Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-11
2001-10-16
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S603000, C514S709000, C546S153000, C546S166000, C564S087000, C568S030000, C568S033000, C568S034000
Reexamination Certificate
active
06303630
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to diarylsulfones, substituted diarylsulfones and related derivatives which possess anti-immunodeficiency virus efficacy.
BACKGROUND OF THE INVENTION
Diarylsulfones are known chemotherapeutic agents which are a new class of non-nucleoside reverse transcriptase inhibitors with various structural features responsible for their antiviral activity having been identified.
Variously substituted diaryl sulfones and related derivatives showing activity against immunodeficiency virus (HIV) have been reported in McMahon et al.,
Antimicrobial Agents and Chemotherapy
, 37(4): 754-760 (1993), “Diaryl-sulfones, A New Chemical Class of Nonnucleoside Antiviral Inhibitors of Human Immunodeficiency Antiviral inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase”. In the reference, substituted diaryl sulfones and related derivatives were found to specifically prevent HIV Type 1 (HIV-1) replication and HIV-1 induced cell killing in vitro. As reported in McMahon et al., 2-nitrophenyl phenylsulfone was found to display high efficacy in protecting human cells in culture from HIV-1 cytopathic effects, as well as inhibition of HIV-1 replication via inhibition of HIV-1 reverse transcriptase. The base structure for compounds tested for biological activity in this reference is as follows:
Buckheit et al.,
Antiviral Chemistry
&
Chemotherapy
7(5): 243-252 (1996) reports structure-activity relationship evaluations with several diarylsulfone non-nucleoside reverse transcriptase inhibitors. As set forth in this reference, it was observed that steric properties of various molecules and compound lipophilicity contributed to compound biological activity against HIV-1, with the most active compounds being diarylsulfones having an orthonitro group yielding anti-HIV-1 activity at sub-micromolar concentrations. Further, diarylsulfone compounds were found to exhibit antiviral properties in a manner similar to other members of the class of HIV-1 specific reverse transcriptase inhibitors, as well as synergistic inhibitors of HIV-1 by certain diarylsulfone compounds used in combination with nucleoside analogues AZT, ddI, 3TC, d4T, and protease inhibitor KN1-272.
In Antico et al.,
Arch. Pharm
. (Weinheim) 328, 223-229 (1995), several diarylsulfone compounds were found to be selectively active as anti-HIV-1 agents with the most efficacy shown by 2-nitrophenyl 1-pyrryl sulfone wizh a carbethoxy group at the 2 position of pyrrole. In fact, unlike 2-nitro-phenyl phenyl sulfone (NPPS), only derivatives bearing a carbethoxy group in the pyrrole ring 2 position were shown to exhibit anti-HIV-1 efficacy. Thus, as reported, in Artico et al., unlike the NPPS diarylsulfone structure,
in order to act as an anti-HIV agent, the 2-nitrophenyl 1-pyrryl sulfone skeleton must have the presence of a carbethoxy functional group, such as,
Other references which describe inhibition of HIV reverse transcriptase by sulfones are U.S. Pat. No. 5,308,854 (thiamorpholinyl sulfone) and U.S. Pat. No. 5,565,200 (divinyl sulfone) in which the sulfone group is not a linking group between aryl groups.
Further, U.S. Pat. No. 5,545,750 describes retroviral protease inhibiting compounds of the formula A-X-B, wherein X can be a sulfone linking group, and in which A and B can be functionalized, cyclic groups which are limited to heterocyclic groups. Bis-(2-phenyl ethyl) sulfone is also discussed in this reference
U.S. Pat. No. 4,505,929 describes an anti-retroviral-exhibiting compound in which a sulfone group is a linking group between an “R” group which may be a phenyl group and a diphenyl ether group (a sulfone phenyl diphenyl ether).
Additionally, U.S. Pat. No. 5,278,173 discloses the use of diaminodiphenyl sulfone in inhibiting HIV activity in vivo.
