Non-nucleoside reverse transcriptase inhibitors

Details Non-nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors

2002-07-25

2004-01-06

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S495000

Reexamination Certificate

active

06673791

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to novel compounds and pharmaceutically acceptable salts thereof, their use, either alone or in combination with other therapeutic agents, in the treatment or prophylaxis of HIV infection, and to pharmaceutical compositions comprising the compounds that are active against NNRTI resistant mutants.
BACKGROUND OF THE INVENTION
The disease known as acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), particularly the strain known as HIV-1. In order for HIV to be replicated by a host cell, the information of the viral genome must be integrated into the host cell's DNA. However, HIV is a retrovirus, meaning that its genetic information is in the form of RNA. The HIV replication cycle therefore requires a step of transcription of the viral genome (RNA) into DNA, which is the reverse of the normal chain of events. An enzyme that has been aptly dubbed reverse transcriptase (RT) accomplishes the transcription of the viral RNA into DNA. The HIV virion includes a copy of RT along with the viral RNA.
Reverse transcriptase has three known enzymatic functions; it acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA, and frees the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by another enzyme called integrase.
Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects, as demonstrated by known RT inhibitors such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddl), 2′,3′-dideoxycytidine (ddC), d4T, 3TC, Nevirapine, Delavirdine, Efavirenz, Abacavir, and Tenofovir, the main drugs thus far approved for use in the treatment of AIDS.
As with any antiviral therapy, use of RT inhibitors in the treatment of AIDS eventually leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that occur in the reverse transcriptase segment of the pol gene. Several mutant strains of HIV have been characterised, and resistance to known therapeutic agents is believed to be due to mutations in the RT gene. One of the more commonly observed mutants clinically for the non-nucleoside reverse transcriptase inhibitors, is the Y181C mutant, in which a tyrosine (Y), at codon 181, has been mutated to a cysteine (C) residue. Other mutants, which emerge with increasing frequency during treatment using known antivirals, include single mutants K103N, V106A, G190A, Y188C, and P236L, and double mutants K103N/Y181C, K103N/P225H, K103N/V108I and K103N/L100I.
As antiviral use in therapy and prevention of HIV infection continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of RT, which have different patterns of effectiveness against the various resistant mutants.
Compounds having tricyclic structures, which are inhibitors of HIV-1, are described in U.S. Pat. No. 5,366,972. Other inhibitors of HIV-1 reverse transcriptase are described in Hargrave et al., J. Med Chem., 34, 2231 (1991), Cywin et al., J. Med. Chem., 41, 2972 (1998) and Klunder et al., J. Med. Chem., 41, 2960 (1998).
U.S. Pat. No. 5,705,499 proposes 8-arylalkyl- and 8-arylheteroalkyl-5,11 -dihydro-6H-dipyrido[3,2-B:2′,3′-E][1,4]diazepines as inhibitors of RT. The exemplified compounds are shown to have some activity against HIV WT reverse transcriptase.
WO 01/96338A1 discloses diazepine structures having quinoline and quinoline-N-oxide substituents as inhibitors of RT. The exemplified compounds have activity against HIV WT, single and double mutant strains.
