| Title: |
METHODS FOR INHIBITING DRUG DEGRADATION |
| Document Number: |
20110098237 |
| Publication Date: |
April 28, 2011 |
| Appl. No: |
12/919012 |
| Application Filed: |
February 23, 2009 |
| Abstract: |
Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters to improve the pharmacokinetics, enhance the bioavailability, and enhance the therapeutic effect of drugs that undergo in vivo degradation by cytochrome P450 enzymes. |
| Inventors: |
Eissenstat, Michael (Frederick, MD, US); Duan, Dehui (Frederick, MD, US); Gulnik, Sergi (Frederick, MD, US); Erickson, John W. (Potomac, MD, US) |
| Assignees: |
Sequoia Pharmaceuticals, Inc. (Gaithersburg, MD, US) |
| Claim: |
1. A method of inhibiting cytochrome P450 monooxygenase comprising administering to a patient a compound represented by a formula: X-A-B—X′ wherein: X is a lipophilic group containing from 1 to 12 carbon atoms optionally containing from 1 to 3 heteroatoms independently selected from the group consisting of O, S, and N, A is —OCON(R2)-, —S(O)nN(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-, —N(R2)S(O)nN(R2)-, N(R2)CO or —N(R2)COO—; B is —(CG1G2)m-, wherein m is 2-6 and wherein G1 and G2 are the same or different and wherein each G1 and G2 independently is selected from the group consisting of a bond, H, halo, haloalkyl, OR, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and optionally substituted heterocycloalkyl wherein each optional substitution independently is selected from the group consisting of alkyl, halo, cyano, CF3, OR, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, N(R2)2, OR3, SR3, NR2R3, OR6, SR6, and NR2R6, and wherein G1 and G2, together with the atoms to which they are attached, optionally may form a 3-7-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from the group consisting of N, S and O, and wherein said ring optionally may be substituted with up to 3 R7 moieties, X′ is [chemical expression included] wherein J is selected from: N(D)-SOn—, —N(D)-COn—, —N(D)-(R8)q-, —N(CO-D)-(R8)q-, —N(SOn-D)-(R8)q-, —SOn—N(D)-(R8)q-, or —COn—N(D)-(R8)q-, wherein D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl, O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl, O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl, N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl, N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, N(R2)-aralkyl, wherein D optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl; wherein R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein each R2 is independently selected from the group consisting of H, C1-C12 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl each further optionally substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R); or each R2 is independently selected from the group consisting of C1-C6 alkyl; substituted by aryl or heteroaryl; which groups optionally are substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR; R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or heterocyclo; which groups optionally are substituted with one or more substituents selected from the group consisting of halo, OR2, R2-OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, oxo, ═N—OR2, ═N—N(R2)2, ═NR2, ═NNRC(O)N(R2)2, ═NNR2C(O)nR2, ═NNR2S(O)nN(R2)2, and ═NNR2S(O)n(R2); R6 is aryl or heteroaryl, wherein said aryl or heteroaryl optionally are substituted with one or more groups selected from the group consisting of aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, OC(O)R2, OC(S)R2, OC(O)N(R2)2, and OC(S)N(R2)2; R7 is H, oxo, C1-C12 alkyl; C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl, each further optionally substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R); R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein n=1-2, and wherein q=0-1, provided that: when X is a 5-7 membered non-aromatic monocyclic heterocycle, optionally fused or bridged with one or more 3-7 membered non-aromatic monocyclic heterocycle to form a polycyclic system, wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, and P, and when B is [chemical expression included] wherein U is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted aralkyl, then J cannot be —N(D)-SOn— or —N(D)-COn—. |
| Claim: |
2. The method according to claim 1 wherein X is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein X optionally is substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R). |
| Claim: |
3. The method according to claim 1, wherein X is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. |
