U.S. patent application number 10/806295 was filed with the patent office on 2004-09-16 for phenylindoles for the treatment of hiv.
This patent application is currently assigned to IDENIX PHARMACEUTICALS INC.. Invention is credited to Artico, Marino, LaColla, Paulo, Sommadossi, Jean-Pierre.
Application Number | 20040180888 10/806295 |
Document ID | / |
Family ID | 23085844 |
Filed Date | 2004-09-16 |
United States Patent
Application |
20040180888 |
Kind Code |
A1 |
LaColla, Paulo ; et
al. |
September 16, 2004 |
Phenylindoles for the treatment of HIV
Abstract
The invention as disclosed herein is a method and composition
for the treatment of HIV in humans and other host animals, that
includes the administration of an effective HIV treatment amount of
a phenylindole as described herein or a pharmaceutically acceptable
salt or prodrug thereof, optionally in a pharmaceutically
acceptable carrier. The compounds of this invention either possess
antiviral (i.e., anti-HIV) activity, or are metabolized to a
compound that exhibits such activity.
Inventors: |
LaColla, Paulo; (Cagliari,
IT) ; Artico, Marino; (Roma, IT) ; Sommadossi,
Jean-Pierre; (Cambridge, MA) |
Correspondence
Address: |
Sherry M. Knowles
45th Floor
191 Peachtree Street, N.E.
Atlanta
GA
30303
US
|
Assignee: |
IDENIX PHARMACEUTICALS INC.
|
Family ID: |
23085844 |
Appl. No.: |
10/806295 |
Filed: |
March 22, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10806295 |
Mar 22, 2004 |
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10122252 |
Apr 11, 2002 |
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6710068 |
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60283393 |
Apr 11, 2001 |
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Current U.S.
Class: |
514/232.5 ;
514/414; 544/143; 548/465 |
Current CPC
Class: |
C07D 403/12 20130101;
C07D 413/12 20130101; A61K 45/06 20130101; A61P 31/18 20180101;
C07D 401/04 20130101; C07D 209/42 20130101; A61K 31/4178 20130101;
C07D 209/20 20130101; A61K 31/404 20130101 |
Class at
Publication: |
514/232.5 ;
514/414; 544/143; 548/465 |
International
Class: |
A61K 031/5377; A61K
031/405; C07D 413/02; C07D 43/02 |
Claims
We claim:
1. A compound of the formula (I) 32or its pharmaceutically
acceptable salt or thereof, wherein (a) R.sup.1 is hydrogen; acyl;
--C(.dbd.O)H; --C(.dbd.W)H; --C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2;
--C(.dbd.O)OH; --C(.dbd.W)OH; --C(.dbd.O)OR.sup.2;
--C(.dbd.W)OR.sup.2; --C(.dbd.O)SH; --C(.dbd.W)SH;
--C(.dbd.O)SR.sup.2; --C(.dbd.W)SR.sup.2; --C(.dbd.O)NH.sub.2;
--C(.dbd.W)NH.sub.2; --C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)NR.sup.2R.su- p.3;
--C(.dbd.W)NH--(CH.sub.2).sub.p-(amino acid) or
--(CH.sub.2).sub.p-(amino acid); (b) R.sup.4', R.sup.5', R.sup.6',
R.sup.7', R.sup.2", R.sup.3", R.sup.4", R.sup.5" and R.sup.6" are
each independently H; halo (F, Cl, Br or I); --NO.sub.2; --CN;
--OH; --OR.sup.2; --SH; --SR.sup.2; --NH.sub.2; --NHR.sup.2;
--NR.sup.2R.sup.3; --NHSO.sub.2--C.sub.1-3alkyl;
--NR.sup.2SO.sub.2--C.sub.1-3alkyl; --NHCO--C.sub.1-3alkyl;
--NR.sup.2CO--C.sub.1-3alkyl; optionally substituted or
unsubstituted branched or unbranched alkyl, alkenyl or alkynyl
(such as an optionally substituted or unsubstituted branched or
unbranched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl,
and in particular CH.sub.3, CF.sub.3, vinyl bromide,
--CR.sup.2R.sup.2--S(O).sub- .n--R.sup.3,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; alkacyl; optionally
substituted or unsubstituted acyl; --C(.dbd.O)H; --C(.dbd.W)H;
--C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)OR.sup.2;
--C(.dbd.O)--SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; --C(.dbd.O)NH.sub.2; --C(.dbd.W)NH.sub.2;
--C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)--NR.sup.2R.- sup.3,
--C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid), a residue of an amino
acid or --(CH.sub.2).sub.p(amino acid); wherein if R.sup.5' is
hydrogen, F, Cl, Br, --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl or
--NHCO--C.sub.1-3alkyl, then at least one of R.sup.4', R.sup.6' and
R.sup.7' is not hydrogen or alternatively, wherein at least two of
R.sup.4', R.sup.5', R.sup.6', R.sup.7' are not hydrogen. (c) Z is
optionally substituted or unsubstituted acyl, --C(.dbd.O)NH.sub.2;
--C(.dbd.W)--NH.sub.2; --C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)NR.sup.2R.su- p.3;
--C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid); a residue of an amino
acid, --(CH.sub.2).sub.p-(amino acid); --C(.dbd.O)R.sup.3;
--C(.dbd.O)H; --C(.dbd.W)H; --C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2;
--C(.dbd.O)OR.sup.3; --C(.dbd.O)OH; --C(.dbd.W)OH;
--C(.dbd.O)OR.sup.2; --C(.dbd.W)--OR.sup.2; --C(.dbd.O)--SH;
--C(.dbd.W)SH; --C(.dbd.O)SR.sup.2; --C(.dbd.W)SR.sup.2; optionally
substituted or unsubstituted branched or unbranched alkyl, alkenyl
or alkynyl (such as an optionally substituted or unsubstituted
branched or unbranched C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, and in particular CH.sub.3, CF.sub.3, vinyl
bromide, --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3- ,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; --CN, or halo (F, Cl, Br or
I); (d) Y is O, S or S(O).sub.n; (e) each W is independently O, S,
--NH.sub.2, --NHR.sup.2, --NR.sup.2R.sup.2, --N--CN, --N--NH.sub.2,
--N--NHR.sup.2, --N--NR.sup.2R.sup.3, --N--OH or --N--OR.sup.2; (f)
each R.sup.2 is independently hydrogen or an optionally substituted
or unsubstituted branched or unbranched lower alkyl, alkenyl or
alkynyl (such as an optionally substituted or unsubstituted
branched or unbranched C.sub.1-3alkyl, C.sub.2-4alkenyl or
C.sub.2-4alkynyl, and in particular CH.sub.3, CF.sub.3, vinyl
bromide, --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2); (g) each R.sup.3 is
independently hydrogen; optionally substituted or unsubstituted
branched or unbranched alkyl, alkenyl or alkynyl (such as an
optionally substituted or unsubstituted branched or unbranched
C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl, and in
particular CH.sub.3, CF.sub.3, vinyl bromide,
--CR.sup.2R.sup.2--S(O).sub.n--R.sup.3, --CR.sup.2R.sup.2NH.sub.2,
--CR.sup.2R.sup.2NHR.sup.2, --CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2); optionally substituted or
unsubstituted aryl (such as phenyl); optionally substituted or
unsubstituted heterocycle; optionally substituted or unsubstituted
alkylaryl, optionally substituted or unsubstituted
alkylhereterocycle, optionally substituted or unsubstituted
aralkyl, optionally substituted or unsubstituted heterocycle-alkyl;
(h) each n is independently 0, 1 or 2; (i) each p is independently
0, 1, 2, 3, 4 or 5; and (j) wherein if one or more of the
optionally substituted branched or unbranched alkyl, alkenyl,
alkynyl, lower alkyl, lower alkenyl or lower alkynyl; acyl; aryl;
heterocycle; alkaryl; alkheterocycle; arylalkyl or alkylheterocycle
substitutents is substituted, then preferably it is substituted
with one or more of halogen (F, Cl, Br or I), --OH, --OR.sup.2,
--SH, --SR.sup.2, oxime (defined herein as --CH.dbd.N--OH),
hydrazine (defined herein as --NH--NH.sub.2), --C(.dbd.O)H,
--C(.dbd.W)H, --C(.dbd.O)R.sup.2, --C(.dbd.W)R.sup.2,
--C(.dbd.O)OH, --C(.dbd.W)OH, --C(.dbd.O)OR.sup.2,
--C(.dbd.W)OR.sup.2, --C(.dbd.O)SH, --C(.dbd.W)SH,
--C(.dbd.O)SR.sup.2, --C(.dbd.W)SR.sup.2, --C(.dbd.O)NH.sub.2,
--C(.dbd.W)NH.sub.2, --C(.dbd.O)--NHR.sup.2, --C(.dbd.W)NHR.sup.2,
--C(.dbd.O)NR.sup.2R.sup.3, --C(.dbd.W)--NR.sup.2R.sup.3,
--NH.sub.2, --NHR.sup.2, --NR.sup.2R.sup.3,
--NHSO.sub.2--C.sub.1-3alkyl, --NR.sup.2SO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, --NR.sup.2CO--C.sub.1-3alkyl,
--S(O).sub.n--R.sup.3, C.sub.1-3 alkoxy, C.sub.1-3thioether, a
residue of an amino acid such as --NH(CH.sub.2).sub.p-(amino acid)
or --C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid).
2. The compound of claim 1, wherein Y is SO.sub.2.
3. The compound of claim 1, wherein Z is an amide.
4. The compound of claim 1, wherein R.sup.1 is hydrogen.
5. The compound of claim 1, wherein (a) R.sup.1 is hydrogen; (b)
R.sup.4', R.sup.5', R.sup.6' and R.sup.7' are independently
hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime, hydrazine, or C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
--C(O)H, --COOH, halogen (F, Cl, Br or I), --NR.sup.2R.sup.2,
--C.sub.1-3 alkoxy or --C.sub.1-3 thioether; wherein if R.sup.5' is
hydrogen, F, Cl, Br, --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl or
--NHCO--C.sub.1-3alkyl, then at least one of R.sup.4', R.sup.6' and
R.sup.7' is not hydrogen; (c) R.sup.2", R.sup.3", R.sup.4",
R.sup.5" and R.sup.6" are independently hydrogen, halogen (F, Cl,
Br or I), --NO.sub.2, --CN, --OH, --OR.sup.2, --NR.sup.2R.sup.2,
--NHSO.sub.2--C.sub.1-3alkyl, --NHCO--C.sub.1-3alkyl, --C.sub.1-5
alkoxy, oxime, hydrazine, --C.sub.1-5 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, --C(O)H, --COOH,
halogen (F, Cl, Br or I), --NR.sup.2R.sup.2, --C.sub.1-5 thioether
or --C.sub.1-5 alkoxy; (d) Z is --CN, --C(.dbd.W)NR.sup.2R.sup.3,
--C(.dbd.O)R.sup.3, --C(.dbd.O)OR.sup.3,
--CR.sup.2R.sup.2--S(O).sub.n--R- .sup.3,
--CR.sup.2R.sup.2NHR.sup.2, --CR.sup.2R.sup.2--CO--R.sup.3 or
substituted or unsubstituted lower alkyl; (e) Y is O, S, or
S(O).sub.n; (f) each W is independently O, S, --N--CN or
--N--OR.sup.2; (g) R.sup.2 is hydrogen or C.sub.1-3 alkyl; (h)
R.sup.3 is hydrogen, substituted or unsubstituted alkyl, alkenyl,
aryl, or heterocycle, --C.sub.1-5 alkoxy, --OH, --NR.sup.2R.sup.2,
or --(CH.sub.2).sub.pC(O)NR.sup.2R.sup.2, (i) each n is
independently 0, 1 or 2; and (j) each p is independently 0, 1, 2,
3, 4, or 5.
6. the compound of claim 1, wherein (a) R.sup.1 is hydrogen; (b)
R.sup.4', R.sup.5', R.sup.6', R.sup.7', are independently hydrogen,
halogen (F, Cl, Br or I), --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime (defined herein as --CH.dbd.N--OH),
hydrazine (defined herein as --NH--NH.sub.2), or C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or
C.sub.1-3 thioether; wherein if R.sup.5' is hydrogen, F, Cl, Br,
--NO.sub.2, --CN, --OR.sup.2, --NR.sup.2R.sup.2,
--NHSO.sub.2--C.sub.1-3a- lkyl or --NHCO--C.sub.1-3alkyl, then at
least one of R.sup.4', R.sup.6' and R.sup.7' is not hydrogen; (c)
R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6", are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OR.sup.2, --NHSO.sub.2--C.sub.1-3alkyl, --NHCO--C.sub.1-3alkyl,
oxime, hydrazine, --C.sub.1-5 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-5 thioether, or C.sub.1-5 alkoxy,
--C.sub.1-5 alkoxy, --OH, or --NR.sup.2R.sup.2, (d) Z is
--C(W)NR.sup.2R.sup.3, or --COR.sup.3, (e) Y is --S(O).sub.n-- or
--O--, in which n is 0, 1 or 2. (f) W is O, S, --N--CN or
--N--OR.sup.2; (g) R.sup.2 is hydrogen or C.sub.1-3 alkyl, (h)
R.sup.3 is C.sub.1-5 alkyl, C.sub.1-5 alkenyl, aryl, or
heterocycle, substituted with one or more of C(O)NR.sup.2R.sup.2,
--NR.sup.2R.sup.2, --(CH.sub.2).sub.mC(O)NR.sup.2R.s- up.2,
--(CH.sub.2).sub.mC(=W)--NH(CH.sub.2).sub.p-(amino acid); (i) each
n is independently 0, 1 or 2; and (j) each p is independently 0, 1,
2, 3, 4, or 5.
7. A compound of the formula 33or a pharmaceutically acceptable
salt thereof.
8. A compound of the formula 34or a pharmaceutically acceptable
salt thereof.
9. A compound of the formula 35or a pharmaceutically acceptable
salt thereof.
10. A compound of the formula 36or a pharmaceutically acceptable
salt thereof.
11. A compound of the formula 37or a pharmaceutically acceptable
salt thereof.
12. A compound of the formula 38or a pharmaceutically acceptable
salt thereof.
13. A compound of the formula 39or a pharmaceutically acceptable
salt thereof.
14. A compound of the formula 40or a pharmaceutically acceptable
salt thereof.
15. A pharmaceutical composition comprising an effective anti-HIV
treatment amount of a compound of claim 1, or its pharmaceutically
acceptable salt thereof, together with a pharmaceutically
acceptable carrier or diluent.
16. A pharmaceutical composition comprising an effective anti-HIV
treatment amount of a compound of claim 1, or its pharmaceutically
acceptable salt thereof, in combination with one or more other
anti-HIV agent, optionally with a pharmaceutically acceptable
carrier or diluent.
17. The pharmaceutical composition of claim 16, wherein the other
anti-HIV agent is a reverse transcriptase inhibitor.
18. The pharmaceutical composition of claim 17, wherein the reverse
transcriptase inhibitor induces a mutation lysine
103.fwdarw.asparagine and/or tyrosine 181.fwdarw.cysteimie in HIV
reverse transcriptase.
