 Modulators of pharmacokinetic properties of therapeutic agents
专利摘要:
公开号:ES2546378T9 申请号:ES07836007.0T 申请日:2007-07-06 公开日:2016-01-26 发明作者:Manoj C. Desai；Allen Yu Hong；Hongtao Liu；Lianhong Xu；Randall W. Vivian 申请人:Gilead Sciences Inc； IPC主号:
专利说明:
image 1 image2 image3 image4 image5 image6 image7 image8 in the present document. In another embodiment, the compounds of formula IIB have one of the following structures: image9 10 image10 image11 image12 image13 image14 fifteen image15 image16 image17 5-6 unsubstituted or substituted members containing 1-2 heteroatoms selected from the group consisting of N and O, and the 5-6 membered heterocyclyl ring is optionally substituted with a C1-2 alkyl. In yet another embodiment of the compounds of formula IIC, R13 is - (CH2) 0-3CR17R18NR20R21. In a particular embodiment, R13 is a C1-4-NH2 alkylene group, or a C1-4-N (alkyl) 2 alkylene group. In yet another embodiment of the compounds of formula IIC, R13 is - (CH2) 0-3CR17R18NR17C (O) -NR20R21. In a particular embodiment, R13 is a C1-4-C (O) NH2 alkylene group or a C1-4-C (O) N (alkyl) 2 alkylene group. In yet another embodiment of the compounds of formula IIC, R13 is -CH2OH, -CH2CH2NHC (O) CH3 or image18 In yet another embodiment, the compound of the present invention has an inhibitory activity against P450 at a 15 level equal to or better than the inhibition activity of a compound represented by an IC50 of less than about 2000 nM, less than about 1500 nM, less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than approximately 700 nM, less than approximately 650 nM, less than approximately 600 nM, less than approximately 550 nM, less than approximately 500 nM, less than approximately 400 nM, less than approximately 350 nM, less than approximately 300 nM, less than approximately 250 nM, less than about 200 nM, less than about 100 nM, or less than about 50 nM. In yet another embodiment, the compound of the present invention has an inhibitory activity against an isozyme of P450, for example, 3A in a range represented by an IC50 of about 2000 nM at 25 approximately 100 nM, approximately 1000 nM to approximately 100 nM, approximately 900 nM to approximately 200 nM, approximately 800 nM to approximately 300 nM, approximately 700 nM to approximately 200 nM, approximately 600 nM to approximately 200 nM, from about 500 nM to about 200 nM, from about 700 nM to about 300 nM, from about 600 nM to about 300 nM, from about 700 nM to about 400 nM, from about 600 nM to about 400 nM, from about 400 nM to approximately 100 nM, approximately 300 nM to approximately 100 nM, or approximately 600 nM to approximately 150 nM. In yet another embodiment, the compound of the present invention has an inhibitory activity against P450 at a 35 level equal to or better than the inhibition activity of a compound represented by an IC50 of less than about 2000 nM, less than about 1500 nM, less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than approximately 700 nM, less than approximately 650 nM, less than approximately 600 nM, less than approximately 550 nM, less than approximately 500 nM, less than approximately 400 nM, less than approximately 350 nM, less than approximately 300 nM, less than approximately 250 nM, less than approximately 200 nM, less than approximately 100 nM, or less than approximately 50 nM, provided that such a compound substantially does not show biological activities other than its inhibition activity against P450. For example, the compound of the present invention may have a reduced or non-significant activity of protease inhibition, including without limitation a level of protease as represented represented by a higher HIV EC50. 45 of approximately 1000 nM, greater than approximately 900 nM, greater than approximately 800 nM, greater than approximately 700 nM, greater than approximately 600 nM, greater than approximately 500 nM, greater than approximately 400 nM, greater than approximately 300 nM, greater than approximately 200 nM, greater than approximately 100 nM, greater than approximately 50 nM, greater than approximately 40 nM, greater than approximately 30 nM, greater than approximately 20 nM, greater than approximately 10 nM, greater than approximately 5 nM, or greater than approximately 1 nM. In yet another embodiment, the compound of the present invention has an inhibition activity specifically against one or more P450 isozymes that includes without limitation 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, and 3A4, 5, 7, etc. . In yet another embodiment, the compound of the present invention has an inhibitory activity specifically against a P450 isozyme that is involved in the metabolism of antiviral drugs, for example, indinavir, nelfinavir, ritonavir, saquinavir etc. In yet another embodiment, the compound of the present invention has an inhibitory activity specifically against one or more P450 isozymes, but not against the other (s). For example, the compound of the present invention may have an inhibition activity specifically against P450 3A, but an insubstantial or minimal inhibition activity against another P450 isozyme, for example, P450 2C9. 