Non-nucleoside reverse transcriptase inhibitors

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

2001-06-12

2002-07-16

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

06420359

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to novel compounds and pharmaceutically acceptable as 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.
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. The transcription of the viral RNA into DNA is accomplished by an enzyme that has been aptly dubbed reverse transcriptase (RT). 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 (ddI), 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 due to mutations in the RT gene. Some of the most commonly observed mutants clinically are: the Y181C mutant, in which a tyrosine (Y), at codon 181, has been mutated to a cysteine (C) residue, and K103N where the lysine (K) at position 103 has been replaced by asparagine (N). Other mutants which emerge with increasing frequency during treatment with known antivirals include the single mutants V106A, G190A, Y188C, and P236L; and the double mutants K103N/Y181C, K103N/P225H, K103N/V108I, and K103N/L100I.
As therapy and prevention of HIV infection using antivirals continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of RT, with different patterns of effectiveness against the various mutants.
Compounds having tricyclic structures which are inhibitors of HIV 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).
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 wild type and mutant HIV-1 RT, particularly Y181C and other single mutants such as K103N albeit less effectively.
Specifically, the compounds of the present invention are effective at inhibiting the Y181C and K103N mutants as well as a broad range of other single mutants and certain commonly found double mutants such as K103N/Y181C and K103N/P225H.
SUMMARY OF THE INVENTION
The invention reduces the difficulties and disadvantages of the prior art by providing novel compounds that are potent inhibitors of single and double mutant strains of HIV-1 RT.
In a first aspect the invention provides a compound of the general formula I:
wherein
R
2
is selected from the group consisting of H, F, Cl, C
1-4
alkyl, C
3-4
cycloalkyl and CF
3
;
R
4
is H or Me;
R
5
is H, Me or Et, with the proviso that R
4
and R
5
are not both Me, and if R
4
is Me then R
5
cannot be Et;
R
11
is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl;
Q is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
In a second aspect, the invention provides an inhibitor of HIV replication, of the general formula I, or a pharmaceutically acceptable salt thereof.
In a third aspect, the invention provides an inhibitor of a reverse transcriptase enzyme of HIV, of the general formula I, or a pharmaceutically acceptable salt thereof.
In a fourth aspect, the invention provides a method for the treatment or prevention of HIV infection, comprising administering to a patient an HIV inhibiting amount of a compound of formula IL or a pharmaceutically acceptable salt thereof.
In a fifth aspect, the invention provides a pharmaceutical composition for the treatment or prevention of HIV infection, comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a sixth aspect, the invention provides a method for preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the term “C
3-4
alkyl” is intended to mean linear or branched alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.
As used herein, the term “C
3-4
cycloalkyl” is intended to mean saturated cyclic hydrocarbon radicals containing three to four carbon atoms and includes cyclopropyl and cyclobutyl.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENT
According to a preferred embodiment, compounds of the invention are defined according to formula I wherein R
2
is preferably Cl, F, or H. More preferably, R
2
is Cl or H. Most preferably, R
2
is H.
According to a preferred embodiment, compounds of the invention are defined according to formula I wherein R
4
is preferably H.
According to an alternative embodiment, compounds of the invention are defined according to formula I wherein preferably R
5
is Me.
Preferably, compounds of the invention are defined according to formula I wherein R
11
is Et or cyclopropyl. More preferably, R
11
is Et.
According to a preferred embodiment, compounds of the invention are defined according to formula I wherein Q is preferably selected from the group consisting of:
More preferably, Q is:
Alternatively, preferred embodiments of the invention include compounds selected from the group consisting of:
The compounds of the invention are effective inhibitors of wild type reverse transcriptase as well as inhibiting, for example, the single mutation enzymes Y181C, K103N, V106A, G190A, Y188C, and P236L. The compounds also inhibit the double mutation enzymes K103N/Y181C, K103N/P225H, K103N/V108I and K103N/L100I.
The compounds of formula I possess inhibitory activity against HIV-1 reverse transcriptase. When administered in suitable dosage forms, they are useful in the treatment of AIDS, ARC and related disorders associated with HIV-1 infection. Another aspect of the invention, therefore, is a method for treating HIV-1 infection which comprises administering to a human being, infected by HIV-1, a therapeutically effective amount of a novel compound of formula I, as described above. Whether it be termed treatment or prophylaxis, the compounds may also be used to prevent perinatal tra

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