19. A method for the treatment or prophylaxis of an HIV-infection
in a host comprising administering to said host an effective
anti-HIV treatment amount of a compound of claim 1, or its
pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier or diluent.
20. A method for the treatment or prophylaxis of an HIV-infection
in a host comprising administering to said host an effective
anti-HIV treatment amount of a compound of claim 1, or its
pharmaceutically acceptable salt thereof, in combination and/or
alternation with one or more other anti-HIV agent, optionally in a
pharmaceutically acceptable carrier or diluent.
21. The method of claim 20, wherein the other anti-HIV agent is a
reverse transcriptase inhibitor.
22. The method of claim 21, wherein the reverse transcriptase
inhibitor induces a mutation lysine 103.fwdarw.asparagine and/or
tyrosine 181.fwdarw.cysteine in HIV reverse transcriptase.
23. A method for the treatment or prophylaxis of an HIV-infection
in a host, wherein the HIV has a mutation at lysine
103.fwdarw.asparagine and/or tyrosine 181.fwdarw.cysteine in HIV
reverse transcriptase, comprising administering to said host an
effective anti-HIV treatment amount of a compound of claim 1, or
its pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier or diluent.
24. A method for the treatment or prophylaxis of an HIV-infection
in a host, wherein the HIV is resistant to one or more reverse
transcriptase inhibitor(s), comprising administering to said host
an effective anti-HIV treatment amount of a compound of claim 1, or
its pharmaceutically acceptable salt thereof, in combination and/or
alternation with one or more other anti-HIV agent, optionally in a
pharmaceutically acceptable carrier or diluent.
25. A method for salvage therapy in the treatment or prophylaxis of
an HIV-infection in a host, comprising administering to said host
an effective anti-HIV treatment amount of a compound of claim 1, or
its pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier or diluent.
26. A method for salvage therapy in the treatment or prophylaxis of
an HIV-infection in a host, comprising administering to said host
an effective anti-HIV treatment amount of a compound of claim 1, or
its pharmaceutically acceptable salt thereof, in combination and/or
alternation with one or more other anti-HIV agent, optionally in a
pharmaceutically acceptable carrier or diluent.
27. A method for the treatment or prophylaxis of an HIV-infection
in a host, wherein the HIV is resistant to one or more reverse
transcriptase inhibitor(s), comprising administering to said host
an effective anti-HIV treatment amount of a compound of claim 1, or
its pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier or diluent.
28. A method for the treatment or prophylaxis of an HIV-infection
in a host, wherein the HIV has a mutation at lysine
103.fwdarw.asparagine and/or tyrosine 181.fwdarw.cysteine in HIV
reverse transcriptase, comprising administering to said host an
effective anti-HIV treatment amount of a compound of claim 1, or
its pharmaceutically acceptable salt thereof, in combination and/or
alternation with one or more other anti-HIV agent, optionally in a
pharmaceutically acceptable carrier or diluent.
29. The method of any one of claims 19-28 wherein the host is a
human.
Description
[0001] This application claims priority to U.S. Provisional
Application No. 60/283,393, filed on Apr. 11, 2001.
FIELD OF THE INVENTION
[0002] This invention is in the area of phenylindoles that are
useful for the treatment of HIV infection, and, in particular,
phenylindoles that exhibit significant activity against resistant
strains of HIV.
BACKGROUND OF THE INVENTION
[0003] In 1983, the etiological cause of AIDS was determined to be
the human immunodeficiency virus (HIV). Numerous compounds have
since been synthesized to combat the virus, designed to inhibit
progression beyond various stages of the virus's lifecycle. A focal
point in AIDS research efforts has been the development of
inhibitors of human immunodeficiency virus (HIV-1) reverse
transcriptase (RT), an enzyme responsible for the reverse
transcription of the retroviral RNA to proviral DNA (Greene, W. C.,
New England Journal of Medicine, 1991, 324, 308-317; Mitsuya, H. et
al., Science, 1990, 249, 1533-1544; De Clercq, E., J. Acquired
Immune Defic. Syndr. Res. Human. Retrovirus, 1992, 8, 119-134).
Promising inhibitors include nonnucleoside inhibitors (NNI), which
bind to a specific allosteric site of HIV-1 RT near the polymerase
site and interfere with reverse transcription by altering either
the conformation or mobility of RT, thereby leading to
noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al.,
Science, 1992, 256, 1783-1790).
[0004] Several classes of compounds have been identified as NNI of
HIV-1 RT. Examples include the following:
[0005] (a) 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymines
(HEPT; Tanaka, H. et al., J. Med. Chem., 1991, 34, 349-357;
Pontikis, R. et al., J. Med. Chem., 1997, 40, 1845-1854; Danel, K.,
et al., J. Med. Chem., 1996, 39, 2427-2431; Baba, M., et al.,
Antiviral Res, 1992, 17, 245-264);
[0006] (b) bis(heteroaryl)piperazines (BHAP; Romero, D. L. et al.,
J. Med. Chem., 1993, 36, 1505-1508);
[0007] (c) dihydroalkoxybenzyloxopyrimidine (DABO; Danel, K. et
al., Acta Chemica Scandinavica, 1997, 51, 426-430; Mai, A. et al.,
J. Med. Chem., 1997, 40, 1447-1454);
[0008] (d)
2'-5'-bis-O-(tertbutyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",
2"-oxathiole-2", 2"-dioxide) pyrimidines (TSAO; Balzarini, J. et
al., Proc. Natl. Acad. Sci. USA, 1992, 89, 4392-4396);
[0009] (e) phenethylthiazolylthiourea (PETT) derivatives (Bell, F.
W. et al., J. Med. Chem., 1995, 38, 4929-4936; Cantrell, A. S. et
al., J. Med. Chem., 1996, 39, 4261-4274);
[0010] (f)
tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and
-thione (TIBO) derivatives (Pauwels, R. et al. Nature, 1990, 343,
470-474);
[0011] (g) alpha-anilinophenylacetamide (alpha-APA) derivatives
(Pauwels, R. et al. Proceedings of the National Academy of Sciences
USA, 1993, 90, 1711-1715); and
[0012] (h) indole derivatives (Williams et al., U.S. Pat. No.
5,527,819 (Jun. 18, 1996); and its counterpart PCT application
PCT/US94/01694, published as WO 94/19321 on Sep. 1, 1994).
[0013] The indole derivatives identified by Williams et al.,
assigned to Merck & Co., in U.S. Pat. No. 5,527,819 received
particular interest because of their ability to potently inhibit
HIV reverse transcriptase. A number of these compounds displayed
EC.sub.90s against HIV reverse transcriptase at concentrations as
low as 2 micromolar. However, this work was not pursued, perhaps
because HIV virus that had been exposed to other drugs was shown to
be cross resistant to these indoles (Williams et al., Journal of
Medicinal Chemistry, 1993, 36(9), 1291-94).
[0014] The class of compounds disclosed in the '819 patent
encompasses a large class of compounds represented generally by the
following broad structural formula: 1
[0015] in which the variables X, Y, Z, R and R.sup.6 were broadly
defined to encompass a plethora of compounds. The patent presented
examples for nearly one hundred of the compounds encompassed by the
structure, and included several examples in which Z was
--C(O)NH.sub.2, Y was SO.sub.2 and R was phenyl or substituted
phenyl.
[0016] U.S. Pat. No. 5,124,327, issued Jun. 23, 1992 to Greenlee et
al. and assigned to Merck disclosed a class of compounds of the
general formula above, in which X is H, R.sup.6 is H, Y is S, and R
is phenyl. The patent disclosed that the compounds act as reverse
transcriptase inhibitors.
[0017] Indoles have been used for the treatment of a variety of
diseases other than HIV. For example, Farina et al., in U.S. Pat.
No. 5,981,525 (Nov. 9, 1999), disclose a complex array of indoles
that are useful for the treatment of osteoporosis, because they
reduce bone resorption by inhibiting osteoclast H.sup.+-ATPase.
[0018] U.S. Pat. No. 6,025,390, granted Feb. 15, 2000 to Farina et
al., discloses another complex array of indole derivatives,
referred to as heteroaromatic pentadienoic acid derivatives, and
again suggest their use for the treatment of osteoporosis.
[0019] U.S. Pat. No. 5,489,685, granted Feb. 6, 1996, Houpis et al.
discloses a similar set of compounds in the fiuro(2,3-B) pyridine
carboxylic acid ester class, and specifically suggest their use for
the treatment of HIV.
[0020] U.S. Pat. No. 5,945,440 to Kleinschroth et al. discloses a
class of indolocarbazole amides, and proposes their use for a
variety of diseases including cancer, viral diseases (including
HIV), heart and blood vessel diseases, bronchopulmonary diseases,
degenerative diseases of the central nervous system, inflammatory
disorders, and other diseases.
[0021] Gunasekera et al., in U.S. Pat. No. 4,866,084 (Sep. 12,
1989), disclose a class of bisindole alkaloid compounds, and state
that the compounds are useful as antiviral and antitumor agents.
The patent also describes the compounds' activity against HSV
(herpes simplex virus).
[0022] Matsunaga et al., in U.S. Pat. No. 5,852,011 (Dec. 22,
1998), disclose a class of indole derivates substituted by a
heteroaryl function and an amide function. The compounds are said
to possess antitumor, antiviral, and antimicrobial properties.
[0023] Dykstra et al., in U.S. Pat. No. 5,935,982 disclose a class
of bis-indoles and specifically propose their use for treating
retroviral infections, and especially infection by HIV.
[0024] Domagala et al., in U.S. Pat. No. 5,929,114 (Jul. 27, 1999)
disclose a class of arylthio and bithiobisarylamide compounds that
reportedly have antibacterial and antiviral activity. The invention
is said to encompass indole derivatives as well.
[0025] Pevear et al., in U.S. Pat. No. 5,830,894 (Nov. 3, 1998)
disclose a class of triazinoindole derivatives that reportedly have
pestivirus activity, most notably BVDV activity.
[0026] It is known that over a period of time, antiviral agents
that are active against HIV induce mutations in the virus that
reduce the efficacy of the drug. This was apparently the problem
exhibited by the Merck indoles in U.S. Pat. No. 5,527,819 (Williams
et al, Journal of Medicinal Chemistry, 1993, 36(9), 1291-94). Drug
resistance most typically occurs by mutation of a gene that encodes
for an enzyme used in viral replication, and most typically in the
case of HIV, reverse transcriptase, protease, or DNA integrase. It
has been demonstrated that the efficacy of a drug against HIV
infection can be prolonged, augmented, or restored by administering
the compound in combination or alternation with a second, and
perhaps third, antiviral compound that induces a different mutation
from that caused by the principle drug. Alternatively, the
pharmacokinetics, biodistribution, or other parameters of a drug
can be altered by such combination or alternation therapy. In
general, combination therapy is typically preferred over
alternation therapy since combination therapy induces multiple
simultaneous pressures on the virus. However, one cannot predict
which mutations will be induced in the HIV-1 genome by a given
drug, whether the mutations are permanent or transient, or how an
infected cell with a mutated HIV-1 sequence will respond to therapy
with other agents in combination or alternation. These factors are
exacerbated by the fact that there is a paucity of data on the
kinetics of drug resistance in long-term cell cultures treated with
modern antiretroviral agents.
[0027] Therefore, there is a need to improve the duration of
antiviral efficacy produced by antiretroviral drugs, and to provide
antiviral drugs that are effective against strains of the virus
that have developed cross resistance through mutational adaptation.
Further, although many of the non-nucleotide reverse transcriptase
inhibitors (NNRTI) in the prior art exhibit favorable
pharmacokinetic and biodistribution profiles, there remains a need
to improve upon these parameters.
[0028] It is an object of the present invention to provide new
compounds for the treatment of patients infected with HIV. There is
a special need to provide new compositions and methods for the
treatment of patients infected with HIV that exhibit significant
activity against drug-resistant forms of the virus.
SUMMARY OF THE INVENTION
[0029] A novel class of phenylindoles has been discovered that
display significant antiviral activity against HIV, and in
particular, strains of the HIV that have developed cross resistance
to other anti-HIV drugs. It has surprisingly been discovered that
HIV activity can be enhanced, and in certain cases cross resistance
can be substantially overcome, by incorporating into the molecule
at least two moieties other than hydrogen on either the phenyl ring
or the benzyl ring of the indole function, or on both rings. The
substituents are preferably contained at the 3" and 5" positions if
located on phenyl ring, and at the 4' and 5'; 5' and 6' or the 5'
and 7' positions if located on the benzyl ring of the indole
function. Methyl is a preferred group for substitution on the
phenyl ring. Preferred substituents for the benzyl ring of the
indole function are small moieties, and include substituents such
as chlorine, fluorine, bromine, CF.sub.3, vinyl bromide and
NO.sub.2.
[0030] In one embodiment of the present invention, the compound can
be represented generally by the following chemical formula: 2
[0031] or its pharmaceutically acceptable salt or prodrug,
wherein
[0032] (a) R.sup.1 is hydrogen; acyl; --C(.dbd.O)H; --C(.dbd.W)H;
--C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)OR.sup.2;
--C(.dbd.O)SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; --C(.dbd.O)NH.sub.2; --C(.dbd.W)NH.sub.2;
--C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)NR.sup.2R.sup.3;
--C(.dbd.W)NH--(CH.sub.2).sub.p-(amino acid) or
--(CH.sub.2).sub.p-(amino acid);
[0033] (b) R.sup.4', R.sup.5', R.sup.6', R.sup.7', R.sup.2",
R.sup.3", R.sup.4", R.sup.5" and R.sup.6" are each independently H;
halo (F, Cl, Br or I); --NO.sub.2; --CN; --OH; --OR.sup.2; --SH;
--SR.sup.2; --NH.sub.2; --NHR.sup.2; --NR.sup.2R.sup.3;
--NHSO.sub.2--C.sub.1-3alkyl; --NR.sup.2SO.sub.2--C.sub.1-3alkyl;
--NHCO--C.sub.1-3alkyl; --NR.sup.2CO--C.sub.1-3alkyl; optionally
substituted or unsubstituted branched or unbranched alkyl, alkenyl
or alkynyl (such as an optionally substituted or unsubstituted
branched or unbranched C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, and in particular CH.sub.3, CF.sub.3, vinyl
bromide, --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; alkacyl; optionally
substituted or unsubstituted acyl; --C(.dbd.O)H; --C(.dbd.W)H;
--C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)OR.sup.2;
--C(.dbd.O)--SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; --C(.dbd.O)NH.sub.2; --C(.dbd.W)NH.sub.2;
--C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)--NR.sup.2R.- sup.3,
--C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid), a residue of an amino
acid or --(CH.sub.2).sub.p(amino acid); wherein if R.sup.5' is
hydrogen, F, Cl, Br, --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl or
--NHCO--C.sub.1-3alkyl, then at least one of R.sup.4', R.sup.6' and
R.sup.7' is not hydrogen or alternatively, wherein at least two of
R.sup.4', R.sup.5', R.sup.6', R.sup.7' are not hydrogen.
