Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-06-19
2003-05-27
Rotman, Alan L. (Department: 1628)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S057000
Reexamination Certificate
active
06569897
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds useful for antiviral applications. More particularly, this invention relates to non-nucleoside HIV-1 reverse transcriptase inhibitors having a common alkenyldiarylmethane structure.
BACKGROUND AND SUMMARY OF THE INVENTION
The non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are a structurally diverse set of compounds that inhibit reverse transcriptase by an allosteric mechanism involving binding to a site adjacent to the deoxyribonucleoside triphosphate binding site of the enzyme. Familiar examples of NNRTIs include hydroxyethoxymethylphenylthiothymine (HEPT), tetrahydroimidazobenzodiazepinone (TIBO), dipyridodiazepinone (nevirapine), pyridinone, bis(heteroaryl)piperazine (BHAP), tertbutyldimethylsilylspiroaminooxathiole dioxide (TSAO), and &agr;-anilinophenylacetamide (&agr;-APA) derivatives. Nevirapine has recently been approved for clinical use as an anti-AIDS agent.
The use of NNRTIs as anti-AIDs agents has been limited by the development of viral resistance to the NNRTIs. Although the rapid emergence of resistant viral strains has hampered the clinical development of the NNRTIs for the treatment of AIDS, several strategies have emerged for overcoming resistance, including switching to another NNRTI to which the virus has remained sensitive, using higher doses of the NNRTI against the resistant strain, employing of combinations of agents which elicit mutations that counteract one another, and combining NNRTIs with nucleoside reverse transcriptase inhibitors (RTIs). Accordingly, a need remains for additional NNRTIs having unique patterns of resistance mutations in order to facilitate the application of these strategies.
The synthesis and biological evaluation of NNRTIs in the alkenyldiarylmethane (ADAM) series has recently been reported. Several of the alkenyldiarylmethane compounds were disclosed as inhibiting the cytopathic effect of a wide variety of HIV-1 strains in CEM, MT-4, and monocyte-macrophage cultures. (Cushman et al.
J. Med. Chem
1996, 39, 3217-3227) The most potent of these disclosed compounds was ADAM I (1), which displayed anti-HIV activity vs. a wide range of HIV-1 isolates and was synergistic with AZT. However, the potency of ADAM I (1) against a variety of non-resistant HIV-1 strains was lower than that generally observed with many of the known NNRTIs, ranging from 0.56 &mgr;M vs. HIV-1
65
in MT-4 cells to 151 &mgr;M vs. HIV-1
N119
in MT-4 cells.
The present invention is directed to a series of ADAM I related compounds that are inhibitors of reverse transcriptase activity and inhibit the cytopathic activity of HIV strains.
DETAILED DESCRIPTION OF THE INVENTION
The design of additional alkenyldiarylmethanes has been aided by the availability of X-ray structures of HIV-1 reverse transcriptase complexed with nevirapine, &agr;-APA, and TIBO. These structures reveal that nevirapine, &agr;-APA, and TIBO assume a similar butterfly shape and bind to the enzyme in a similar manner with considerable overlap. Analysis of the X-ray crystallography structures allows the construction of a hypothetical model of the binding of ADAM I (1) to HIV-1 RT. The model was constructed by overlapping the structure of ADAM I (1) with that of nevirapine (2) in the binding pocket of HIV-1 RT (Sculpt® 2.0, Interactive Simulations, San Diego, Calif.). During this process, it was assumed that the hexenyl side chain of ADAM I (1) would point in the same direction as the cyclopropyl substituent of nevirapine. The nevirapine structure was then removed, the structure of the protein “frozen”, and the energy of the complex minimized while allowing the ligand to move. The resulting hypothetical structure was consistent with the reported structures of NNRTI enzyme complexes, and was also supported by prior mutagenesis studies of the alkenyldiarylmethane binding site of HIV-1 reverse transcriptase, in which it was determined that the resistance mutations to ADAM 1 circumscribe a well-defined binding pocket.
According to the model generated by this analysis, the end of the ADAM I (1) side chain occupies a cavity formed by Glu 138, Lys 103, Tyr 181, and Val 179 of the HIV-1 RT. Several functional groups are present that would be capable of hydrogen bonding, including the phenolic hydroxyl group of Tyr 181, the backbone amide and side chain carboxylate of Glu 138, and the terminal amino group of Lys 103. It was anticipated that the incorporation of functional groups at the end of the alkenyl chain of the ligand which are capable of hydrogen bonding might allow favorable interactions with the adjacent residues of the RT. Therefore, alkenyldiarylmethane related compounds were synthesized to incorporate functionalities at the end of the alkenyl side chain that would be capable of hydrogen bonding.
