Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-13
2004-04-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S183000, C540S495000
Reexamination Certificate
active
06716836
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 and Abacavir, 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, is the Y181 C 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 K103NNY181C, K103N/P225H, K103NN1081 and K103N/L1001.
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-arylhetroalkyl-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 sultam-containing compounds that are potent inhibitors of wild-type (WT) and double mutant strains of HIV-1 RT, particularly the double mutation K103N/Y181C.
According to a first aspect of the invention, there is provided a compound of formula I:
wherein
A is a connecting chain of (C
1-3
) alkyl;
B is O or S;
R
1
is H, (C
1-6
)alkyl, halo, CF
3
, or OR
1a
wherein R
1a
is H or (C
1-6
)alkyl;
R
2
is H or Me;
R
3
is H or Me;
R
4
is selected from the group consisting of: H, (C
1-4
) alkyl, (C
3-4
) cycloalkyl and (C
1-4
)alkyl-(C
3-4
)cycloalkyl;
W is selected from
wherein,
a) one of Y is SO
2
and the other Y is NR
5
, provided that both are not the same, wherein R
5
is selected from the group consisting of: H, (C
1-6
)alkyl, (C
3-6
) cycloalkyl,
said alkyl being optionally substituted with a substituent selected from the group consisting of:
(i) (C
3-6
cycloalkyl);
(ii) 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S, said heterocycle being optionally substituted with (C
1-6
)alkyl;
(iii) NR
5a
R
5b
, wherein R
5a
and R
5b
is both H or (C
1-6
)alkyl said alkyl being optionally substituted with (C
1-6
)alkoxy, (C
6-10
)aryl or 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S, said heterocycle being optionally mono- or di-substituted with (C
1-6
)alkyl;
(iv) OR
5c
wherein R
5c
is H, (C
1-6
) alkyl or 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S;
(v) OCONR
5d
R
5e
, wherein R
5d
and R
5e
are both H; or R
5d
is H and R
5e
is (C
1-6
)alkyl;
(vi) COOR
5f
, wherein R
5f
is H or (C
1-6
)alkyl;
(vii) CONR
5g
R
5h
wherein R
5g
and R
5h
is H or (C
1-6
)alkyl; or R
5g
is H and R
5h
is (C
3-7
)cycloalkyl, said alkyl and said cycloalkyl being optionally substituted with COOR
5i
wherein R
5i
is selected from the group consisting of:
H and (C
1-6
)alkyl;
or CONHNH
2
; or OH or (C
1-6
)alkoxy; or (C
6-10
)aryl; or 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S, said heterocycle being optionally mono- or di-substituted with (C
1-6
)alkyl;
or R
5h
is NR
5j
R
5k
wherein when R
5j
and R
5k
are both H; or R
5j
is H and R
5k
is CH
2
CF
3
;
or R
5
h is 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S;
(viii) COR
5l
wherein R
5l
is (C
1-6
) alkyl or 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, said heterocycle being optionally substituted with (C
1-6
)alkyl;
(ix) SO
2
R
5m
, wherein R
5
m is (C
1-6
)alkyl or NH
2
; and
(x) SO
3
H;
or R
5
is COR
5n
wherein R
5n
is (C
1-6
) alkyl or 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S, said heterocycle being optionally substituted with (C
1-6
)alkyl;
COOR
5o
wherein R
5o
is (C
1-6
) alkyl;
CONR
5p
R
5q
wherein R
5p
and R
5q
is H, OH, (C
1-6
)alkoxy, or (C
1-6
)alkyl said alkyl being optionally substituted with (C
1-6
)alkoxy, (C
6-10
)aryl, 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S, said heterocycle being optionally mono- or di-substituted with (C
1-6
)alkyl; and
COCH
2
NR
5r
R
5s
wherein R
5r
and R
5s
is H or (C
1-6
)alkyl, said alkyl being optionally substituted with (C
1-6
)alkoxy, (C
6-10
)aryl, or 5- or 6-membered heterocycle having 1 to 4 heteroatom selected from O, N, and S, said heterocycle being optionally mono- or di-substituted with (C
1-6
)alkyl;
and each R
8
is independently H, (C
1-4
) alkyl, (C
3-6
) cycloalkyl, or (C
1-4
) alkyl-(C
3-6
) cycloalkyl;
b) E is CR
8a
R
8b
wherein R
8a
and R
8b
is H, (C
1-4
) alkyl, (C
3-6
) cycloalkyl, or (C
1-4
) alkyl-(C
3-6
) cycloalkyl, and J is CH
2
; or J is CR
8a
R
8b
wherein R
8a
and R
8b
are as defined above and E is CH
2
, wherein the dotted line represents a single bond; or
c) E is C(O) and J is CR
8a
R
8b
wherein R
8a
Cameron Dale R.
Deziel Robert
Naud Julie
O'Meara Jeffrey
Ogilvie William W.
Boehringer Ingelheim (Canada) Ltd.
Devlin Mary-Ellen M.
Patel Sudhaker B.
Raymond Robert P.
Shah Mukund J.
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