[0034] (c) Z is optionally substituted or unsubstituted acyl,
--C(.dbd.O)NH.sub.2; --C(.dbd.W)--NH.sub.2; --C(.dbd.O)NHR.sup.2;
--C(.dbd.W)NHR.sup.2; --C(.dbd.O)NR.sup.2R.sup.3;
--C(.dbd.W)NR.sup.2R.su- p.3; --C(.dbd.W)NH(CH.sub.2).sub.p-(amino
acid); a residue of an amino acid, --(CH.sub.2).sub.p-(amino acid);
--C(.dbd.O)R.sup.3; --C(.dbd.O)H; --C(.dbd.W)H; --C(.dbd.O)R.sup.2;
--C(.dbd.W)R.sup.2; --C(.dbd.O)OR.sup.3; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)--OR.sup.2;
--C(.dbd.O)--SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; optionally substituted or unsubstituted
branched or unbranched alkyl, alkenyl or alkynyl (such as an
optionally substituted or unsubstituted branched or unbranched
C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl, and in
particular CH.sub.3, CF.sub.3, vinyl bromide,
--CR.sup.2R.sup.2--S(O).sub.n--R.sup.3- ,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; --CN, or halo (F, Cl, Br or
I);
[0035] (d) Y is O, S or S(O).sub.n;
[0036] (e) each W is independently O, S, --NH.sub.2, --NHR.sup.2,
--NR.sup.2R.sup.2, --N--CN, --N--NH.sub.2, --N--NHR.sup.2,
--N--NR.sup.2R.sup.3, --N--OH or --N--OR.sup.2;
[0037] (f) each R.sup.2 is independently hydrogen or an optionally
substituted or unsubstituted branched or unbranched lower alkyl,
alkenyl or alkynyl (such as an optionally substituted or
unsubstituted branched or unbranched C.sub.1-3alkyl,
C.sub.2-4alkenyl or C.sub.2-4alkynyl, and in particular CH.sub.3,
CF.sub.3, vinyl bromide, --CR.sup.2R.sup.2--S(O).- sub.n--R.sup.3,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ;
[0038] (g) each R.sup.3 is independently hydrogen; optionally
substituted or unsubstituted branched or unbranched alkyl, alkenyl
or alkynyl (such as an optionally substituted or unsubstituted
branched or unbranched C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, and in particular CH.sub.3, CF.sub.3, vinyl
bromide, --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3- ,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; optionally substituted or
unsubstituted aryl (such as phenyl); optionally substituted or
unsubstituted heterocycle; optionally substituted or unsubstituted
alkylaryl, optionally substituted or unsubstituted
alkylhereterocycle, optionally substituted or unsubstituted
aralkyl, optionally substituted or unsubstituted
heterocycle-alkyl;
[0039] (h) each n is independently 0, 1 or 2; and
[0040] (i) each p is independently 0, 1, 2, 3, 4 or 5;
[0041] (j) wherein if one or more of the optionally substituted
branched or unbranched alkyl, alkenyl, alkynyl, lower alkyl, lower
alkenyl or lower alkynyl; acyl; aryl; heterocycle; alkaryl;
alkheterocycle; arylalkyl or alkylheterocycle substitutents is
substituted, then preferably it is substituted with one or more of
halogen (F, Cl, Br or I), --OH, --OR.sup.2, --SH, --SR.sup.2, oxime
(defined herein as --CH.dbd.N--OH), hydrazine (defined herein as
--NH--NH.sub.2), --C(.dbd.O)H, --C(.dbd.W)H, --C(.dbd.O)R.sup.2,
--C(.dbd.W)R.sup.2, --C(.dbd.O)OH, --C(.dbd.W)OH,
--C(.dbd.O)OR.sup.2, --C(.dbd.W)OR.sup.2, --C(.dbd.O)SH,
--C(.dbd.W)SH, --C(.dbd.O)SR.sup.2, --C(.dbd.W)SR.sup.2,
--C(.dbd.O)NH.sub.2, --C(.dbd.W)NH.sub.2, --C(.dbd.O)--NHR.sup.2,
--C(.dbd.W)NHR.sup.2, --C(.dbd.O)NR.sup.2R.sup.3,
--C(.dbd.W)--NR.sup.2R.- sup.3, --NH.sub.2, --NHR.sup.2,
--NR.sup.2R.sup.3, --NHSO.sub.2--C.sub.1-3- alkyl,
--NR.sup.2SO.sub.2--C.sub.1-3alkyl, --NHCO--C.sub.1-3alkyl,
--NR.sup.2CO--C.sub.1-3alkyl, --S(O).sub.n--R.sup.3, C.sub.1-3
alkoxy, C.sub.1-3thioether, a residue of an amino acid such as
--NH(CH.sub.2).sub.p-(amino acid) or
--C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid).
[0042] In a preferred embodiment, Y is SO.sub.2. In another
preferred embodiment, Z is an amide function.
[0043] In an altemative embodiment, the hydrogen attached to the
indole nitrogen can be replaced with lower alkyl, for example,
methyl, or aryl, alkaryl or aralkyl.
[0044] In another embodiment the invention provides a phenylindole
represented generally by formula (I) above, and methods of using
such phenylindoles in the treatment of HIV, wherein:
[0045] (a) R.sup.1 is hydrogen;
[0046] (b) R.sup.4', R.sup.5', R.sup.6' and R.sup.7' are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OR.sup.2, --NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime, hydrazine, or C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
--C(O)H, --COOH, halogen (F, Cl, Br or I), --NR.sup.2R.sup.2,
--C.sub.1-3 alkoxy or --C.sub.1-3 thioether; wherein if R.sup.5' is
hydrogen, F, Cl, Br, --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl or
--NHCO--C.sub.1-3alkyl, then at least one of R.sup.4', R.sup.6' and
R.sup.7' is not hydrogen;
[0047] (c) R.sup.2", R.sup.3", R.sup.4", R.sup.5" and R.sup.6" are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OH, --OR.sup.2, --NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, --C.sub.1-5 alkoxy, oxime, hydrazine,
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, --C(O)H, --COOH, halogen (F, Cl, Br or I),
--NR.sup.2R.sup.2, --C.sub.1-5 thioether or --C.sub.1-5 alkoxy;
[0048] (d) Z is --CN, --C(.dbd.W)NR.sup.2R.sup.3,
--C(.dbd.O)R.sup.3, --C(.dbd.O)OR.sup.3,
--CR.sup.2R.sup.2--S(O).sub.n--R.sup.3, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2--CO--R.sup.3 or substituted or unsubstituted
lower alkyl;
[0049] (e) Y is O, S, or S(O).sub.n;
[0050] (f) each W is independently O, S, --N--CN or
--N--OR.sup.2;
[0051] (g) R.sup.2 is hydrogen or C.sub.1-3 alkyl;
[0052] (h) R.sup.3 is hydrogen, substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, --C.sub.1-5 alkoxy, --OH,
--NR.sup.2R.sup.2, or --(CH.sub.2).sub.pC(O)NR.sup.2R.sup.2,
[0053] (i) each n is independently 0, 1 or 2; and
[0054] (j) each p is independently 0, 1, 2, 3, 4, or 5.
[0055] In still another embodiment the invention provides a
phenylindole represented generally by formula (I) above, and
methods of using such phenylindoles in the treatment of HIV,
wherein:
[0056] (a) R.sup.1 is hydrogen;
[0057] (b) R.sup.4', R.sup.5', R.sup.6', R.sup.7', are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OR.sup.2, --NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime (defined herein as --CH.dbd.N--OH),
hydrazine (defined herein as --NH--NH.sub.2), or C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or
C.sub.1-3 thioether; wherein if R.sup.5' is hydrogen, F, Cl, Br,
--NO.sub.2, --CN, --OR.sup.2, --NR.sup.2R.sup.2,
--NHSO.sub.2--C.sub.1-3alkyl or --NHCO--C.sub.1-3alkyl, then at
least one of R.sup.4', R.sup.6' and R.sup.7' is not hydrogen;
[0058] (c) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6",
are independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2,
--CN, --OR.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime, hydrazine, --C.sub.1-5 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-5 thioether, or
C.sub.1-5 alkoxy, --C.sub.1-5 alkoxy, --OH, or
--NR.sup.2R.sup.2,
[0059] (d) Z is --C(W)NR.sup.2R.sup.3, or --COR.sup.3,
[0060] (e) Y is --S(O).sub.n-- or --O--, in which n is 0, 1 or
2.
[0061] (f) W is O, S, --N--CN or --N--OR.sup.2;
[0062] (g) R.sup.2 is hydrogen or C.sub.1-3 alkyl,
[0063] (h) R.sup.3 is C.sub.1-5 alkyl, C.sub.1-5 alkenyl, aryl, or
heterocycle, substituted with one or more of C(O)NR.sup.2R.sup.2,
--NR.sup.2R.sup.2, --(CH.sub.2).sub.mC(O)NR.sup.2R.sup.2,
--(CH.sub.2).sub.mC(.dbd.W)--NH(CH.sub.2).sub.p-(amino acid);
[0064] (k) each n is independently 0, 1 or 2; and
[0065] (l) each p is independently 0, 1, 2, 3, 4, or 5.
[0066] In a particular embodiment, the phenylindole is a compound
of the structure: 3
[0067] or a pharmaceutically acceptable salt or prodrug
thereof.
[0068] In another particular embodiment, the phenylindole is a
compound of the structure: 4
[0069] or a pharmaceutically acceptable salt or prodrug
thereof.
[0070] In yet another particular embodiment, the phenylindole is a
compound of the structure: 5
[0071] or a pharmaceutically acceptable salt or prodrug
thereof.
[0072] In yet another particular embodiment, the phenylindole is a
compound of the structure: 6
[0073] or a pharmaceutically acceptable salt or prodrug
thereof.
[0074] In another particular embodiment, the phenylindole is a
compound of the structure: 7
[0075] or a pharmaceutically acceptable salt or prodrug
thereof.
[0076] In yet another particular embodiment of the present
invention, the phenylindole is a compound of the structure: 8
[0077] or a pharmaceutically acceptable salt or prodrug
thereof.
[0078] In yet another particular embodiment of the present
invention, the phenylindole is a compound of the structure: 9
[0079] or a pharmaceutically acceptable salt or prodrug
thereof.
[0080] In yet another particular embodiment of the present
invention, the phenylindole is a compound of the structure: 10
[0081] or a pharmaceutically acceptable salt or prodrug
thereof.
[0082] The phenylindoles of this invention belong to a class of
anti-HIV agents that may inhibit reverse transcriptase activity.
These compounds can be assessed for their ability to inhibit
reverse transcriptase activity in vitro according to standard
screening methods.
[0083] In one embodiment the efficacy of the anti-HIV compound is
measured according to the concentration of compound necessary to
reduce the plaque number of the virus in vitro, according to
methods set forth more particularly herein, by 50% (i.e. the
compound's EC.sub.50). In preferred embodiments the compound
exhibits an EC.sub.50 of less than 15 or preferably, less than 10
micromolar in vitro.
[0084] In another embodiment, the active compound exhibits
significant activity against drug-resistant forms of HIV, and thus
exhibits decreased cross-resistance against currently approved
antiviral therapies. The term significant activity against a drug
resistant form of HIV means that a compound (or its prodrug or
pharmaceutically acceptable salt) is active against the mutant
strain with an EC.sub.50 against the mutant strain of less than
approximately 50, 25, 10 or 1 micromolar concentration. In a
preferred embodiment, the non--Nucleosides reverse transcriptase
inhibitors (NNRTI) displays an EC.sub.50 (in molar concentrations)
in a mutant HIV strain of less than approximately 5, 2.5, 1 or 0.1
micromolar concentration. In one non limiting embodiment, the HIV
mutant strain is a strain with a reverse transcriptase mutation at
lysine 103.fwdarw.asparagine and/or tyrosine
181.fwdarw.cysteine.
[0085] In still another embodiment, the active compound can be
administered in combination or alternation with another anti-HIV
agent. In combination therapy, effective dosages of two or more
agents are administered together, whereas during alternation
therapy an effective dosage of each agent is administered serially.
The dosages will depend on absorption, inactivation, and excretion
rates of the drug as well as other factors known to those of skill
in the art. It is to be noted that dosage values will also vary
with the severity of the condition to be alleviated. It is to be
further understood that for any particular subject, specific dosage
regimens and schedules should be adjusted over time according to
the individual need and the professional judgment of the person
administering or supervising the administration of the
compositions.
BRIEF DESCRIPTION OF THE FIGURES
[0086] FIG. 1 is a nonlimiting illustrative example of the
synthesis of phenylindoles as described herein; wherein P
represents hydrogen or alkyl, in particular methyl, ethyl, butyl or
propyl, preferably ethyl; and Y' represents oxygen or sulfur.
[0087] FIG. 2 is a nonlimiting illustrative example of the
synthesis of phenylindoles as described herein; wherein P
represents hydrogen or alkyl, in particular methyl, ethyl, butyl or
propyl, preferably ethyl.
[0088] FIGS. 3 and 4 are additional nonlimiting illustrative
example of the synthesis of phenylindoles as described herein.
[0089] FIG. 5 is a schematic of a method of manufacture of the
compound of the formula: 11
DETAILED DESCRIPTION OF THE INVENTION
[0090] The invention as disclosed herein is a method and
composition for the treatment of HIV in humans and other host
animals, that includes the administration of an effective HIV
treatment amount of a phenylindole as described herein or a
pharmaceutically acceptable salt or prodrug thereof, optionally in
a pharmaceutically acceptable carrier.
[0091] The compounds of this invention either possess antiviral
(i.e., anti-HIV) activity, or are metabolized to a compound that
exhibits such activity.