SUMMARY OF THE INVENTION
The invention provides novel fused ring-containing compounds that are potent inhibitors of wild-type (WT) and double mutant strains of HIV-1 RT, particularly the double mutation K103N/Y181C.
In a first aspect the invention provides compounds represented by formula I:
wherein
R
2
is selected from the group consisting of H, halogen, NHNH
2
, (C
1-4
)alkyl, O(C
1-6
)alkyl, and haloalkyl;
R
4
is H or Me;
R
5
is H or (C
1-4
)alkyl;
R
11
is (C
1-4
)alkyl, (C
1-4
)alkyl(C
3-7
)cycloalkyl, or (C
3-7
)cycloalkyl; and
Q is naphthyl, fused phenyl(C
4-7
)cycloalkyl and fused phenyl-5, 6, or 7-membered saturated heterocycle having one to two heteroatom selected from O, N, or S, said Q being substituted with from 1 to 4 R
12
substituents selected from: R
13
, (C
1-6
)alkyl, (C
3-7
)cycloalkyl, or (C
2-6
)alkenyl, said alkyl, cycloalkyl, or alkenyl being optionally substituted with R
13
,
wherein R
13
is defined as:
a) NR
13a
COR
13b
wherein R
13a
and R
13b
are each independently H, (C
1-6
)alkyl, (C
3-7
)cycloalkyl or (C
1-6
)alkyl-(C
3-7
)cycloalkyl, said alkyl, cycloalkyl or alkyl-cycloalkyl being optionally substituted with R
14
;
b) NR
13c
SO
2
R
13d
wherein R
13c
is H, (C
1-6
)alkyl, (C
3-7
)cycloalkyl or (C
1-6
)alkyl-(C
3-7
)cycloalkyl and R
13d
is (C
1-6
)alkyl, haloalkyl, (C
3-7
)cycloalkyl or (C
1-6
)alkyl-(C
3-7
)cycloalkyl, said alkyl, cycloalkyl or alkyl-cycloalkyl being optionally substituted with R
14
;
c) COR
13e
wherein R
13e
has the same definition as R
13d
;
d) COOR
13f
wherein R
13f
has the same definition as R
13c
;
e) CONR
13g
R
13h
wherein R
13g
and R
13h
are both independently H, (C
1-6
)alkyl, (C
3-7
)cycloalkyl, or (C
1-6
)alkyl-(C
3-7
)cycloalkyl; or both R
13g
and R
13h
are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle; or R
13h
is N(R
13i
)
2
wherein each R
13i
is independently H, (C
1-6
)alkyl, (C
3-7
)cycloalkyl, or (C
1-6
)alkyl-(C
3-7
)cycloalkyl or both R
13i
are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl or heterocycle being optionally substituted with R
14
;
f) CONR
13j
SO
2
R
13k
wherein R
13j
has the same definition as R
13c
and R
13k
has the same definition as R
13d
; or
g) SO
2
R
13l
wherein R
13l
is (C
1-6
)alkyl, (C
3-7
)cycloalkyl, or (C
1-6
)alkyl-(C
3-7
)cycloalkyl; or R
13l
is NR
13m
R
13n
wherein R
13m
and R
13n
are both independently H, (C
1-6
)alkyl, (C
3-7
)cycloalkyl, or (C
1-6
)alkyl-(C
3-7
)cycloalkyl; or both R
13m
and R
13n
are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl or heterocycle being optionally substituted with R
14
;
wherein R
14
is defined as:
COOR
14a
, or CON(R
14b
)
2
wherein R
14a
and R
14b
are both independently H, (C
1-6
)alkyl, (C
3-7
)cycloalkyl, or (C
1-6
)alkyl-(C
3-7
)cycloalkyl; or both R
14b
are covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6, or 7-membered saturated heterocycle;
as well as pharmaceutically acceptable salts, esters and prodrugs thereof.
In a first subgeneric aspect the invention provides compounds represented by formula I, wherein:
R
2
is selected from the group consisting of H, F, Cl, NHNH
2
, (C
1-4
alkyl), and CF
3
;
R
4
is H or Me;
R
5
is H or Me;
R
11
is (C
1-4
alkyl), or (C
3-7
cycloalkyl); and
Q is selected from the group consisting of:
 wherein
R
12
is selected from the group consisting of: COOH, (C
1-6
alkyl)COOH, (C
2-6
alkenyl)COOH, (C
1-6
alkyl)COO(C
1-6
alkyl), (C
1-6
alkyl)CONH
2
, (C
3-7
cycloalkyl)COOH, (C
1-6
alkyl)CONHNH
2
, CH
2
CONHSO
2
CH
3

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