The present invention is directed to non-nucleoside compounds that inhibit reverse transcriptase activity, their pharmaceutical compositions and methods utilizing such compounds/compositions for treating patients suffering from a viral infection. More particularly the compounds of the present invention are useful for treating patients suffering from a disease of retroviral origin, such as AIDs.
The compounds of the present invention are alkenyldiarylmethane compounds of formula I:
wherein X is selected from the group consisting of
wherein R
1
and R
6
are H or halo;
R
2
and R
5
are independently OR
11
;
R
3
and R
4
are CO
2
R
12
or Z; or
R
2
and R
3
taken together with the carbon atoms (C
2
, C
3
) to which they are attached and R
4
and R
5
taken together with the carbon atoms (C
4
, C
5
) to which they are attached form a 5- or 6-membered ring of the formula
wherein Q is O, S, or Se;
R
1
is C
1
-C
4
alkyl,
B is —OR
1
or ═O, and
r is 1 or 0;
provided that when B is ═O, r is 1 and bond a is a single bond and when B is —OR
1
, r is 0 and bond a is a double bond;
R
7
is hydrogen;
R
8
is selected from the group consisting of (CH
2
)
m
OR
13
, (CH
2
)
m
N
3
, (CH
2
)
m
COOR
14
, (CH
2
)
m
Z, and (CH
2
)
m
NH
2
;
R
9
and R
10
are independently selected from the group consisting of H, (C
1
-C
5
) alkyl, (CH
2
)
n
OR
13
, (CH
2
)
n
N
3
, (CH
2
)
n
COOR
14
, (CH
2
)
m
Z and (CH
2
)
n
NH
2
;
R
11
, R
12
, R
13
and R
14
are independently selected from the group consisting of H and (C
1
-C
5
) alkyl; m is 1-4; n is 0-4: and Z is selected from the following subtituent groups:
with the proviso that when X is
R
8
is not (CH
2
)
2
OH.
In one embodiment of this invention there is provided a compound of the above formula I, wherein X is
R
1
and R
6
are independently Br or Cl, R
2
and R
5
are each OCH
3
, R
3
and R
4
are each CO
2
CH
3
or Z, R
7
is H and R
8
is (CH
2
)
m
OH, (CH
2
)
m
COOCH
3
, (CH
2
)
m
Z, or (CH
2
)
m
N
3
, wherein m is 2 or 3. These compounds inhibit the cytopathic effect of HIV-1
RF
in CEM-SS cells. (See Table 1 below).
In another embodiment of this invention there is provided a reverse transcriptase inhibiting compound of the above formula I wherein X is
R
1
and R
6
are halo;
R
2
and R
5
are OCH
3
;
R
3
and R
4
are CO
2
CH
3
;
R
7
is H;
R
8
is (C
2
-C
5
) alkyl, (CH
2
)
m
OR
13
, (CH
2
)
m
N
3
, (CH
2
)
m
COOR
14
, (CH
2
)
m
Z, and (CH
2
)
m
NH
3
;
R
13
and R
14
are independently selected from the group consisting of H and (C
1
-C
5
) alkyl; and m is 2-4.
In still another embodiment of the invention R
1
and R
6
are both chloro or bromo.
The compounds of this invention are readily formulated into pharmaceutical compositions, also within the scope of this invention, for use in the presently described method for treatment of patients suffering from a disease of retroviral origin. In one embodiment of this invention, the pharmaceutical composition comprises a reverse transcriptase inhibitory effective amount of a compound of formula I:
wherein X is selected from the group consisting of
wherein R
1
and R
6
are H or halo;
R
2
and R
5
are independently OR
11
;
R
3
and R
4
are CO
2
R
12
or Z; or
R
2
and R
3
taken together with the carbon atoms (C
2
, C
3
)
Casimiro-Garcia Agustin
Cushman Mark S.
Rice William G.
Barnes & Thornburg
Purdue Research Foundation
Rotman Alan L.
Shameem Golam M. M.
LandOfFree
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