[0092] In summary, the present invention includes the following
features:
[0093] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein;
[0094] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein substantially free of
other chemical entities;
[0095] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein that are effective against
HIV in a host;
[0096] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein that are effective against
drug-resistant strains of HIV in a host;
[0097] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein that are effective against
drug-resistant strains of HIV due to a reverse transcriptase
mutation, such as lysine 103.fwdarw.asparagine and/or tyrosine
181.fwdarw.cysteine;
[0098] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the treatment
or prophylaxis of an HIV infection. in a host, especially in
individuals diagnosed as having an HIV infection or being at risk
for becoming infected by HIV;
[0099] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection in a host, especially in individuals diagnosed as having
an HIV infection or being at risk for becoming infected by HIV;
[0100] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the treatment
or prophylaxis of an HIV infection, which is resistant to one or
more reverse transcriptase inhibitors, in a host;
[0101] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection, which is resistant to one or more reverse transcriptase
inhibitors, in a host;
[0102] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the treatment
or prophylaxis of an HIV infection as a form of salvage therapy in
a host, especially in individuals diagnosed as having an HIV
infection or being at risk for becoming infected by HIV;
[0103] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection as a form of salvage therapy in a host, especially in
individuals diagnosed as having an HIV infection or being at risk
for becoming infected by HIV;
[0104] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the treatment
or prophylaxis of an HIV infection that is resistant to one or more
reverse transcriptase inhibitors due to a reverse transcriptase
mutation, such as lysine 103.fwdarw.asparagine and/or tyrosine
181.fwdarw.cysteine, in a host, especially in individuals diagnosed
as having an HIV infection or being at risk for becoming infected
by HIV;
[0105] phenylindoles and their pharmaceutically acceptable salts
and prodrugs thereof as described herein for use in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection that is resistant to one or more reverse transcriptase
inhibitors due to a reverse transcriptase mutation, such as lysine
103.fwdarw.asparagine and/or tyrosine 181.fwdarw.cysteine, in a
host, especially in individuals diagnosed as having an HIV
infection or being at risk for becoming infected by HIV;
[0106] processes for the preparation of phenylindoles, as described
in more detail below;
[0107] processes for the preparation of phenylindoles substantially
isolated from other chemical entities;
[0108] pharmaceutical compositions comprising an effective anti-HIV
treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof together with a pharmaceutically
acceptable carrier or diluent;
[0109] pharmaceutical compositions comprising an effective anti-HIV
treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof in combination with one or more
other anti-HIV agent, optionally with a pharmaceutically acceptable
carrier or diluent;
[0110] pharmaceutical compositions for the treatment or prophylaxis
of an HIV infection in a host comprising an effective anti-HIV
treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof, optionally in combination with
one or more other anti-HIV agent, optionally with a
pharmaceutically acceptable carrier or diluent;
[0111] pharmaceutical compositions for the treatment or prophylaxis
of an HIV infection, which is resistant to one or more reverse
transcriptase inhibitors, in a host comprising an effective
anti-HIV treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof, optionally in combination with
one or more other anti-HIV agent, optionally with a
pharmaceutically acceptable carrier or diluent;
[0112] pharmaceutical compositions for the treatment or prophylaxis
of an HIV infection in a host as a form of salvage therapy
comprising an effective anti-HIV treatment amount of a phenylindole
or its pharmaceutically acceptable salt or prodrug thereof,
optionally in combination with one or more other anti-HIV agent,
optionally with a pharmaceutically acceptable carrier or
diluent;
[0113] pharmaceutical compositions for the treatment or prophylaxis
of an HIV infection, which is resistant to one or more reverse
transcriptase inhibitors due to a reverse transcriptase mutation,
such as lysine 103.fwdarw.asparagine and/or tyrosine
181.fwdarw.cysteine, in a host comprising an effective anti-HIV
treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof, optionally in combination with
one or more other anti-HIV agent, optionally with a
pharmaceutically acceptable carrier or diluent;
[0114] methods for the treatment or prophylaxis of an HIV infection
in a host comprising administering to said host an effective
anti-HIV treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof, optionally in combination
and/or alternation with one or more other anti-HIV agent,
optionally with a pharmaceutically acceptable carrier or
diluent;
[0115] methods for the treatment or prophylaxis of an HIV
infection, which is resistant to one or more reverse transcriptase
inhibitors, in a host comprising administering to said host an
effective anti-HIV treatment amount of a phenylindole or its
pharmaceutically acceptable salt or prodrug thereof, optionally in
combination and/or alternation with one or more other anti-HIV
agent, optionally with a pharmaceutically acceptable carrier or
diluent;
[0116] methods for the treatment or prophylaxis of an HIV infection
in a host as a form of salvage therapy comprising administering to
said host an effective anti-HIV treatment amount of a phenylindole
or its pharmaceutically acceptable salt or prodrug thereof,
optionally in combination and/or alternation with one or more other
anti-HIV agent, optionally with a pharmaceutically acceptable
carrier or diluent;
[0117] methods for the treatment or prophylaxis of an HIV
infection, which is resistant to one or more reverse transcriptase
inhibitors due to a reverse transcriptase mutation, such as lysine
103.fwdarw.asparagine and/or tyrosine 181.fwdarw.cysteine, in a
host comprising administering to said host an effective anti-HIV
treatment amount of a phenylindole or its pharmaceutically
acceptable salt or prodrug thereof, optionally in combination
and/or alternation with one or more other anti-HIV agent,
optionally with a pharmaceutically acceptable carrier or
diluent;
[0118] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent for the treatment
or prophylaxis of an HIV infection in a host;
[0119] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent for the treatment
or prophylaxis of an HIV infection, which is resistant to one or
more reverse transcriptase inhibitors, in a host;
[0120] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent for the treatment
or prophylaxis of an HIV infection in a host as a form of salvage
therapy;
[0121] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent for the treatment
or prophylaxis of an HIV infection, which is resistant to one or
more reverse transcriptase inhibitors due to a reverse
transcriptase mutation, such as lysine 103.fwdarw.asparagine and/or
tyrosine 181.fwdarw.cysteine, in a host;
[0122] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection in a host;
[0123] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection, which is resistant to one or more reverse transcriptase
inhibitors, in a host;
[0124] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection in a host as a form of salvage therapy; and
[0125] use of a phenylindole or its pharmaceutically acceptable
salt or prodrug thereof, optionally in combination and/or
alternation with one or more other anti-HIV agent, optionally with
a pharmaceutically acceptable carrier or diluent in the manufacture
of a medicament for the treatment or prophylaxis of an HIV
infection, which is resistant to one or more reverse transcriptase
inhibitors due to a reverse transcriptase mutation, such as lysine
103.fwdarw.asparagine and/or tyrosine 181.fwdarw.cysteine, in a
host.
[0126] I. Active Compounds of the Present Invention
[0127] Suitable phenylindoles for practicing the present invention
can be represented generally by formula (I): 12
[0128] or its pharmaceutically acceptable salt or prodrug thereof,
and are defined below.
[0129] In one embodiment of the present invention the compound of
formula (I) is defined as follows:
[0130] (a) R.sup.1 is hydrogen; acyl; --C(.dbd.O)H; --C(.dbd.W)H;
--C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)OR.sup.2;
--C(.dbd.O)SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; --C(.dbd.O)NH.sub.2; --C(.dbd.W)NH.sub.2;
--C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)NR.sup.2R.sup.3;
--C(.dbd.W)NH--(CH.sub.2).sub.p-(arnino acid) or
--(CH.sub.2).sub.p-(amin- o acid);
[0131] (b) R.sup.4', R.sup.5', R.sup.6', R.sup.7', R.sup.2",
R.sup.3", R.sup.4", R.sup.5" and R.sup.6" are each independently H;
halo (F, Cl, Br or I); --NO.sub.2; --CN; --OH; --OR.sup.2; --SH;
--SR.sup.2; --NH.sub.2; --NHR.sup.2; --NR.sup.2R.sup.3;
--NHSO.sub.2--C.sub.1-3alkyl; --NR.sup.2SO.sub.2--C.sub.1-3alkyl;
--NHCO--C.sub.1-3alkyl; --NR.sup.2CO--C.sub.1-3alkyl; optionally
substituted or unsubstituted branched or unbranched alkyl, alkenyl
or alkynyl (such as an optionally substituted or unsubstituted
branched or unbranched C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, and in particular CH.sub.3, CF.sub.3, vinyl
bromide, --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; alkacyl; optionally
substituted or unsubstituted acyl; --C(.dbd.O)H; --C(.dbd.W)H;
--C(.dbd.O)R.sup.2; --C(.dbd.W)R.sup.2; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)OR.sup.2;
--C(.dbd.O)--SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; --C(.dbd.O)NH.sub.2; --C(.dbd.W)NH.sub.2;
--C(.dbd.O)NHR.sup.2; --C(.dbd.W)NHR.sup.2;
--C(.dbd.O)NR.sup.2R.sup.3; --C(.dbd.W)--NR.sup.2R.- sup.3,
--C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid), a residue of an amino
acid or --(CH.sub.2).sub.p(amino acid); wherein if R.sup.5 is
hydrogen, F, Cl, Br, --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl or
--NHCO--C.sub.1-3alkyl, then at least one of R.sup.4', R.sup.6' and
R.sup.7' is not hydrogen;
[0132] (c) Z is optionally substituted or unsubstituted acyl,
--C(.dbd.O)NH.sub.2; --C(.dbd.W)--NH.sub.2; --C(.dbd.O)NHR.sup.2;
--C(.dbd.W)NHR.sup.2; --C(.dbd.O)NR.sup.2R.sup.3;
--C(.dbd.W)NR.sup.2R.su- p.3; --C(.dbd.W)NH(CH.sub.2).sub.p-(amino
acid); a residue of an amino acid, --(CH.sub.2).sub.p-(amino acid);
--C(.dbd.O)R.sup.3; --C(.dbd.O)H; --C(.dbd.W)H; --C(.dbd.O)R.sup.2;
--C(.dbd.W)R.sup.2; --C(.dbd.O)OR.sup.3; --C(.dbd.O)OH;
--C(.dbd.W)OH; --C(.dbd.O)OR.sup.2; --C(.dbd.W)--OR.sup.2;
--C(.dbd.O)--SH; --C(.dbd.W)SH; --C(.dbd.O)SR.sup.2;
--C(.dbd.W)SR.sup.2; optionally substituted or unsubstituted
branched or unbranched alkyl, alkenyl or alkynyl (such as an
optionally substituted or unsubstituted branched or unbranched
C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl, and in
particular CH.sub.3, CF.sub.3, vinyl bromide,
--CR.sup.2R.sup.2--S(O).sub.n--R.sup.3- ,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; --CN, or halo (F, Cl, Br or
I);
[0133] (d) Y is O, S or S(O).sub.n;
[0134] (e) each W is independently O, S, --NH.sub.2, --NHR.sup.2,
--NR.sup.2R.sup.2, --N--CN, --N--NH.sub.2, --N--NHR.sup.2,
--N--NR.sup.2R.sup.3, --N--OH or --N--OR.sup.2;
[0135] (f) each R.sup.2 is independently hydrogen or an optionally
substituted or unsubstituted branched or unbranched lower alkyl,
alkenyl or alkynyl (such as an optionally substituted or
unsubstituted branched or unbranched C.sub.1-3alkyl,
C.sub.2-4alkenyl or C.sub.2-4alkynyl, and in particular CH.sub.3,
CF.sub.3, vinyl bromide, --CR.sup.2R.sup.2--S(O).- sub.n--R.sup.3,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2HR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ;
[0136] (g) each R.sup.3 is independently hydrogen; optionally
substituted or unsubstituted branched or unbranched alkyl, alkenyl
or alkynyl (such as an optionally substituted or unsubstituted
branched or unbranched C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, and in particular CH.sub.3, CF.sub.3, vinyl
bromide, --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3- ,
--CR.sup.2R.sup.2NH.sub.2, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2NR.sup.2R.sup.3 and
--CR.sup.2R.sup.2--C(.dbd.O)R.sup.2)- ; optionally substituted or
unsubstituted aryl (such as phenyl); optionally substituted or
unsubstituted heterocycle; optionally substituted or unsubstituted
alkylaryl,. optionally substituted or unsubstituted
alkylhereterocycle, optionally substituted or unsubstituted
aralkyl, optionally substituted or unsubstituted
heterocycle-alkyl;
[0137] (h) each n is independently 0, 1 or 2; and
[0138] (i) each p is independently 0, 1, 2, 3, 4 or 5;
[0139] (j) wherein if one or more of the optionally substituted
branched or unbranched alkyl, alkenyl, alkynyl, lower alkyl, lower
alkenyl or lower alkynyl; acyl; aryl; heterocycle; alkaryl;
alkheterocycle; arylalkyl or alkylheterocycle substitutents is
substituted, then preferably it is substituted with one or more of
halogen (F, Cl, Br or I), --OH, --OR.sup.2, --SH, --SR.sup.2,
oxime, hydrazine, --C(.dbd.O)H, --C(.dbd.W)H, --C(.dbd.O)R.sup.2,
--C(.dbd.W)R.sup.2, --C(.dbd.O)OH, --C(.dbd.W)OH,
--C(.dbd.O)OR.sup.2, --C(.dbd.W)OR.sup.2, --C(.dbd.O)SH,
--C(.dbd.W)SH, --C(.dbd.O)SR.sup.2, --C(.dbd.W)SR.sup.2,
--C(.dbd.O)NH.sub.2, --C(.dbd.W)NH.sub.2, --C(.dbd.O)--NHR.sup.2,
--C(.dbd.W)NHR.sup.2, --C(.dbd.O)NR.sup.2R.sup.3,
--C(.dbd.W)--NR.sup.2R.- sup.3, --NH.sub.2, --NHR.sup.2,
--NR.sup.2R.sup.3, --NHSO.sub.2--C.sub.1-3- alkyl,
--NR.sup.2SO.sub.2--C.sub.1-3alkyl, --NHCO--C.sub.1-3alkyl,
--NR.sup.2CO--C.sub.1-3alkyl, --S(O).sub.n--R.sup.3, C.sub.1-3
alkoxy, C.sub.1-3thioether, a residue of an amino acid such as
--NH(CH.sub.2).sub.p-(amino acid) or
--C(.dbd.W)NH(CH.sub.2).sub.p-(amino acid.
[0140] In a preferred embodiment, Y is SO.sub.2. In another
preferred embodiment, Z is an amide function.
[0141] In an alternative embodiment, the hydrogen attached to the
indole nitrogen can be replaced with lower alkyl, for example,
methyl, or aryl, alkaryl or aralkyl.
[0142] In another embodiment the invention provides a phenylindole
represented generally by formula (I) above, wherein:
[0143] (a) R.sup.1 is hydrogen;
[0144] (b) R.sup.4', R.sup.5', R.sup.6' and R.sup.7' are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OR.sup.2, --NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime, hydrazine, or C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
--C(O)H, --COOH, halogen (F, Cl, Br or I), --NR.sup.2R.sup.2,
--C.sub.1-3 alkoxy or --C.sub.1-3 thioether; wherein if R.sup.5' is
hydrogen, F, Cl, Br, --NO.sub.2, --CN, --OR.sup.2,
--NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl or
--NHCO--C.sub.1-3alkyl, then at least one of R.sup.4', R.sup.6' and
R.sup.7' is not hydrogen;
[0145] (c) R.sup.2", R.sup.3", R.sup.4", R.sup.5" and R.sup.6" are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OH, --OR.sup.2, --NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, --C.sub.1-5 alkoxy, oxime, hydrazine,
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, --C(O)H, --COOH, halogen (F, Cl, Br or I),
--NR.sup.2R.sup.2, --C.sub.1-5 thioether or --C.sub.1-5 alkoxy;
[0146] (d) Z is --CN, --C(.dbd.W)NR.sup.2R.sup.3,
--C(.dbd.O)R.sup.3, --C(.dbd.O)OR.sup.3,
--CR.sup.2R.sup.2--S(O).sub.n--R.sup.3, --CR.sup.2R.sup.2NHR.sup.2,
--CR.sup.2R.sup.2--CO--R.sup.3 or substituted or unsubstituted
lower alkyl;
[0147] (e) Y is O, S, or S(O).sub.n;
[0148] (f) each W is independently O, S, --N--CN or
--N--OR.sup.2;
[0149] (g) R.sup.2 is hydrogen or C.sub.1-3 alkyl;
[0150] (h) R.sup.3 is hydrogen,. substituted or unsubstituted
alkyl, alkenyl, aryl, or heterocycle, --C.sub.1-5 alkoxy, --OH,
--NR.sup.2R.sup.2, or --(CH.sub.2).sub.pC(O)NR.sup.2R.sup.2,
[0151] (i) each n is independently 0, 1 or 2; and
[0152] (j) each p is independently 0, 1, 2, 3, 4, or 5.
