METHOD FOR IMPROVING PHARMACOKINETICS OF PROTEASE INHIBITORS AND PROTEASE INHIBITOR PRECURSORS
The present invention provides methods for improving the pharmacokinetics of protease inhibitors and protease inhibitor precursors and pharmaceutical composition comprising protease inhibitors or protease inhibitor precursors of formula I and a cytochrome P450 monooxigenase inhibitor; when the compound of formula I comprises an amino group, pharmaceutically acceptable ammonium salts thereof, wherein R 1 may be, for example, (HO) 2 P(O)—, (NaO) 2 P(O)—, alkyl-CO— or cycloalkyl-CO—, wherein X may be, for example, F, Cl, and Br, and wherein R 2 and R 3 are as defined herein.
1 . A method of treating or preventing an HIV infection or of treating or preventing AIDS, the method comprising administering a pharmaceutical composition to a mammal in need thereof, wherein said pharmaceutical composition comprises:
a) a compound of formula I
or a pharmaceutically acceptable salt thereof,
wherein n is 3 or 4,
wherein X and Y are the same or different and are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF 3 , —OCF 3 , —CN, —NO 2 , —NR 4 R 5 , —NHCOR 4 , —OR 4 , —COOR 4 , —COR 4 , and —CH 2 OH, or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula —OCH 2 O— and an ethylenedioxy group of formula —OCH 2 CH 2 O—,
wherein R 6 is selected from the group consisting of a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
wherein R 3 is selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula R 3A —CO—, R 3A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, —CH 2 OH, —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH 3 O 2 C—, CH 3 O 2 CCH 2 —, Acetyl-OCH 2 CH 2 —, HO 2 CCH 2 —, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH 3 OC 6 H 4 CH 2 —, CH 3 NH—, (CH 3 ) 2 N—, (CH 3 CH 2 ) 2 N—, (CH 3 CH 2 CH 2 ) 2 N—, HOCH 2 CH 2 NH—, CH 3 OCH 2 O—, CH 3 OCH 2 CH 2 O—, C 6 H 5 CH 2 O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
a picolyl group selected from the group consisting of
a picolyloxy group selected from the group consisting of
a substituted pyridyl group selected from the group consisting of
and
a group of formula
wherein X′ and Y′ are the same or different and are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF 3 , —NO 2 , —NR 4 R 5 , —NHCOR 4 , —OR 4 , —SR 4 , —COOR 4 , —COR 4 , and —CH 2 OH,
wherein R 4 and R 5 are the same or different and are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,
wherein R 2 is selected from the group consisting of a diphenylmethyl group of formula IV
a naphthyl-1-CH 2 — group of formula V
a naphthyl-2-CH 2 — group of formula VI
a biphenylmethyl group of formula VII
and
an anthryl-9-CH 2 — group of formula VIII
wherein R 1 is H or a physiologically cleavable unit, whereby upon physiological conditions said compound is converted into an active protease inhibitor;
b) a cytochrome P450 monooxygenase (CYP450) inhibitor; and
c) a pharmaceutically acceptable carrier;
wherein the ratio (w/w) of said compound of formula I, or a pharmaceutically acceptable salt thereof, to said CYP450 inhibitor is between about 6:1 and more than about 3:1.
2 . The method of claim 1 , wherein R 1 is selected from the group consisting of H, (HO) 2 P(O), (MO) 2 P(O), and a group of formula R 1A —CO—, R 1A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atom, —CH 2 OH, CH 3 O 2 C—, CH 3 O 2 CCH 2 —, Acetyl-OCH 2 CH 2 —, HO 2 CCH 2 —, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH 3 ) 2 NCH 2 —, (CH 3 ) 2 CHCH(NH 2 )—, HOCH 2 CH 2 NH—, CH 3 OCH 2 O—, CH 3 OCH 2 CH 2 O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
a picolyl group selected from the group consisting of
a picolyloxy group selected from the group consisting of
a substituted pyridyl group selected from the group consisting of
and
a group of formula,
wherein M is an alkali metal or alkaline earth metal, and wherein X′, Y′, R 4 , and R 5 are as defined in claim 1 .
