyclophillin inhibitors are selected from the group consisting of DEBIO-025, SCY-635, and NIM811, (24) said HCV IRES inhibitors are MCI-067, and (25) other drugs for treating HCV are selected from the group consisting of thymosin alpha 1, nitazoxanide (NTZ), BIVN-401, PYN-17, KPE02003002, CPG-10101, KRN-7000, hepatitis C immune globulin human antibodies,GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, bavituximab, MDX-1106 (ONO-4538), oglufanide, and VX-497 (merimepodib).

21. A method for inhibiting cytochrome P450 monooxygenase in a patient comprising administering to a patient in need thereof an amount of a compound of claim 1, or a pharmaceutically acceptable salt, and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase.
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