[0153] In still another embodiment the invention provides a
phenylindole represented generally by formula (I) above,
wherein:
[0154] (a) R.sup.1 is hydrogen;
[0155] (b) R.sup.4', R.sup.5', R.sup.6', R.sup.7', are
independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2, --CN,
--OR.sup.2, --NR.sup.2R.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime, hydrazine, or C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or
C.sub.1-3 thioether; wherein if R.sup.5' is hydrogen, F, Cl, Br,
--NO.sub.2, --CN, --OR.sup.2, --NR.sup.2R.sup.2,
--NHSO.sub.2--C.sub.1-3alkyl or --NHCO--C.sub.1-3alkyl, then at
least one of R.sup.4', R.sup.6' and R.sup.7' is not hydrogen;
[0156] (c) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6",
are independently hydrogen, halogen (F, Cl, Br or I), --NO.sub.2,
--CN, --OR.sup.2, --NHSO.sub.2--C.sub.1-3alkyl,
--NHCO--C.sub.1-3alkyl, oxime, hydrazine, --C.sub.1-5 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-5 thioether, or
C.sub.1-5 alkoxy, --C.sub.1-5 alkoxy, --OH, or
--NR.sup.2R.sup.2,
[0157] (d) Z is --C(W)NR.sup.2R.sup.3, or --COR.sup.3,
[0158] (e) Y is --S(O).sub.n-- or --O--, in which n is 0, 1 or
2.
[0159] (f) W is O, S, --N--CN or --N--OR.sup.2;
[0160] (g) R.sup.2 is hydrogen or C.sub.1-3 alkyl,
[0161] (h) R.sup.3 is C.sub.1-5 alkyl, C.sub.1-5 alkenyl, aryl, or
heterocycle, substituted with one or more of C(O)NR.sup.2R.sup.2,
--NR.sup.2R.sup.2, --(CH.sub.2).sub.mC(O)NR.sup.2R.sup.2,
--(CH.sub.2).sub.mC(.dbd.W)--NH(CH.sub.2).sub.p-(amino acid);
[0162] (k) each n is independently 0, 1 or 2; and
[0163] (l) each p is independently 0, 1, 2, 3, 4, or 5.
[0164] In the first principal embodiment, the variables are defined
as follows:
[0165] (a) Z is (i) --C(W)NR.sup.2R.sup.3, or (ii) --COR.sup.3,
[0166] (b) R.sup.2 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH, or NR.sup.2R.sup.2,
[0167] (c) R.sup.3 is (i) --NR.sup.2R.sup.2, or (ii)
--(CH.sub.2).sub.mC(O)NR.sup.2R.sup.2, (iii) C.sub.1-5 alkyl,
C.sub.1-5 alkenyl, aryl, or heterocycle, substituted with one or
more of C(O)NR.sup.2R.sup.2, or (iv) a residue of an amino acid or
--NH(CH.sub.2).sub.p-(amino acid),
[0168] (d) W is O, S, --N--CN, or --N--OR.sup.2,
[0169] (e) m is 1, 2, 3, 4, or 5,
[0170] (f) R.sup.4', R.sup.5', R.sup.6', R.sup.7', are
independently (i) H, (ii), halo, (iii) --NO.sub.2, (iv) --CN, (v)
--OR.sup.2, (vi) --NR.sup.2R.sup.2, (vii)
--NHSO.sub.2--C.sub.1-3alkyl, (viii) --NHCO--C.sub.1-3alkyl, (ix)
oxime, (x) hydrazine, or (xi) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0171] (g) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6",
are independently (i) hydrogen, (ii) halogen, (iii) NO.sub.2, (iv)
--CN, (v) --OR.sup.2, (vi) --NHSO.sub.2--C.sub.1-3alkyl, (vii)
--NHCO--C.sub.1-3alkyl, (viii) oxime, (ix) hydrazine, (x)
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, C(O)H, COOH, halogen, NR.sup.2R.sup.2,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy, (xi) --C.sub.1-5 alkoxy,
(xii) --OH, or (ix) --NR.sup.2R.sup.2, and
[0172] (h) Y is --S(O).sub.n-- or --O--, in which n is 0, 1, or
2.
[0173] A first series of preferred subembodiments of the first
principal embodiment are defined when Z is defined as follows:
[0174] 1) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is NR.sup.2R.sup.2
[0175] 2) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is NR.sup.2R.sup.2, and R.sup.2 is C.sub.1-5 alkyl
optionally substituted with OH
[0176] 3) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is (CH.sub.2).sub.mC(O)NR.sup.2R.sup.2
[0177] 4) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is alkyl substituted by substituted or unsubstituted aryl
or heterocycle
[0178] 5) Z is C(O)R.sup.3, R.sup.3 is a residue of an amino acid
or --NH(CH.sub.2).sub.p-(amino acid)
[0179] 6) Z is --C(O)NHNHC.sub.2H.sub.5OH,
[0180] 7) Z is --C(O)NHCH.sub.2C(O)NH.sub.2
[0181] 8) Z is --C(O)NHCH.sub.2CONHNH.sub.2
[0182] 9) Z is --C(O)NHCH.sub.2CH.sub.2-(2NO.sub.2,5Me
imidazole)
[0183] 10) Z is --C(O)NHCH.sub.2NHCH(CH.sub.3)COOH
[0184] 11) Z is --C(O)CH.dbd.CHC(O)NH.sub.2
[0185] A second series of preferred subembodiments of the first
principal embodiment are defined when R.sup.4', R.sup.5', R.sup.6',
and R.sup.7' are defined as follows:
[0186] 1) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0187] 2) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0188] 3) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0189] 4) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0190] 5) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0191] 6) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0192] 7) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0193] 8) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0194] 9) R.sup.4' and R.sup.7' are hydrogen, and R.sub.5' and
R.sup.6' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0195] 10) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0196] 11) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are Cl, F, CF.sub.3, or vinyl bromide
[0197] 12) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are Cl, F, CF.sub.3, or vinyl bromide
[0198] 13) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are Cl, F, CF.sub.3, or vinyl bromide
[0199] 14) R.sup.4', R.sup.6' and R.sup.7' are hydrogen, and
R.sup.5' is (i) oxime, (ii) hydrazine, or (iii) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or
C.sub.1-3 thioether
[0200] 15) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is Cl
[0201] 16) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are Cl
[0202] 17) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are Cl
[0203] 18) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are F
[0204] 19) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are F
[0205] 20) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are F
[0206] 21) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' is Cl,
and R.sup.6' is F
[0207] 22) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' is Cl,
and R.sup.6' is CF.sub.3
[0208] 23) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is CF.sub.3
[0209] 24) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is vinyl bromide
[0210] A third series of preferred subembodiments of the first
principal embodiment are defined when R.sup.2", R.sup.3", R.sup.4",
R.sup.5", and R.sup.6", are defined as follows:
[0211] 1) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --NHSO.sub.2--C.sub.1-3alkyl, (vi)
--NHCO--C.sub.1-3allyl, (vii) oxime, (vii) hydrazine, (viii)
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, C(O)H, COOH, halogen, NR.sup.2R.sup.2,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy, (ix) --C.sub.1-5 alkoxy,
(x) --OH, or (xi) --NR.sup.2R.sup.2
[0212] 2) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --C.sub.1-5 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, COOH,
halogen, NR.sup.2R.sup.2, C.sub.1-5 thioether, or C.sub.1-5 alkoxy,
(vi) --C.sub.1-5 alkoxy, (vii) --OH, or (viii)
--NR.sup.2R.sup.2
[0213] 3) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --C.sub.1-3 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, COOH,
halogen, or NH.sub.2, (vi) --C.sub.1-3 alkoxy, (vii) --OH, or
(viii) --NR.sup.2R.sup.2
[0214] 4) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, or (ii)
--C.sub.1-3 alkyl or alkenyl optionally substituted with one or
more halogen
[0215] 5) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6", are
H
[0216] 6) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are methyl
[0217] 7) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are Cl
[0218] 8) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are F
[0219] 9) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are CF.sub.3
[0220] A fourth series of preferred subembodiments are defined when
Z is as defined in any one of the first series of preferred
subembodiments of the first principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in any one of the
second series of preferred subembodiments of the first principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in the first principal embodiment.
[0221] A fifth series of preferred subembodiments are defined when
Z is as defined in any one of the first series of preferred
subembodiments of the first principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in the first
principal embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5",
and R.sup.6", are as defined in any one of the third series of
preferred subembodiment of the first principal embodiment.
[0222] A sixth series of preferred subembodiments are defined when
Z is as defined in the first principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in any one of the
second series of preferred subembodiments of the first principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in any one of the third series of
preferred subembodiments of the first principal embodiment.
[0223] A seventh series of preferred subembodiments are defined
when Z is as defined in any one of the first series of preferred
subembodiments of the first principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defmed in any one of the
second series of preferred subembodiments of the first principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in any one of the third series of
preferred subembodiments of the first principal embodiment.
[0224] In each of the subembodiments within the first, second,
third, fourth, fifth, sixth, and seventh preferred series of
subembodiments of the first principal embodiment, Y is preferably
SO.sub.2.
[0225] Preferred species of the first principal embodiment are
defined when:
[0226] 1) Z is --C(O)NHNHC.sub.2H.sub.5OH, R.sup.4', R.sup.6', and
R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2;
[0227] 2) Z is --C(O)NHCH.sub.2C(O)NH.sub.2, R.sup.4', R.sup.6',
and R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2;
[0228] 3) Z is --C(O)NHCH.sub.2CONHNH.sub.2, R.sup.4', R.sup.6',
and R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2;
[0229] 4) Z is --C(O)NHCH.sub.2CH.sub.2-(2NO.sub.2,5Me imidazole),
R.sup.4', R.sup.6', and R.sup.7' are hydrogen, R.sup.5' is Cl,
R.sup.2", R.sup.4", and R.sup.6", are H, R.sup.3" and R.sup.5" are
methyl, and Y is SO.sub.2;
[0230] 5) Z is --C(O)NHCH.sub.2NHCH(CH.sub.3)COOH, R.sup.4',
R.sup.6', and R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2",
R.sup.4", and R.sup.6", are H, R.sup.3" and R.sup.5" are methyl,
and Y is SO.sub.2; and
[0231] 6) Z is --C(O)CH.dbd.CHC(O)NH.sub.2, R.sup.4', R.sup.6', and
R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0232] In a second principal the compound of formula (I) is defined
as follows:
[0233] (a) either (a1) R.sup.4', R.sup.5', R.sup.6', R.sup.7', are
independently (i) H, (ii), halo, (iii) --NO.sub.2, (iv) --CN, (v)
--OR.sup.2, (vi) --NR.sup.2R.sup.2, (vii)
--NHSO.sub.2--C.sub.1-3alkyl, (viii) --NHCO--C.sub.1-3alkyl, (ix)
oxime, (x) hydrazine, or (xi) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether, wherein
at least 2 of R.sup.4', R.sup.5', R.sup.6', and R.sup.7', are not
hydrogen, or (a2) R.sup.4', R.sup.5', R.sup.6, R.sup.7, are
independently (i) H, (ii), halo, (iii) --NO.sub.2, (iv) --CN, (v)
--OR.sup.2, (vi) --NR.sup.2R.sup.2, (vii)
--NHSO.sub.2--C.sub.1-3alkyl, (viii) --NHCO--C.sub.1-3alkyl, (ix)
oxime, (x) hydrazine, or (xi) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether, wherein
at least one of R.sup.4', R.sup.5', R.sup.6', and R.sup.7', is not
hydrogen, halogen, --NHSO.sub.2--C.sub.1-3alkyl, or OR.sup.2,
[0234] (b) Z is (i) C(W)NR.sup.2R.sup.3, (ii) --COR.sup.3, (iii)
--COOR.sup.3, (iv) --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3, (v)
--CR.sup.2R.sup.2NHR.sup.2, (vi) --CR.sup.2R.sup.2--CO--R.sup.3,
(vii) substituted or unsubstituted lower alkyl, or (viii) --CN;
[0235] (c) R.sup.2 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH, or NR.sup.2R.sup.2,
[0236] (d) R.sup.3 is (i) substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, (ii) --C.sub.1-5 alkoxy, (iii) --OH,
(iv) hydrogen, (v) --NR.sup.2R.sup.2, (vi)
--(CH.sub.2).sub.mC(O)--NR.sup.2R.sup.2, or (vii) a residue of an
amino acid or --NH(CH.sub.2).sub.p-(amino acid);
[0237] (e) W is O, S, --N--CN, or --N--OR.sup.2;
[0238] (f) m is 1, 2, 3, 4, or 5;
[0239] (g) p is 0, 1, 2, 3, 4, or 5, and
[0240] (h) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6",
are independently (i) hydrogen, (ii) halogen, (iii) NO.sub.2, (iv)
--CN, (v) --OR.sup.2, (vi) --NHSO.sub.2--C.sub.1-3alkyl, (vii)
--NHCO--C.sub.1-3alkyl, (viii) oxime, (ix) hydrazine, (x)
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, C(O)H, COOH, halogen, NR.sup.2R.sup.2,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy, (xi) --C.sub.1-5 alkoxy,
(xii) --OH, or (ix) --NR.sup.2R.sup.2.
[0241] In a first series of preferred subembodiments of the second
principal embodiment, Z is defined as follows:
[0242] 1) Z is C(W)NR.sup.2R.sup.3
[0243] 2) Z is C(O)NR.sup.2R.sup.3
[0244] 3) Z is C(O)NR.sup.2R.sup.3, and R.sup.2 is hydrogen
[0245] 4) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is NR.sup.2R.sup.2
[0246] 5) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is NR.sup.2R.sup.2, and R.sup.2 is C.sub.1-5 alkyl
optionally substituted with OH
[0247] 6) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is (CH.sub.2).sub.mC(O)NR.sup.2R.sup.2
[0248] 7) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is substituted or unsubstituted alkyl
[0249] 8) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is alkyl substituted by substituted or unsubstituted aryl
or heterocycle
[0250] 9) Z is C(O)R.sup.3, R.sup.3 is a residue of an amino acid
or --NH(CH.sub.2).sub.p-(amino acid)
[0251] 10) Z is --C(O)NH.sub.2.