| Claim: |
4. The method according to claim 1, wherein X optionally is substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, CN, COnR, CON(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, oxo, and ═N—OR. |
| Claim: |
5. (canceled) |
| Claim: |
6. The method according to claim 1, wherein G1 and G2 are the same or different and independently are selected from the group consisting of a bond, H, OR, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl. |
| Claim: |
7. The method according to claim 1, wherein: (a) G1 and G2 do not form a ring; (b) at least one G1 and at least one G2 form a ring; (c) G1 and G2 are different; (d) neither G1 nor G2 is OH; or (e) G1 and G2 are selected from the group consisting of H, O-alkyl, alkyl, optionally substituted aryl and optionally substituted aralkyl. |
| Claim: |
8-11. (canceled) |
| Claim: |
12. The method according to claim 1, wherein J is [chemical expression included] —N(D)-(R8)q-, —SOn—N(D)-(R8)q-, or —COn—N(D)-(R8)q-. |
| Claim: |
13-16. (canceled) |
| Claim: |
17. The method according to claim 1, wherein D is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroaralkyl and aralkyl, wherein D optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl. |
| Claim: |
18-25. (canceled) |
| Claim: |
26. A method of inhibiting cytochrome P450 monooxygenase comprising administering to a patient a compound represented by a formula: X-A-B—X′ wherein: X is a lipophilic group containing from 1 to 12 carbon atoms optionally containing from 1 to 3 heteroatoms independently selected from the group consisting of O, S, and N, A is selected from the group consisting of a bond, —OCON(R2)-, —S(O)nN(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-, —N(R2)S(O)nN(R2)-, N(R2)CO or —N(R2)COO—; B is —(CG1G2)m-, wherein m is 0-6 and wherein G1 and G2 are the same or different and wherein each G1 and G2 independently is selected from the group consisting of a bond, H, halo, haloalkyl, OR, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and optionally substituted heterocycloalkyl wherein each optional substitution independently is selected from the group consisting of alkyl, halo, cyano, CF3, OR, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, N(R2)2, OR3, SR3, NR2R3, OR6, SR6, and NR2R6, and wherein G1 and G2, together with the atoms to which they are attached, optionally may form a 3-7-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from the group consisting of N, S and O, and wherein said ring optionally may be substituted with up to 3 R7 moieties, X′ is [chemical expression included] wherein M is selected from the group consisting of: a bond, OC(R8)q-, —CO—, —SOn—, —O—, —O—CO—, —N(D)-SOn—, —N(D)-COn—, —N(D)-(R8)q-, —N(CO-D)-(R8)q-, —N(SOn-D)-(R8)q-, —SOn—N(D)-(R8)q-, or —COn—N(D)-(R8)q-, wherein M can be linked in either orientation with respect to the benzofuran ring, wherein D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl, O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl, O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl, N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl, N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, and N(R2)-aralkyl, wherein D optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl; wherein R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein each R2 is independently selected from the group consisting of H, C1-C12 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl each further optionally substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo, halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R); or each R2 is independently selected from the group consisting of C1-C6 alkyl; substituted by aryl or heteroaryl; which groups optionally are substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR; R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or heterocyclo; which groups optionally are substituted with one or more substituents selected from the group consisting of halo, OR2, R2-OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, oxo, ═N—OR2, ═N—N(R2)2, ═NR2, ═NNRC(O)N(R2)2, ═NNR2C(O)nR2, ═NNR2S(O)nN(R2)2, and ═NNR2S(O)n(R2); R6 is aryl or heteroaryl, wherein said aryl or heteroaryl optionally is substituted with one or more groups selected from the group consisting of aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, OC(O)R2, OC(S)R2, OC(O)N(R2)2, and OC(S)N(R2)2; R7 is H, oxo, C1-C12 alkyl; C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl, each further optionally substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R); R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein n=1-2, and q=0-1, wherein the benzene ring of the benzofuran moiety optionally is substituted by up to three substituents independently selected from the group consisting of R2, halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, and NRPOnOR, wherein said up to three substituents do not form a ring between any adjacent carbon atoms of said benzene ring, and with the proviso that said compound does not contain a basic aliphatic amine function and does not contain a carboxylic acid group, and provided that: when X is a 5-7 membered non-aromatic monocyclic heterocycle, optionally fused or bridged with one or more 3-7 membered non-aromatic monocyclic heterocycle to form a polycyclic system, wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, and P, and when B is [chemical expression included] wherein U is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted aralkyl, then J cannot be —N(D)-SOn— or —N(D)-COn. |
| Claim: |
27. The method according to claim 26, wherein the compound is administered prior to, and/or substantially contemporaneously with, a drug wherein efficacy of said drug is compromised due to degradation by cytochrome P450 monooxygenase. |
| Claim: |
28. The method according to claim 26, wherein the drug is selected from the group consisting of Cyclosporine, Tacrolimus (FK506), Sirolimus (rapamycin), Indinavir, Ritonavir, Saquinavir, Felodipine, Isradipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine, Nifedipine, Verapamil, Etoposide, Tamoxifen, Vinblastine, Vincristine, Taxol, Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin, Terfenadine, Loratadine, Astemizole, Alfentanil, Carbamazepine, Azithromycin, Clarithromycin, Erythromycin, Itraconazole, Rifabutin, Lidocaine, Cisapride, Sertraline, Pimozide, Triazolam, Anastrazole, Busulfan, Corticosteroids (dexamethasone, methylprednisone and prednisone), Cyclophosphamide, Cytarabine, Docetaxel, Doxorubicin, Erlotinib, Exemestane, Gefitinib, Idarubicin, Ifosphamide, Imatinib mesylate, Irinotecan, Ketoconazole, Letrozole, Paclitaxel, Teniposide, Tretinoin, Vinorelbine, quinidine, alprazolam, diazepam, midazolam, nelfinavir, chlorpheniramine, amlodipine, diltiazem, lercanidipine, cerivastatin, estradiol, hydrocortisone, progesterone, testosterone, alfentanyl, aripiprazole, cafergot, caffeine, cilostazol, cocaine, codeine, dapsone, dextromethorphan, domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol, irinotecan, Levo-Alpha Acetyl Methadol (LAAM), methadone, nateglinide, odansetron, propranolol, quinine, salmeterol, sildenafil, trazodone, vincristine, zaleplon, zolpidem, ixabepilone, Agenerase (APV), Aptivus (TPV), Crixivan (IDV), Invirase (SQV), Lexiva (FPV), Prezista (DRV), Reyataz (ATV) Viracept (NFV), Elvitegravir, Selzentry, Vicriviroc, Telaprevir, Telithromycin, tandospirone or buspirone. |
| Claim: |
29. A compound represented by a formula: X-A-B—X′ wherein: X is a lipophilic group containing from 1 to 12 carbon atoms optionally containing from 1 to 3 heteroatoms independently selected from the group consisting of O, S, and N, A is —OCON(R2)-, —S(O)nN(R2)-, —CON(R2)-, —COCO(NR2)-, —N(R2)CON(R2)-, —N(R2)S(O)nN(R2)-, N(R2)CO or —N(R2)COO—; B is —(CG1G2)m-, wherein m is 2-6 and wherein G1 and G2 are the same or different and wherein each G1 and G2 independently is selected from the group consisting of a bond, H, halo, haloalkyl, OR, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, and optionally substituted heterocycloalkyl wherein each optional substitution independently is selected from the group consisting of alkyl, halo, cyano, CF3, OR, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, N(R2)2, OR3, SR3, NR2R3, OR6, SR6, and NR2R6, and wherein G1 and G2, together with the atoms to which they are attached, optionally may form a 3-7-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from the group consisting of N, S and O, and wherein said ring optionally may be substituted with up to 3 R7 moieties, X′ is [chemical expression included] wherein J is selected from: —N(D)-SOn—, —N(D)-COn—, —N(D)-(R8)q-, —N(CO-D)-(R8)q-, —N(SOn-D)-(R8)q-, —SOn—N(D)-(R8)q-, or —COn—N(D)-(R8)q-, wherein D is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, heteroaralkyl or aralkyl, O-alkyl, O-cycloalkyl, O-cycloalkylalkyl, O-heterocycloalkyl, O-heterocycloalkylalkyl, O-heteroaralkyl, O-aralkyl, N(R2)-alkyl, N(R2)-cycloalkyl, N(R2)-cycloalkylalkyl, N(R2)-heterocycloalkyl, N(R2)-heterocycloalkylalkyl, N(R2)-heteroaralkyl, N(R2)-aralkyl, wherein D optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl; wherein R is H, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein each R2 is independently selected from the group consisting of H, C1-C12 alkyl, C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl each further optionally substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R); or each R2 is independently selected from the group consisting of C1-C6 alkyl; substituted by aryl or heteroaryl; which groups optionally are substituted with one or more substituents selected from the group consisting of halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR; R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or heterocyclo; which groups optionally are substituted with one or more substituents selected from the group consisting of halo, OR2, R2-OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, oxo, ═N—OR2, ═N—N(R2)2, ═NR2, ═NNRC(O)N(R2)2, ═NNR2C(O)nR2, ═NNR2S(O)nN(R2)2, and ═NNR2S(O)n(R2); R6 is aryl or heteroaryl, wherein said aryl or heteroaryl optionally are substituted with one or more groups selected from the group consisting of aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO2, CN, COnR2, C(O)N(R2)2, C(O)N(R2)N(R2)2, C(S)R2, C(S)N(R2)2, S(O)nN(R2)2, SR2, SOnR2, N(R)2, N(R2)COnR2, NR2S(O)nR2, NR2C[═N(R2)]N(R2)2, N(R2)N(R2)COnR2, OC(O)R2, OC(S)R2, OC(O)N(R2)2, and OC(S)N(R2)2; R7 is H, oxo, C1-C12 alkyl; C3-C8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl, each further optionally substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R); R8 is alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein n=1-2, and wherein q=0-1, provided that: when X is a 5-7 membered non-aromatic monocyclic heterocycle, optionally fused or bridged with one or more 3-7 membered non-aromatic monocyclic heterocycle to form a polycyclic system, wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, and P, and when B is [chemical expression included] wherein U is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted aralkyl, then J cannot be —N(D)-SOn— or —N(D)-COn—. |
| Claim: |
30. The compound according to claim 29, a wherein X is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, and heteroaralkyl; wherein X optionally is substituted with one or more substituents selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; halo, OR, ROH, R-halo, NO2, CN, COnR, CON(R)2, C(S)R, C(S)N(R)2, SOnN(R)2, SR, SOnR, N(R)2, N(R)COnR, NRS(O)nR, NRC[═N(R)]N(R)2, N(R)N(R)COnR, NRPOnN(R)2, NRPOnOR, oxo, ═N—OR, ═N—N(R)2, ═NR, ═NNRC(O)N(R)2, ═NNRCOnR, ═NNRS(O)nN(R)2, and ═NNRS(O)n(R). |
| Claim: |
31-33. (canceled) |
| Claim: |
34. The compound according to claim 29, wherein G1 and G2 are the same or different and independently are selected from the group consisting of a bond, H, OR, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl. |
| Claim: |
35. The compound according to claim 29, wherein: (a) G1 and G2 do not form a ring; (b) at least one G1 and at least one G2 form a ring; (c) G1 and G2 are different; (d) neither G1 nor G2 is OH; or (e) G1 and G2 are selected from the group consisting of H, O-alkyl, alkyl, optionally substituted aryl and optionally substituted aralkyl. |
| Claim: |
36-39. (canceled) |
| Claim: |
40. The method according to claim 29, wherein J is [chemical expression included] —N(D)-(R8)q-, —SOn—N(D)-(R8)q-, or —COn—N(D)-(R8)q-. |
| Claim: |
41-44. (canceled) |
| Claim: |
45. The compound according to claim 29, wherein D is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroaralkyl and aralkyl, wherein D optionally is substituted by alkyl, halo, nitro, cyano, O-alkyl, or S-alkyl. |
| Claim: |
46-49. (canceled) |
| Claim: |
50. A formulation comprising a effective amount of a compound according to claim 29, and a pharmaceutically acceptable diluent, carrier, or excipient. |
| Claim: |
51. A composition comprising an effective amount of a compound according to claim 29, and an effective amount of a drug wherein in vivo efficacy of said drug is compromised due to degradation by cytochrome P450 monooxygenase. |
| Claim: |
52. A composition comprising a compound of claim 29 and an antiretroviral agent. |
| Claim: |
53-54. (canceled) |
| Current U.S. Class: |
514/205 |
| Current International Class: |
61; 07; 07; 07; 07; 07; 07; 07; 07; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61 |
| Accession Number: |
edspap.20110098237 |
| Database: |
USPTO Patent Applications |