3 . A method of treating or preventing an HIV infection or of treating or preventing AIDS, the method comprising administering a pharmaceutical composition to a mammal in need thereof, wherein said pharmaceutical composition comprises:
a) a compound of formula II
or a pharmaceutically acceptable salt thereof,
wherein n is 3 or 4,
wherein X and Y are the same or different and are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF 3 , —OCF 3 , —CN, —NO 2 , —NR 4 R 5 , —NHCOR 4 , —COOR 4 , —COR 4 , and —CH 2 OH, or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula —OCH 2 O— and an ethylenedioxy group of formula —OCH 2 CH 2 O—,
wherein R 6 is selected from the group consisting of a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof,
wherein R 3 is selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and a group of formula R 3A —CO—, R 3A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, —CH 2 OH, —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH 3 O 2 C—, CH 3 O 2 CCH 2 —, Acetyl-OCH 2 CH 2 —, HO 2 CCH 2 —, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH 3 OC 6 H 4 CH 2 —, CH 3 NH—, (CH 3 ) 2 N—, (CH 3 CH 2 ) 2 N—, (CH 3 CH 2 CH 2 ) 2 N—, HOCH 2 CH 2 NH—, CH 3 OCH 2 O—, CH 3 OCH 2 CH 2 O—, C 6 H 5 CH 2 O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
a picolyl group selected from the group consisting of
a picolyloxy group selected from the group consisting of
a substituted pyridyl group selected from the group consisting of
and
a group of formula
wherein X′ and Y′ are the same or different and are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF 3 , —NO 2 , —NR 4 R 5 , —NHCOR 4 , —OR 4 , —SR 4 , —COOR 4 , —COR 4 , and —CH 2 OH,
wherein R 4 and R 5 are the same or different and are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms,
wherein R 2 is selected from the group consisting of a diphenylmethyl group of formula IV
a naphthyl-1-CH 2 — group of formula V
a naphthyl-2-CH 2 — group of formula VI
a biphenylmethyl group of formula VII
and
an anthryl-9-CH 2 — group of formula VIII
wherein R 1 is H or a physiologically cleavable unit, whereby upon physiological conditions said compound is converted into an active protease inhibitor;
b) a cytochrome P450 monooxygenase (CYP450) inhibitor; and
c) a pharmaceutically acceptable carrier;
wherein the ratio (w/w) of said compound of formula I, or a pharmaceutically acceptable salt thereof, to said CYP450 inhibitor is between about 6:1 and more than about 3:1.
4 . The method of claim 3 , wherein R 1 is selected from the group consisting of H, (HO) 2 P(O), (MO) 2 P(O), and a group of formula R 1A —CO—, R 1A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, —CH 2 OH, CH 3 O 2 C—, CH 3 O 2 CCH 2 —, Acetyl-OCH 2 CH 2 —, HO 2 CCH 2 —, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH 3 ) 2 NCH 2 —, (CH 3 ) 2 CHCH(NH 2 )—, HOCH 2 CH 2 NH—, CH 3 OCH 2 O—, CH 3 OCH 2 CH 2 O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
a picolyl group selected from the group consisting of
a picolyloxy group selected from the group consisting of
a substituted pyridyl group selected from the group consisting of
and
a group of formula
wherein M is an alkali metal or alkaline earth metal, and wherein X′, Y′, R 4 , and R 5 are as defined in claim 1 .
5 . The method of claim 4 , wherein R 6 is iso-butyl and n is 3 or 4.
6 . The method of claim 5 , wherein R 1 is selected from the group consisting of H, (HO) 2 P(O), (NaO) 2 P(O), CH 3 CO, 3-pyridyl-CO, (CH 3 ) 2 NCH 2 CO, and (CH 3 ) 2 CHCH(NH 2 )CO.
7 . The method of claim 6 , wherein R 3 is selected from the group consisting of CH 3 CO, CH 3 O—CO, (CH 3 ) 2 N—CO, 3-pyridyl-CO, 4-pyridyl-CO, and 4-morpholine-CO.
8 . The method of claim 7 , wherein X is 4-NH 2 and Y is H or F.
9 . The method of claim 8 , wherein R 2 is selected from the group consisting of a diphenylmethyl group of formula IV, a naphthyl-1-CH 2 — group of formula V, a naphthyl-2-CH 2 -group of formula VI, a biphenylmethyl group of formula VII, and an anthryl-9-CH 2 — group of formula VIII.