[0252] 11) Z is --C(O)NHNHC.sub.2H.sub.5OH
[0253] 12) Z is --C(O)NHCH.sub.2C(O)NH.sub.2
[0254] 13) Z is --C(O)NHCH.sub.2CONHNH.sub.2
[0255] 14) Z is --C(O)NHCH.sub.2CH.sub.2-(2NO.sub.2,5Me
imidazole)
[0256] 15) Z is --C(O)NHCH.sub.2NHCH(CH.sub.3)COOH
[0257] 16) Z is --C(O)CH.dbd.CHC(O)NH.sub.2
[0258] A second series of preferred subembodiments of the second
principal embodiment is defined when R.sup.4', R.sup.5', R.sup.6',
R.sup.7', are defined as follows:
[0259] 1) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0260] 2) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0261] 3) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0262] 4) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0263] 5) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0264] 6) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0265] 7) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0266] 8) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0267] 9) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0268] 10) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are Cl, F, CF.sub.3, or vinyl bromide,
[0269] 11) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are Cl, F, CF.sub.3, or vinyl bromide,
[0270] 12) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are Cl, F, CF.sub.3, or vinyl bromide,
[0271] 13) R.sup.4', R.sup.6' and R.sup.7' are hydrogen, and
R.sup.5' is (i) oxime, (ii) hydrazine, or (iii) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or
C.sub.1-3 thioether,
[0272] 14) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are Cl,
[0273] 15) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are Cl,
[0274] 16) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are F,
[0275] 17) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are F,
[0276] 18) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are F,
[0277] 19) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' is Cl,
and R.sup.6' is F,
[0278] 20) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' is Cl,
and R.sup.6' is CF.sub.3,
[0279] 21) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is CF.sub.3,
[0280] 22) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is vinyl bromide.
[0281] A third series of preferred subembodiments of the second
principal embodiment are defined when R.sup.2", R.sup.3", R.sup.4",
R.sup.5", and R.sup.6", are defined as follows:
[0282] 1) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --NHSO.sub.2--C.sub.1-3alkyl, (vi)
--NHCO--C.sub.1-3alkyl, (vii) oxime, (vii) hydrazine, (viii)
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, C(O)H, COOH, halogen, NR.sup.2R.sup.2,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy, (ix) --C.sub.1-5 alkoxy,
(x) --OH, or (xi) --NR.sup.2R.sup.2
[0283] 2) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --C.sub.1-5 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, COOH,
halogen, NR.sup.2R.sup.2, C.sub.1-5 thioether, or C.sub.1-5 alkoxy,
(vi) --C.sub.1-5 alkoxy, (vii) --OH, or (viii)
--NR.sup.2R.sup.2
[0284] 3) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --C.sub.1-3 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, COOH,
halogen, or NH.sub.2, (vi) --C.sub.1-3 alkoxy, (vii) --OH, or
(viii) --NR.sup.2R.sup.2
[0285] 4) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, or (ii)
--C.sub.1-3 alkyl or alkenyl optionally substituted with one or
more halogen
[0286] 5) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6", are
H
[0287] 6) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are methyl
[0288] 7) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are Cl
[0289] 8) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are F
[0290] 9) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are CF.sub.3
[0291] A fourth series of preferred subembodiments of the second
principal embodiment are defined when Z is as defined in any one of
the first series of preferred subembodiments of the second
principal embodiment, R.sup.4', R.sup.5', R.sup.6', and R.sup.7'
are as defined in any one of the second series of preferred
subembodiments of the second principal embodiment, and R.sup.2",
R.sup.3", R.sup.4", R.sup.5", and R.sup.6", are as defined in the
second principal embodiment.
[0292] A fifth series of preferred subembodiments are defined when
Z is as defined in any one of the first series of preferred
subembodiments of the second principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in the second
principal embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5",
and R.sup.6", are as defined in any one of the third series of
preferred subembodiment of the second principal embodiment.
[0293] A sixth series of preferred subembodiments are defined when
Z is as defined in the second principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7" are as defined in any one of the
second series of preferred subembodiments of the second principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in any one of the third series of
preferred subembodiments of the second principal embodiment.
[0294] A seventh series of preferred subembodiments. are defined
when Z is as defined in any one of the first series of preferred
subembodiments of the second principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in any one of the
second series of preferred subembodiments of the second principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in any one of the third series of
preferred subembodiments of the second principal embodiment.
[0295] In each of the subembodiments within the first, second,
third, fourth, fifth, sixth, and seventh preferred series of
subembodiments of the second principal embodiment, Y is preferably
SO.sub.2.
[0296] Preferred species of the second principal embodiment are
defined when:
[0297] 1) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' and R.sup.6' are Cl, R.sup.2", R.sup.3", R.sup.4",
R.sup.5", and R.sup.6" are H, and Y is SO.sub.2.
[0298] 2) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' and R.sup.6' are Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0299] 3) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.6' are hydrogen,
R.sup.5' and R.sup.7' are Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0300] 4) Z is --C(O)NH.sub.2, R.sup.6' and R.sup.7' are hydrogen,
R.sup.4' and R.sup.5' are F, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0301] 5) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' and R.sup.6' are F, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0302] 6) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.6' are hydrogen,
R.sup.5' and R.sup.7' are F, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0303] 7) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' is Cl, and R.sup.6' is F, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0304] 8) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' is Cl, and R.sup.6' is CF.sub.3, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0305] 9) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7' are
hydrogen, R.sup.5' is CF.sub.3, R.sup.2", R.sup.4", and R.sup.6",
are H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0306] 10) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7'
are hydrogen, R.sup.5' is vinyl bromide, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0307] A third principal embodiment of the invention compound (I)
is defined as follows:
[0308] (a) Z is (i) C(W)NR.sup.2R.sup.3, (ii) --COR.sup.3, (iii)
--COOR.sup.3, (iv) --CR.sup.2R.sup.2--S(O).sub.n--R.sup.3, (v)
--CR.sup.2R.sup.2NHR.sup.2, (vi) --CR.sup.2R.sup.2--CO--R.sup.3,
(vii) substituted or unsubstituted lower alkyl, or (viii) --CN;
[0309] (i) R.sup.2 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH, or NR.sup.2R.sup.2,
[0310] (b) R.sup.3 is (i) substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, (ii) --C.sub.1-5 alkoxy, (iii) --OH,
(iv) hydrogen, (v) --NR.sup.2R.sup.2, (vi)
--(CH.sub.2).sub.mC(O)NR.sup.2R.sup.2, or (vii) a residue of an
amino acid or --NH(CH.sub.2).sub.p-(amino acid);
[0311] (c) W is O, S, --N--CN, or --N--OR.sup.2;
[0312] (d) m is 1, 2, 3, 4, or 5;
[0313] (e) p is 0, 1, 2, 3, 4, or 5;
[0314] (f) R.sup.4', R.sup.5', R.sup.6', R.sup.7', are
independently (i) H, (ii), halo, (iii) --NO.sub.2, (iv) --CN, (v)
--OR.sup.2, (vi) --NR.sup.2R.sup.2, (vii)
--NHSO.sub.2--C.sub.1-3alkyl, (viii) --NHCO--C.sub.1-3alkyl, (ix)
oxime, (x) hydrazine, or (xi) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether; and
[0315] (g) R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6",
are independently (i) hydrogen, (ii) halogen, (iii) NO.sub.2, (iv)
--CN, (v) --OR.sup.2, (vi) --NHSO.sub.2--C.sub.1-3alkyl, (vii)
--NHCO--C.sub.1-3alkyl, (viii) oxime, (ix) hydrazine, (x)
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, C(O)H, COOH, halogen, NR.sup.2R.sup.2,
C.sub.1-5 thioeiher, or C.sub.1-5 alkoxy, (xi) --C.sub.1-5 alkoxy,
(xii) --OH, or (ix) --NR.sup.2R.sup.2, wherein (i) at least 2 of
R.sup.2", R.sup.3", R.sup.4", R.sup.5", and R.sup.6" are not
hydrogen, or (ii) at least 1 of R.sup.2", R.sup.3", R.sup.4",
R.sup.5", and R.sup.6" is not hydrogen, halogen, or OR.sup.2.
[0316] A first series of preferred subembodiments of the third
principal embodiment are defined when Z is as follows:
[0317] 1) Z is C(W)NR.sup.2R.sup.3
[0318] 2) Z is C(O)NR.sup.2R.sup.3
[0319] 3) Z is C(O)NR.sup.2R.sup.3, and R.sup.2 is hydrogen
[0320] 4) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is NR.sup.2R.sup.2
[0321] 5) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is NR.sup.2R.sup.2, and R.sup.2 is C.sub.1-5 alkyl
optionally substituted with OH
[0322] 6) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is (CH.sub.2).sub.mC(O)NR.sup.2R.sup.2
[0323] 7) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is substituted or unsubstituted alkyl
[0324] 8) Z is C(O)NR.sup.2R.sup.3, R.sup.2 is hydrogen, and
R.sup.3 is alkyl substituted by substituted or unsubstituted aryl
or heterocycle
[0325] 9) Z is C(O)R.sup.3, R.sup.3 is a residue of an amino acid
or --NH(CH.sub.2).sub.p-(aminoacid)
[0326] 10) Z is --C(O)NH.sub.2.
[0327] 11) Z is --C(O)NHNHC.sub.2H.sub.5OH
[0328] 12) Z is --C(O)NHCH.sub.2C(O)NH.sub.2
[0329] 13) Z is --C(O)NHCH.sub.2CONHNH.sub.2
[0330] 14) Z is --C(O)NHCH.sub.2CH.sub.2-(2NO.sub.2,5Me
imidazole)
[0331] 15) Z is --C(O)NHCH.sub.2NHCH(CH.sub.3)COOH
[0332] 16) Z is --C(O)CH.dbd.CHC(O)NH.sub.2
[0333] A second series of preferred embodiments of the second
principal embodiment is defined when R.sup.4', R.sup.5', R.sup.6',
and R.sup.7' are defined as follows:
[0334] 1) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0335] 2) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0336] 3) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2; (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0337] 4) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-3alkyl, (viii)
oxime, (ix) hydrazine, or (x) C.sub.1-3 alkyl or alkenyl optionally
substituted with one or more of --OH, --SH, C(O)H, COOH, halogen,
NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or C.sub.1-3 thioether,
[0338] 5) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0339] 6) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (ivOR.sup.2,
(v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, C(O)H, COOH,
halogen, or NH.sub.2,
[0340] 7) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are (i), halo, (ii) --NO.sub.2, (iii) --CN, (iv)
--OR.sup.2, (v) --NR.sup.2R.sup.2, or (vi) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, or NH.sub.2,
[0341] 8) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0342] 9) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0343] 10) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are halo or C.sub.1-3 alkyl or alkenyl substituted with
one or more halo,
[0344] 11) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are Cl, F, CF.sub.3, or vinyl bromide
[0345] 12) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are Cl, F, CF.sub.3, or vinyl bromide
[0346] 13) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are Cl, F, CF.sub.3, or vinyl bromide
[0347] 14) R.sup.4', R.sup.6' and R.sup.7' are hydrogen, and
R.sup.5' is (i) oxime, (ii) hydrazine, or (iii) C.sub.1-3 alkyl or
alkenyl optionally substituted with one or more of --OH, --SH,
C(O)H, COOH, halogen, NR.sup.2R.sup.2, C.sub.1-3 alkoxy, or
C.sub.1-3 thioether
[0348] 15) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is Cl
[0349] 16) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are Cl
[0350] 17) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are Cl
[0351] 18) R.sup.6' and R.sup.7' are hydrogen, and R.sup.4' and
R.sup.5' are F
[0352] 19) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' and
R.sup.6' are F
[0353] 20) R.sup.4' and R.sup.6' are hydrogen, and R.sup.5' and
R.sup.7' are F
[0354] 21) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' is Cl,
and R.sup.6' is F
[0355] 22) R.sup.4' and R.sup.7' are hydrogen, and R.sup.5' is Cl,
and R.sup.6' is CF.sub.3
[0356] 23) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is CF.sub.3
[0357] 24) R.sup.4', R.sup.6', and R.sup.7' are hydrogen, and
R.sup.5' is vinyl bromide
[0358] A third series of preferred subembodiments of the third
principal embodiment is defined when R.sup.2", R.sup.3", R.sup.4",
R.sup.5", and R.sup.6" are defined as follows:
[0359] 1) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --NHSO.sub.2--C.sub.1-3alkyl, (vi)
--NHCO--C.sub.1-3alkyl, (vii) oxime, (vii) hydrazine, (viii)
--C.sub.1-5 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, C(O)H, COOH, halogen, NR.sup.2R.sup.2,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy, (ix) --C.sub.1-5 alkoxy,
(x) --OH, or (xi) --NR.sup.2R.sup.2
[0360] 2) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --C.sub.1-5 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, COOH,
halogen, NR.sup.2R.sup.2, C.sub.1-5 thioether, or C.sub.1-5 alkoxy,
(vi) --C.sub.1-5 alkoxy, (vii) --OH, or (viii)
--NR.sup.2R.sup.2
[0361] 3) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, (ii) NO.sub.2,
(iii) --CN, (iv) --OR.sup.2, (v) --C.sub.1-3 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, COOH,
halogen, or NH.sub.2, (vi) --C.sub.1-3 alkoxy, (vii) --OH, or
(viii) --NR.sup.2R.sup.2
[0362] 4) R.sup.2", R.sup.4", and R.sup.6", are hydrogen, and
R.sup.3" and R.sup.5" are independently (i) halogen, or (ii)
--C.sub.1-3 alkyl or alkenyl optionally substituted with one or
more halogen
[0363] 5) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are methyl
[0364] 6) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are Cl
[0365] 7) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are F
[0366] 8) R.sup.2", R.sup.4", and R.sup.6", are H, and R.sup.3" and
R.sup.5" are CF.sub.3
[0367] A fourth series of preferred subembodiments of the third
principal embodiment are defined when Z is as defined in any one of
the first series of preferred subembodiments of the third principal
embodiment, R.sup.4', R.sup.5', R.sup.6', and R.sup.7' are as
defined in any one of the second series of preferred subembodiments
of the third principal embodiment, and R.sup.2", R.sup.3",
R.sup.4", R.sup.5", and R.sup.6", are as defined in the third
principal embodiment.
[0368] A fifth series of preferred subembodiments are defined when
Z is as defined in any one of the first series of preferred
subembodiments of the third principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in the third
principal embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5",
and R.sup.6", are as defined in any one of the third series of
preferred subembodiment of the third principal embodiment.
[0369] A sixth series of preferred subembodiments are defined when
Z is as defined in the third principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in any one of the
second series of preferred subembodiments of the third principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in any one of the third series of
preferred subembodiments of the third principal embodiment.
[0370] A seventh series of preferred subembodiments are defined
when Z is as defined in any one of the first series of preferred
subembodiments of the third principal embodiment, R.sup.4',
R.sup.5', R.sup.6', and R.sup.7' are as defined in any one of the
second series of preferred subembodiments of the third principal
embodiment, and R.sup.2", R.sup.3", R.sup.4", R.sup.5", and
R.sup.6", are as defined in any one of the third series of
preferred subembodiments of the third principal embodiment.
