Non-nucleoside reverse transcriptase inhibitors

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

2003-03-04

2004-03-16

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

06706706

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention concerns 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.
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 (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 characterized, and resistance to known therapeutic agents is due to mutations in the RT gene. Some of the most commonly observed mutants in the clinic 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.
Continued use of antiviral compounds to prevent HIV infection will undoubtedly cause an increased emergence of new resistant strains of HIV. 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-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).
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, particularlyY181C and other single mutants such as K103N albeit less effectively.
WO 01/96338A1 and U.S. Pat. No. 6,420,359 disclose 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 substituted benzoic acid 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 of the invention, there is provided a compound of formula I:
wherein
R
2
is H, halogen, (C
1-4
)alkyl, O(C
1-4
)alkyl, NH(C
1-4
alkyl) or N(C
1-4
alkyl)
2
;
R
4
is H or CH
3
;
R
5
is H or CH
3
;
R
12
is H, halogen, (C
1-4
)alkyl, CF
3
, or NO
2
;
R
13
is H, (C
1-4
)alkyl, halogen, OH, or NH
2
, with the proviso that R
12
and R
13
are not both H; and
R
14
is COOR
14a
wherein R
14a
is H or (C
1-6
)alkyl; or R
14
is (C
2-4
)alkenylCOOR
14a
wherein R
14a
is as defined herein; or R
14
is (C
1-4
)alkylCOOR
14a
wherein R
14a
is as defined herein;
or a salt or a prodrug thereof
According to a second aspect of the invention, there is provided a pharmaceutical composition for the treatment or prevention of HIV infection, comprising a compound of formula I, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
According to a third aspect of the invention, there is provided a method for the treatment or prevention of HIV infection, comprising administering to a patient an HIV inhibiting amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, both as defined herein.
According to a fourth aspect of the invention, there is provided a method for treating or preventing HIV infection comprising administering a pharmaceutical composition comprising a compound of formula I, as described herein, in combination with an antiretroviral drug.
According to a fifth aspect of the invention, there is provided a method for preventing perinatal transmission of HIV-1 from mother to baby, comprising administering a compound of formula I or a pharmaceutical composition, as described herein, to the mother before giving birth.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The following definitions apply unless otherwise noted:
As used herein, the terms “(C
1-2
)alkyl”, “(C
1-4
)alkyl” and “(C
1-6
)alkyl”, either alone or in combination with another radical, is intended to mean acyclic alkyl radicals containing up to two, four, or six carbon atoms respectively. Examples of such radicals include methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl.
As used herein, the term “(C
2-4
)alkenyl”, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic radical containing two to four carbon atoms.
As used herein, the term “halogen” means a halogen atom and includes fluorine, chlorine, bromine and iodine.
As used herein, the term “pharmaceutically acceptable salt” includes those derived from pharmaceutically acceptable bases and is non-toxic. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na
+
, K
+
, and Ca
++
salts are also contemplated to be within the scope of the invention (also see Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein by reference).
As used herein, the term “prodrug” refers to pharmacologically acceptable derivatives, such that the resulting biotransformation product of the derivative is the active drug, as defined in compounds of formula I. Examples of such derivatives include, but are not limited to, esters and amides. (see Goodman and Gilman in The Pharmacological Basis of Therapeutics, 9
th
ed., McGraw-Hill, Int. Ed. 1995, “Biotransformation of Drugs, p 11-16, incorporated herein by reference).
Detailed Description of Preferred Embodiments
Preferably, R
2
is H, halogen, (C
1-4
)alkyl, O(C
1-4
)alkyl or N(C
1-4
alkyl)
2
. Even preferably, R
2
is H, Cl, F, (C
1-4
)alkyl, O(C
1-4
)alkyl, or N(C
1-4
alkyl)
2
. M

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