19 image19 sodium lauryl sulfate. The choice of oils or fats suitable for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy product, which does not stain and washable with a suitable consistency to prevent dripping from the tubes or other containers. Mono or dibasic straight or branched chain alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester, or coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2 palmitate can be used -ethylhexyl or a mixture of branched chain esters known as Crodamol CAP., the last three being the preferred esters. They can be used alone or in combination depending on the properties that are needed. Alternatively, lipids with high melting point such as soft white paraffin and / or liquid paraffin or other mineral oils are used. Pharmaceutical formulations according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active substance may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions that are intended for oral use may be prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preservatives , in order to provide a palatable preparation. Tablets containing the active substance mixed with pharmaceutically acceptable non-toxic excipients that are suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques that include microencapsulation for delayed disintegration and absorption in the intestinal tract and thus providing sustained action over a longer period. For example, a time delay material such as glyceryl monostearate and glyceryl distearate alone or with a wax can be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft capsules in which the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil. The aqueous suspensions of the invention contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents such as naturally occurring phosphatides (eg, lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxyethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. The oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth herein, and flavoring agents that may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. The dispersible powders and granules of the invention suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by what has been previously disclosed. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture of these. Suitable emulsifying agents, such as soy lecithin, twenty-one image20 image21 image22 image23 image24 image25 image26 image27 image28 image29 image30 image31 image32 image33 image34 image35 image36 image37 image38 image39 image40 image41 image42 image43 image44 image45 image46 image47 image48 image49 image50 image51 image52 image53 image54 image55 image56 image57 image58 image59 image60 image61 image62 image63 image64 image65 image66 image67 image68 image69 image70 image71 image72 image73 image74 image75 image76 image77 image78 image79 image80 image81 image82 image83 image84 image85 image86 image87 image88 image89 image90 image91 image92 image93 image94 image95 image96 image97 image98 Compound 134 Compound 134 was prepared using the procedure described for compound 76, except that CBZ-D-alaninol was used instead of CBZ-L-alaninol. Compound 135 Compound 135 was prepared following the procedure used to prepare compound 8, except that compound 134 was used instead of compound 22. Example CP Example CP (12 mg) was prepared following the procedure used to prepare example C, except for that compounds 135 and 49 were used instead of compounds 8 and 7. m / z 597.2 (M + H) +. Example CO Example CQ (11 mg) was prepared following the procedure used to prepare example C, except for that compounds 135 and 13d were used instead of compounds 8 and 7. m / z 611.2 (M + H) +. Example CR Example CR (7 mg) was prepared following the procedure used to prepare Example P, except that Example CP was used instead of Example O. 1 H NMR (CDCl 3) δ 8.82 (1 H, s), 7.88 (1 H, s), 7.02 (1 H, s), 6, 92 (1 H, m), 5.28 (2 H, s), 5.10 (1 H, m), 4.5 (2 H, m), 4.15 (2 H, m), 3, 88 (1 H, m), 3.8 -3.5 (2 H, m), 3.35 (1 H, m), 3.0 (3 H, s), 1.5 -1.0 ( 16 H, m); m / z: 541.1 (M + H) +. Example CS Example CS (8 mg) was prepared following the procedure used to prepare example CO, except that example CQ was used instead of example CN. 1 H NMR (CDCl 3) δ 8.83 (1 H, s), 7.88 (1 H, s), 6.98 (1 H, s), 6.81 (1 H, m), 6.58 (1 H, m), 5.28 (2 H, s), 5.18 (1 H, m), 4.4 -4.3 (2 H, m), 4.03 (1 H, m) , 3.85 (1 H, m), 3.58 (2 H, m), 3.3 (1 H, m), 2.99 (3 H, s), 1.5 -0.98 (19 H, m); m / z: 555.2 (M + H) +. 100 image99 image100 image101 image102 image103
权利要求:
Claims (1) [1] image 1 image2 image3 image4 image5 image6 image7 image8 image9 image10 image11
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申请号 | 申请日 | 专利标题 US81931506P| true| 2006-07-07|2006-07-07| US819315P|2006-07-07| US83237106P| true| 2006-07-21|2006-07-21| US832371P|2006-07-21| US90322807P| true| 2007-02-23|2007-02-23| US903228P|2007-02-23| PCT/US2007/015604|WO2008010921A2|2006-07-07|2007-07-06|Modulators of pharmacokinetic properties of therapeutics| 相关专利
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