[0371] In each of the subembodiments within the first, second,
third, fourth, fifth, sixth, and seventh preferred series of
subembodiments of the third principal embodiment, Y is preferably
SO.sub.2.
[0372] Preferred species of the third principal embodiment are
defined as follows:
[0373] 1) Z is --C(O)NHNHC.sub.2H.sub.5OH, R.sup.4', R.sup.6', and
R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2;
[0374] 2) Z is --C(O)NHCH.sub.2C(O)NH.sub.2, R.sup.4', R.sup.6',
and R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2;
[0375] 3) Z is --C(O)NHCH.sub.2CONHNH.sub.2, R.sup.4', R.sup.6',
and R.sup.7' are hydrogen, R.sup.5" is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2;
[0376] 4) Z is --C(O)NHCH.sub.2CH.sub.2-(2NO.sub.2,5Me imidazole),
R.sup.4', R.sup.6', and R.sup.7' are hydrogen, R.sup.5' is Cl,
R.sup.2", R.sup.4", and R.sup.6", are H, R.sup.3" and R.sup.5" are
methyl, and Y is SO.sub.2;
[0377] 5) Z is --C(O)NHCH.sub.2NHCH(CH.sub.3)COOH, R.sup.4',
R.sup.6', and R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2",
R.sup.4", and R.sup.6", are H, R.sup.3" and R.sup.5" are methyl,
and Y is SO.sub.2; and
[0378] 6) Z is --C(O)CH.dbd.CHC(O)NH.sub.2, R.sup.4', R.sup.6', and
R.sup.7' are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0379] 7) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' and R.sup.6' are Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0380] 8) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.6' are hydrogen,
R.sup.5' and R.sup.7' are Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0381] 9) Z is --C(O)NH.sub.2, R.sup.6' and R.sup.7' are hydrogen,
R.sup.4' and R.sup.5' are F, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0382] 10) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' and R.sup.6' are F, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0383] 11) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.6' are hydrogen,
R.sup.5' and R.sup.7' are F, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are methyl, and Y is SO.sub.2.
[0384] 12) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' is Cl, and R.sup.6' is F, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0385] 13) Z is --C(O)NH.sub.2, R.sup.4' and R.sup.7' are hydrogen,
R.sup.5' is Cl, and R.sup.6' is CF.sub.3, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0386] 14) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7'
are hydrogen, R.sup.5' is CF.sub.3, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0387] 15) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7'
are hydrogen, R.sup.5' is vinyl bromide, R.sup.2", R.sup.4", and
R.sup.6", are H, R.sup.3" and R.sup.5" are methyl, and Y is
SO.sub.2.
[0388] 16) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7'
are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are CF.sub.3, and Y is SO.sub.2.
[0389] 17) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7'
are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are F, and Y is SO.sub.2.
[0390] 18) Z is --C(O)NH.sub.2, R.sup.4', R.sup.6', and R.sup.7'
are hydrogen, R.sup.5' is Cl, R.sup.2", R.sup.4", and R.sup.6", are
H, R.sup.3" and R.sup.5" are Cl, and Y is SO.sub.2.
[0391] In a particular embodiment, the phenylindole is a compound
of the structure: 13
[0392] or a pharmaceutically acceptable salt or prodrug
thereof.
[0393] In another particular embodiment, the phenylindole is a
compound of the structure: 14
[0394] or a pharmaceutically acceptable salt or prodrug
thereof.
[0395] In yet another particular embodiment, the phenylindole is a
compound of the structure: 15
[0396] or a pharmaceutically acceptable salt or prodrug
thereof.
[0397] In yet another particular embodiment, the phenylindole is a
compound of the structure: 16
[0398] or a pharmaceutically acceptable salt or prodrug
thereof.
[0399] In another particular embodiment, the phenylindole is a
compound of the structure: 17
[0400] or a pharmaceutically acceptable salt or prodrug
thereof.
[0401] In yet another particular embodiment of the present
invention, the phenylindole is a compound of the structure: 18
[0402] or a pharmaceutically acceptable salt or prodrug
thereof.
[0403] In yet another particular embodiment of the present
invention, the phenylindole is a compound of the structure: 19
[0404] or a pharmaceutically acceptable salt or prodrug
thereof.
[0405] In yet another particular embodiment of the present
invention, the phenylindole is a compound of the structure: 20
[0406] or a pharmaceutically acceptable salt or prodrug
thereof.
[0407] The phenylindoles of this invention belong to a class of
anti-HIV agents that inhibit HIV reverse transcriptase activity.
Compounds can be screened for their ability to inhibit HIV reverse
transcriptase activity in vitro according to screening methods set
forth more particularly herein. One can readily determine the
spectrum of activity by evaluating the compound in the assays
described herein or with another confirmatory assay.
[0408] In one embodiment the efficacy of the anti-HIV compound is
measured according to the concentration of compound necessary to
reduce the plaque number of the-virus in vitro, according to
methods set forth more particularly herein, by 50% (i.e. the
compound's EC.sub.50). In preferred embodiments the compound
exhibits an EC.sub.50 of less than 15 or 10 micromolar.
[0409] The active compound can be administered as any salt or
prodrug that upon administration to the recipient is capable of
providing directly or indirectly the parent compound, or that
exhibits activity itself. Nonlimiting examples are the
pharmaceutically acceptable salts (alternatively referred to as
"physiologically acceptable salts"). Further, the modifications can
affect the biological activity of the compound, in some cases
increasing the activity over the parent compound. This can easily
be assessed by preparing the salt or prodrug and testing its
antiviral activity according to the methods described herein, or
other methods known to those skilled in the art.
[0410] II. Pharmaceutically Acceptable Salts and Prodrugs
[0411] The term "pharmaceutically acceptable salt or prodrug" is
used throughout the specification to describe any pharmaceutically
acceptable form (such as an ester, amide, salt of an ester, salt of
an amide or a related group) of a compound that, upon
administration to a patient, provides the active compound. As used
herein, the term pharmaceutically acceptable salts refers to salts
that retain the desired biological activity of the
herein-identified compounds and exhibit minimal undesired
toxicological effects. Pharmaceutically acceptable salts include
those derived from pharmaceutically acceptable inorganic or organic
acids and bases. Non-limiting examples of suitable salts include
those derived from inorganic acids such as, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid,
bicarbonic acid, carbonic acid and the like, and salts formed with
organic acids such as amino acid, acetic acid, oxalic acid,
tartaric acid, succinic acid, malic acid, malonic acid, ascorbic
acid, citric acid, benzoic acid, tannic acid, palmoic acid, alginic
acid, polyglutamic acid, tosic acid, methanesulfonic acid,
naphthalenesulfonic acid, naphthalenedisulfonic acid,
.alpha.-ketoglutaric acid, .alpha.-glycerophosphoric acid and
polygalacturonic acid. Suitable salts include those derived from
alkali metals such as lithium, potassium and sodium, alkaline earth
metals such as calcium and magnesium, among numerous other acids
well known in the pharmaceutical art. Other suitable salts include
those derived from other metal cations such as zinc, bismuth,
barium, aluminum, copper, cobalt, nickel, cadmium, and the like, or
with a cation formed from an amine, such as ammonia,
N,N-dibenzylethylene-diamine, D-glucosamine, tetraethylammonium, or
ethylenediamine. Further, suitable salts include those derived from
a combinations of acids and bases, for example, a zinc tannate salt
or the like.
[0412] Pharmaceutically acceptable prodrugs refer to a compound
that is metabolized, for example hydrolyzed or oxidized, in the
host to form the compound of the present invention. Typical
examples of prodrugs include compounds that have biologically
labile protecting groups on a functional moiety of the active
compound. Prodrugs include compounds that can be oxidized, reduced,
aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed,
dehydrolyzed, alkylated, dealkylated, acylated, deacylated,
phosphorylated, dephosphorylated to produce the active compound.
The compounds of this invention either possess antiviral activity
against HIV, or are metabolized to a compound that exhibits such
activity.
[0413] Any of the phenylindoles described herein can be
administered as a prodrug to increase the activity,
bioavailability, stability or otherwise alter the properties of the
phenylindole. A number of prodrug ligands are known. In general,
alkylation, acylation or other lipophilic modification of a
heteroatom of the phenylindole will increase the stability of the
compound. Examples of substituent groups that can replace one or
more hydrogens on a heterocycle include, but are not limited to
alkyl, aryl, steroids, carbohydrates, including sugars,
1,2-diacylglycerol, phospholipids, phosphotidylcholine,
phosphocholine and alcohols. Any of these can be used in
combination with the disclosed phenylindoles to achieve a desired
effect.
[0414] III. Definitions
[0415] The following definitions and term construction are
intended, unless otherwise indicated.
[0416] Specific and preferred values listed below for radicals,
substituents and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0417] Halo is fluoro, chloro, bromo, or iodo.
[0418] Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight
and branched groups; but reference to an individual radical such as
"propyl" embraces only the straight chain radical, a branched chain
isomer such as "isopropyl" being specifically referred to.
[0419] The term alkyl, as used herein, unless otherwise specified,
refers to a saturated straight, branched, or cyclic, primary,
secondary, or tertiary hydrocarbon of C.sub.1 to C.sub.10, and
specifically includes methyl, ethyl, propyl, isopropyl,
cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl,
isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,
cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl. When the context of this document allows alkyl
to be substituted, the moieties with which the alkyl group can be
substituted are selected from the group consisting of hydroxyl,
amino, alkylamino, arylamino, alkoxy, aryloxy, aryl, heterocycle,
halo, carboxy, acyl, acyloxy, amido, nitro, cyano, sulfonic acid,
sulfate, phosphonic acid, phosphate, or phosphonate, either
unprotected, or protected as necessary, as known to those skilled
in the art, for example, as taught in Greene, et al., Protective
Groups in Organic Synthesis, John Wiley and Sons, Second Edition,
1991, hereby incorporated by reference.
[0420] The term lower alkyl, as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.4 saturated straight,
branched, or if appropriate, a cyclic (for example, cyclopropyl)
alkyl group, including both substituted and unsubstituted forms.
Unless otherwise specifically stated in this application, when
alkyl is a suitable moiety, lower alkyl is preferred. Similarly,
when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl
or lower alkyl is preferred.
[0421] The terms alkenyl and alkynyl refer to alkyl moieties,
including both substituted and substituted forms, wherein at least
one saturated C-C bond is replaced by a double or triple bond.
Thus, (C.sub.2-C.sub.6)alkenyl can be vinyl, allyl, 1-propenyl,
2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, or 5-hexenyl. Similarly,
(C.sub.2-C.sub.6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
or 5-hexynyl.
[0422] The term "alkylene" refers to a saturated, straight chain,
divalent alkyl radical of the formula --(CH.sub.2).sub.n--, wherein
n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[0423] As used herein, with exceptions as noted, "aryl" is intended
to mean any stable monocyclic, bicyclic or tricyclic carbon ring of
up to 8 members in each-ring, wherein at least one ring is aromatic
as defined by the Huckel 4n+2 rule. Examples of aryl ring systems
include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl. The
aryl group can be substituted with one or more moieties selected
from the group consisting of hydroxyl, amino, alkylamino,
arylamino, alkoxy, aryloxy, alkyl, heterocycle, halo, carboxy,
acyl, acyloxy, amido, nitro, cyano, sulfonic acid, sulfate,
phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as necessary, as known to those skilled in the art, for
example, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John Wiley and Sons, Second Edition, 1991.
[0424] The term heterocycle or heterocyclic, as used herein except
where noted represents a stable 5- to 7-membered monocyclic or
stable 8- to 11-membered bicyclic heterocyclic ring which is either
saturated or unsaturated, including heteroaryl, and which consists
of carbon atoms and from one to three heteroatoms selected from the
group consisting of N, O, S, and P; and wherein the nitrogen and
sulfur heteroatoms may optionally be oxidized, and the nitrogen
heteroatom may optionally be quatemized, and including any bicyclic
group in which any of the above-defined heterocyclic rings is fused
to a benzene ring. The heterocyclic ring may be attached at any
heteroatom or carbon atom which results in the creation of a stable
structure.
[0425] Nonlimiting examples of heteroaryl and heterocyclic groups
include fliryl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl,
imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofliryl, pyrazolyl,
indolyi, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl,
thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl,
quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,
thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole,
1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole,
isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines,
thiazole, isothiazole, 1,2,3-oxadiazole, thiazine,. pyridine,
pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine,
phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl,
quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,
5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,
pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alkylpurines,
N6-benzylpurine, N6-halopurine, N6-vinypurine, N6-acetylenic
purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl
purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidine,
uracil, N5-alkyl-pyrimidines, N5-benzylpyrimidines,
N5-halopyrimidines, N5-vinyl-pyrimidine, N5-acetylenic pyrimidine,
N5-acyl pyrimidine, N5-hydroxyalkyl purine, and N6-thioalkyl
purine, and isoxazolyl. The heteroaromatic and heterocyclic
moieties can be optionally substituted as described above for aryl,
including substituted with one or more substituents selected from
hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, alkyl,
heterocycle, halo, carboxy, acyl, acyloxy, amido, nitro, cyano,
sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
either unprotected, or protected as necessary, as known to those
skilled in the art, for example, as taught in Greene, el al,
Protective Groups in Organic Synthesis, John Wiley and Sons, Second
Edition, 1991.
[0426] The heteroaromatic can be partially or totally hydrogenated
as desired. As a nonlimiting example, dihydropyridine can be used
in place of pyridine. Functional oxygen and nitrogen groups on the
heteroaryl group can be protected as necessary or desired. Suitable
protecting groups are well known to those skilled in the art, and
include trimethylsilyl, dimethylhexylsilyl, t-butyldi-methylsilyl,
and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl
groups, acyl groups such as acetyl and propionyl, methanesulfonyl,
and p-toluenesulfonyl.
[0427] The term acyl refers to a compound of formula RC(O)--,
wherein R is substituted or unsubstituted alkyl or aryl, as defined
herein. The term carboxyl refers to a compound of the formula
--C(O)OR, wherein R is substituted or unsubstituted alkyl or aryl,
as defined herein.
[0428] The term aralkyl, as used herein, and unless otherwise
specified, refers to an aryl group as defined above linked to the
molecule through an alkyl group as defined above. The term alkaryl,
as used herein, and unless otherwise specified, refers to an alkyl
group as defined above linked to the molecule through an aryl group
as defined above.
[0429] The term alkoxy, as used herein, and unless otherwise
specified, refers to a moiety of the structure --O-alkyl, wherein
alkyl is as defined above.
[0430] The term amino, as used herein, refers to a moiety
represented by the structure --NR.sub.2, and includes primary
amines, and secondary, and tertiary amines substituted by alkyl,
aryl, heterocycle, acyl, and sulfinylalkyl. Thus, R.sub.2 may
represent two hydrogens, two alkyl moieties, or one hydrogen and
one alkyl moiety.
[0431] The term amido, as used herein, refers to a moiety
represented by the structure --C(O)NR.sub.2, wherein R.sub.2 is as
defined for amino.