10 . The method of claim 9 , wherein X′ and Y′ is H.
11 . The method of claim 5 , wherein R 2 is a diphenylmethyl group of formula IV.
12 . The method of claim 11 , wherein R 1 is selected from the group consisting of H, (HO) 2 P(O), (NaO) 2 P(O), CH 3 CO, 3-pyridyl-CO, (CH 3 ) 2 NCH 2 CO, and (CH 3 ) 2 CHCH(NH 2 )CO.
13 . The method of claim 12 , wherein R 3 is selected from the group consisting of CH 3 CO, CH 3 O—CO, (CH 3 ) 2 N—CO, 3-pyridyl-CO, 4-pyridyl-CO, and 4-morpholine-CO.
14 . The method of claim 13 , wherein X is 4-NH 2 and Y is H or F.
15 . The method of claim 13 , wherein X is 4-NH 2 , Y is H or 3-F, X′ is H, Y′ is H, and R 3 is CH 3 O—CO.
16 . The method of claim 15 , wherein R 1 is (HO) 2 P(O), (NaO) 2 P(O), H, 3-pyridyl-CO, (CH 3 ) 2 NCH 2 CO, (CH 3 ) 2 CHCH(NH 2 )CO, or CH 3 CO.
17 . The method of claim 13 , wherein X is 4-NH 2 , Y is H or 3-F, X′ is H, Y′ is H, and R 3 is CH 3 CO.
18 . The method of claim 17 , wherein R 1 is (HO) 2 P(O), (NaO) 2 P(O), or H.
19 . The method of claim 13 , wherein X is 4-NH 2 , Y is H or 3-F, X′ is H, Y′ is H, and
R 3 is 4-morpholine-CO.
20 . The method of claim 10 , wherein R 2 is Naphtyl-1-CH 2 —, Y is H, and R 3 is 4-morpholine-CO or CH 3 O—CO.
21 . The method of claim 1 , wherein said CYP450 inhibitor is selected from the group consisting of ritonavir (RTV), ketoconazole, fluconazole, nefazodone, fluvoxamine, fluoxetine, a macrolide antibiotic, sertraline, sulfaphenazole, and erythromycin.
22 . The method of claim 1 , wherein said composition is administered orally.
23 . The method of claim 1 , wherein said composition is administered twice-daily.
24 . A method of treating or preventing an HIV infection or of treating or preventing AIDS, the method comprising administering
a) a compound of formula I
or a pharmaceutically acceptable salt thereof,
wherein n, X, Y, X′, Y′, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 ; and
b) one or more of a CYP450 inhibitor in an amount which is sufficient to reduce the metabolism of the compound of formula I;
wherein the ratio (w/w) of said compound of formula I, or a pharmaceutically acceptable salt thereof, to said CYP450 inhibitor is between about 6:1 and more than about 3:1.
25 . The method of claim 24 , wherein said CYP450 inhibitor is selected from the group consisting of ritonavir (RTV), ketoconazole, fluconazole, nefazodone, fluvoxamine, fluoxetine, a macrolide antibiotic, sertraline, sulfaphenazole, and erythromycin.
26 . The method of claim 24 , wherein administration of the compound of formula I and the CYP450 inhibitor is performed separately, simultaneously, or sequentially.
27 . The method of claim 26 , wherein administration of the compound of formula I and the CYP450 inhibitor is performed by administering a) a first pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier and b) a second pharmaceutical composition comprising a CYP450 inhibitor and a pharmaceutically acceptable carrier.
28 . The method of claim 26 , wherein administration of the compound of formula I and the CYP450 inhibitor is performed by administering a single pharmaceutical composition comprising a compound of formula I, a CYP450 inhibitor, and a pharmaceutically acceptable carrier.
29 . The method of claim 1 , wherein said method improves the pharmacokinetics of said compound of formula I.
30 . The method of claim 1 , wherein said HIV has a reduced susceptibility to a protease inhibitor other than the protease inhibitor defined by formula I.
31 . The method of claim 30 , wherein said HIV is HIV-1.
32 . The method of claim 31 , wherein said HIV has a reduced susceptibility to one or more of a protease inhibitor selected from the group consisting of Atazanavir, Amprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, and Saquinavir.
33 . The method of claim 32 , wherein said HIV-1 possesses an aspartyl protease having one or more mutations.