SUMMARY OF THE INVENTION
In accordance with this invention, several novel anti-HIV compounds are now provided which have the formulae selected from the group consisting of:
wherein R
1
is hydrogen or C
1
-C
4
alkyl; R
2
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halogen; R
3
is hydrogen, hydroxy, C
1
-C
4
alkyl; C
1
-C
4
alkoxy or halogen; R
4
is hydrogen or halogen; R
5
is hydrogen, C
1
-C
4
alkoxy, nitro, halogen or haloalkyl; R
6
is hydrogen or nitro; R
7
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro or halogen; R
8
is hydrogen, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halogen; R
9
is hydrogen or nitro; R
10
is hydrogen or halogen; R
11
is hydrogen, C
1
-C
4
amine; R
12
is hydrogen, C
1
-C
4
alkyl or halogen; R
13
is hydrogen, C
1
-C
4
amine; R
14
is hydrogen or halogen; R
15
is hydrogen, C
1
-C
4
alkoxy, C
1
-C
4
haloalkyl, nitro, or halogen; R
16
is hydrogen or nitro; R
17
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro or halogen; R
18
is hydrogen, C
1
-C
4
alkoxy, hydroxy, or halogen; R
19
is hydrogen or nitro; and R
20
is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.
In another aspect of the invention, it has been found that the aforesaid compounds which possess an octanol/water partition coefficient (logP) of from about 2.5 to about 4, are preferred in their display of anti-HIV efficacy.
The invention is more fully described with reference to the following detailed description of preferred embodiments and illustrative examples.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
As set forth hereinabove, the present invention provides a series of substituted and unsubstituted diaryl sulfone and diaryl sulfonamide compounds which have unexpectedly and surprisingly been shown to possess anti-HIV efficacy. The compounds of this invention have the following formula:
wherein R
1
is hydrogen or C
1
-C
4
alkyl; R
2
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halogen; R
3
is hydrogen, hydroxy, C
1
-C
4
alkyl; C
1
-C
4
alkoxy or halogen; R
4
is hydrogen or halogen; R
5
is hydrogen, C
1
-C
4
alkoxy, nitro, halogen or haloalkyl; R
6
is hydrogen or nitro; R
7
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro or halogen; R
8
is hydrogen, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halogen; R
9
is hydrogen or nitro; R
10
is hydrogen or halogen; R
11
is hydrogen, C
1
-C
4
amine; R
12
is hydrogen, C
1
-C
4
alkyl or halogen; R
13
is hydrogen, C
1
-C
4
amine; R
14
is hydrogen or halogen; R
15
is hydrogen, C
1
-C
4
alkoxy, C
1
-C
4
haloalkyl, nitro, or halogen; R
16
is hydrogen or nitro; R
17
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, nitro or halogen; R
18
is hydrogen, C
1
-C
4
alkoxy, hydroxy, or halogen; R
19
is hydrogen or nitro; and R
20
is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.
The anti-HIV active diaryl sulfone compounds of the present invention can be prepared, for example, via acid catalyzed rearrangement of N-alkylbenzene sulfonanilides, as set forth, for example, in Khan, “Kinetics and Mechanism of the Acid-Catalyzed Rearrangement of N-Alkyl Arylsulfonanilides”, Ph.D. Dissertation, Philadelphia College of Pharmacy (May 1975), as follows:
Substituted N-methylbenzene sulfonanilides with varying substituents on the aniline portion of the molecule as starting reagents in the preparation of compounds of this invention can be prepared by dissolving the appropriate amine in ethanol along with an equimolar amount of benzenesulfonyl chloride, and then allowing the mixture to react. To this mixture is added 10% sodium hydroxide dropwise with stirring until the solution is lightly alkaline. The precipitate of the corresponding benzenesulfonanilide is obtained upon cooling the reaction mixture. Next, the crude precipitate of the corresponding N-methyl-benzene-sulfonanilide is obtained upon cooling the mixture. Crude precipitates can be crystallized successively from ethanol and glacial acetic acid, with high purity being obtained. Table 1 below includes illustrative benzenesulfonanilides prepared as described above.
TABLE 1
Compound
R
1
LogP
1
4-OCH
3
3.15
2
4-Br
4.06
3
4-Cl
3.81
4
2-Cl
3.81
5
4-Me
3.66
N-alkylbenzenesulfonanilides with varying substituents on the benzene sulfonic acid portio
Duane Morris & Heckscher LLP
Huang Evelyn Mei
University of the Sciences in Philadelphia
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