[0432] As used herein, an "amino acid" is a natural amino acid
residue (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl,
Hyp, Ile, Leu Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D
or L form, or an unnatural amino acid (e.g. phosphoserine;
phosphothreonine; phosphotyrosine; gamma-carboxyglutarnate;
hippuric acid; octahydroindole-2-carboxylic acid; statine;
1,2,3,4,-tetrahydroisoquinoli- ne-3-carboxylic acid; penicillamine;
omithine; citrulline; .alpha.-methyl-alanine;
para-benzoylphenylalanine; phenylglycine; propargyl-glycine;
sarcosine; and tert-butylglycine) residue having one or more open
valences. Other unnatural anino acids include those represented by
the formula NH.sub.2 (CH.sub.2).sub.y COOH, wherein y=2-20, and
preferably 2-12, and include the aminoalkanoic acids such as
.epsilon.-amino caproic acid
(H.sub.2N--(CH.sub.2).sub.5--COOH).
[0433] The term also comprises natural and unnatural amino acids
bearing amino protecting groups such as acetyl, acyl,
trifluoroacetyl, and benzyloxycarbonyl), as well as natural and
unnatural amino acids protected at carboxy with protecting groups
such as a C.sub.1-C.sub.6 alkyl, phenyl or benzyl ester and amide.
Other suitable amino and carboxy protecting groups are known to
those skilled in the art. See for example, T. W. Greene, Protecting
Groups in Organic Synthesis; Wiley: New York, 1981; D. Voet,
Biochemistry, Wiley: New York, 1990; L. Stryer, Biochemistry,
(3.sup.rd Ed), W. H. Freeman and Co.: New York, 1975; J. March,
Advanced Organic Chemistry, Reactions, Mechanisms and Structure,
(2.sup.nd Ed.), McGraw Hill: New York, 1977; F. Carey and R.
Sundberg, Advanced Organic Chemistry, Part B: Reactions and
Synthesis, (2.sup.nd Ed.), Plenum: New York, 1977; and references
cited therein.
[0434] As used herein, a "retrovirus" includes any virus that
expresses reverse transcriptase. Examples of a retrovirus include,
but are not limited to, HIV-1, HIV-2, HTLV-I, HTLV-II, FeLV, FIV,
SIV, AMV, MMTV, and MoMuLV.
[0435] As used herein, "reverse transcriptase (RT)" refers to an
enzyme having an NNI binding site similar to that of HIV-1 RT and
to which ligands which bind the composite binding pocket of the
invention bind. One means by which RT activity can be determined is
by measuring viral replication. One measure of HIV-1 viral
replication is the p24 core antigen enzyme immunoassay, for
example, using the assay commercially available from Coulter
Corporation/Immunotech, Inc. (Westbrooke, Mich.). Another means by
which RT activity is analyzed is by assay of recombinant HIV-1
reverse transcriptase (rRT) activity, for example, using the
Quan-T-RT assay system commercially available from Amersham
(Arlington Heights, Ill.) and described in Bosworth, et al., Nature
1989, 341:167-168.
[0436] As used herein, a compound that "inhibits replication of
human immunodeficiency virus (HIV)" means a compound that, when
contacted with HIV-1, for example, via HIV-infected cells, effects
a reduction in the amount of HIV-1 as compared with untreated
control. Inhibition of replication of HIV-1 can be measured-by
various means known in the art, for example, the p24 assay
disclosed herein.
[0437] As used herein, a compound that is useful in "salvage
therapy," means a compound that can be taken with any regimen.
after a patient's initial treatment regimen has failed.
[0438] The term host, as used herein, refers to an unicellular or
multicellular organism in which the virus can replicate, including
cell lines and animals, and preferably a human. Alternatively, the
host can be carrying a part of the HIV genome, whose replication or
function can be altered by the compounds of the present invention.
The term host specifically refers to infected cells, cells
transfected with all or part of the HIV genome and animals, in
particular, primates (including chimpanzees) and humans. In most
animal applications of the present invention, the host is a human
patient. Veterinary applications, in certain indications, however,
are clearly anticipated by the present invention (such as
chimpanzees).
[0439] IV. Combination or Alternation Therapy
[0440] In a preferred but not. necessary embodiment, phenylindoles
of the present invention is administered in combination or
alternation with another anti-HIV agent. In one embodiment the
effect of administration of the two or more agents in combination
or alternation is synergistic.
[0441] Drug resistance most typically occurs by mutation of a gene
that encodes for an enzyme used in the viral replication cycle, and
most typically in the case of HIV, in either the reverse
transcriptase or protease genes. It has been demonstrated that the
efficacy of a drug against HIV infection can be prolonged,
augmented, or restored by administering the compound in combination
or alternation with a second, and perhaps third, antiviral compound
that induces a different mutation(s) from that selected for by the
principle drug. Alternatively, the pharmacokinetics,
biodistribution or other parameter of the drug can be altered by
such combination or alternation therapy. In general, combination
therapy is typically preferred over alternation therapy because it
induces multiple simultaneous stresses on the virus.
[0442] The second antiviral agent for the treatment of HIV, in one
embodiment, can be a protease inhibitor, a reverse transcriptase
inhibitor (a "RTI"), which can be either a synthetic nucleoside
reverse transcriptase inhibitor (a "NRTI") or a non-nucleoside
reverse transcriptase inhibitor (a "NNRTI"), and HIV-integrase
inhibitor, or a chemokine inhibitor. In other embodiments, the
second (or third) compound can be a pyrophosphate analog, or a
fusion binding inhibitor. A list compiling resistance data
collected in vitro and in vivo for a number of antiviral compounds
is found in Schinazi et al., Mutations in retroviral genes
associated with drug resistance, International Antiviral News,
Volume 5 (8), International Medical Press 1997.
[0443] In preferred embodiments, the phenylindole is administered
in combination or alternation with FTC
(2',3'-dideoxy-3'-thia-5-fluorocytidi- ne); 141W94 (amprenavir,
GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor
(delavirdine); DMP-266 (efavirenz), DDI (2',3'-dideoxyinosine); 3TC
(3'-thia-2',3'-dideoxycytidine); or DDC (2',3'-dideoxycytidine). In
another preferred embodiment, the phenylindole is administered in
combination or alternation with abacavir (1592U89), which is
(1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl-
]-2-cyclopentene-1-methanol succinate, D4T or AZT.
[0444] Other examples of antiviral agents that can be used in
combination or alternation with the compounds disclosed herein for
HIV therapy include 3TC; foscarnet; carbovir, acyclovir,
interferon, stavudine, and .beta.-D-dioxolane nucleosides such as
.beta.-D-dioxolanylguanine (DXG),
.beta.-D-dioxolanyl-2,6-dianinopurine (DAPD), and
.beta.-D-dioxolanyl-6-c- hloropurine (ACP).
[0445] Preferred protease inhibitors include indinavir
({1(1,S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)--
5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazi-
nyl]-2-(phenylmethyl)-D-erythro-pentoamide sulfate; Merck),
nelfinavir (Agouron), ritonavir (Abbott), saquinavir (Roche) and
DMP450
{[4R4(r-a,5-a,6-b,7-6)]-hexahydro-5,6-bis(hydroxy)-1,3-bis(3-amino)phenyl-
]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one)-bismesylate
(Triangle Pharmaceuticals, Inc.).
[0446] Nonlimiting examples of other compounds that can be
administered in combination or alternation with the phenylindole to
augment the properties of the drug on administration include
abacavir:
(1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-m-
ethanol succinate (1592U89, a carbovir analog; Glaxo Wellcome);
BILA 1906:
N-{1S-[[[3-[2S-{(1,1-dimethylethyl)amino]carbonyl)-4R-]3-pyridinylmethyl)-
thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2--
methylpropyl}-2-quinolinecarboxamide (Bio
Mega/Boehringer-Ingelheim); BILA 2185:
N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethyl-phenoxy)-1-oxoethyl]am-
ino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidine-carboxamide
(Bio Mega/Boehringer-Ingelheim); BM+51.0836:triazoloiso-indolinone
derivative; BMS 186,318: aminodiol derivative HIV-1 protease
inhibitor (Bristol-Myers-Squibb); d4API:
9-[2,5-dihydro-5-(phosphonomethoxy)-2-fura- nyl]-adenine (Gilead);
stavudine: d4T, 2',3'-dide-hydro-3'-deoxythymidine
(Bristol-Myers-Squibb); HBY097:
S-4-isopropoxycarbonyl-6-methoxy-3-(methy-
lthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione; HEPT:
1-[(2-hydroxy-ethoxy)methyl]6-(phenylthio)-thymine; KNI-272:
(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containing
tripeptide; L-697,593;
5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-one;
L-735,524: hydroxy-aminopentane amide HIV-1 protease inhibitor
(Merck); L-697,661:
3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6--
methylpyridin-2(1H)-one; L-FDDC: (-)-.sub..beta.-L-5-fluoro-2',3
'-dideoxycytidine; L-FDOC: (-)-.sub..beta.-L-5-fluoro-dioxolane
cytosine; nevirapine:
11-cyclopropyl-5,11-dihydro4-methyl-6H-dipyridol-[3,2-b:2',3'-
-e]diazepin-6-one (Boehringer-Ingelheim); PFA: phosphonofornate
(foscarnet; Astra); PMEA: 9-(2-phosphonylmethoxyethyl) adenine
(Gilead); PMPA: (R)-9-(2-phosphonylmethoxypropyl)-adenine (Gilead);
Ro 31-8959: hydroxyethylamine derivative HIV-1 protease inhibitor
(Roche); RPI-3121: peptidyl protease inhibitor, 1-[(3
s)-3-(n-alpha-benzyloxycarbonyl)-1-asp-
arginyl)-amino-2-hydroxy-4-phenylbutyryl]-n-tert-butyl-1-proline
amide; 2720:
6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydro-quinox-
alin-2(1H)thione; SC-52151: hydroxyethylurea isostere protease
inhibitor (Searle); SC-55389A: hydroxyethyl-urea isostere protease
inhibitor (Searle); TIBO R82150:
(+)-(5S)4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2--
butenyl)-imidazo-[4,5,1-jk]-[1,4]-benzodiazepin-2(1H)-thione
(Janssen); TIBO 82913:
(+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-b-
utenyl)imidazo[4,5,1jk]-[1,4]-benzo-diazepin-2-(1H)-thione
(Janssen); TSAO-m3T:
[2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5'-(4'-amino-1'-
,2'-oxathiole-2',2'-dioxide)]-.beta.-D-pentofuranosyl-N3-methyl-thymine;
U90152:
1-[3-[(1-methylethyl)-amino]2-pyridinyl]-4-[[5-[(methylsulphonyl)-
-amino]-1H-indol-2yl]-carbonyl]-piperazine; UC: thiocarboxanilide
derivatives (Uniroyal);
UC-781=N-[4-chloro-3-(3-methyl-2-butenyloxy)pheny-
l]-2-methyl-3-furan-carbothioamide;
UC-82=N-[4-chloro-3-(3-methyl-2-buteny- loxy
)phenyl]-2-methyl-3-thiophenecarbothioamide; VB 11,328:
hydroxyethyl-sulphonamide protease inhibitor (Vertex); VX-478:
amprenavir, 141W94, hydroxyethyl-sulphonamide protease inhibitor
(Vertex/Glaxo Wellcome); XM 323: cyclic urea protease inhibitor
(Dupont Merck), famciclovir, gancyclovir and penciclovir. In
another embodiment, the phenylindole. is administered in
combination with the protease inhibitor LG 1350.
[0447] In general, during alternation therapy, an effective dosage
of each agent is administered serially, whereas in combination
therapy, effective dosages of two or more agents are administered
together. The dosages will depend on such factors. as absorption,
biodistribution, metabolism and excretion rates for each drug as
well as other factors known to those of skill in the art. It is to
be noted that dosage values will also vary with the severity of the
condition to be alleviated. It is to be further understood that for
any particular subject, specific dosage regimens and schedules
should be adjusted over time according to the individual need and
the professional judgment of the person administering or
supervising the administration of the compositions. Examples of
suitable dosage ranges for anti-HIV compounds, including nucleoside
derivatives (e.g. D4T, DDI, and 3TC) or protease inhibitors, for
example, nelfinavir and indinavir, can be found in the scientific
literature and in the Physicians Desk Reference. Many examples of
suitable dosage ranges for other compounds described herein are
also found in public literature or can be identified using known
procedures. These dosage ranges can be modified as desired to
achieve a desired result.
[0448] The disclosed combination and alternation regiments are
useful in the prevention and treatment of HIV infections and other
related conditions such as AIDS-related complex (ARC), persistent
generalized lymphadenopathy (PGL), AIDS-related neurological
conditions, anti-HIV antibody positive and HIV-positive conditions,
Kaposi's sarcoma, thrombocytopenia purpurea and opportunistic
infections. In addition, these compounds or formulations can be
used prophylactically to prevent or retard the progression of
clinical illness in individuals who are anti-HIV antibody or
HIV-antigen positive or who have been exposed to HIV.
[0449] V. Pharmaceutical Compositions
[0450] Humans suffering from effects caused by any of the diseases
described herein, and in particular, HIV infection, can be treated
by administering to the patient an effective amount of the
phenylindole, optionally in combination or alternation with another
anti-HIV agent, or with a pharmaceutically acceptable salt or
prodrug thereof in the presence of a pharmaceutically acceptable
carrier or diluent. In one embodiment, humans infected with HIV can
be effectively treated by administering to the patient an effective
amount of the phenylindole or a pharmaceutically acceptable salt or
prodrug thereof in the presence of a pharmaceutically acceptable
carrier or diluent. For multiple drug resistant patients, the
phenylindole is either administered alone or in combination. The
active materials can be administered by any appropriate route, for
example, orally, parenterally, enterally, intravenously,
intradermally, subcutaneously, transdermally, intranasally or
topically, in liquid or solid form.
[0451] The active compound(s) are included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to
a patient a therapeutically effective amount of compound to inhibit
viral replication in vivo, especially HIV replication, without
causing serious toxic effects in the treated patient. By
"inhibitory amount" is meant an amount of active ingredient
sufficient to exert an inhibitory effect as measured by, for
example, an assay such as the ones described herein.
[0452] A preferred dose of the compound for all the above-mentioned
conditions will be in the range from about 1 to 75 mg/kg,
preferably 1 to 20 mg/kg, of body. weight per day, more generally
0.1 to about 100 mg per kilogram body weight of the recipient per
day. The effective dosage range of the pharmaceutically acceptable
derivatives can be calculated based on the weight of the parent
phenylindole to be delivered. If the derivative exhibits activity
in itself, the effective dosage can be estimated as above using the
weight of the derivative, or by other means known to those skilled
in the art.
[0453] The compounds are conveniently administered in unit any
suitable dosage form, including but not limited to one containing 7
to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit
dosage form. An oral dosage of 50 to 1000 mg is usually
convenient.
[0454] Ideally, the active ingredient should be administered to
achieve peak plasma concentrations of the active compound of from
about 0.02 to 70 micromolar, preferably about 0.5 to 10 .sub..mu.M.
This may be achieved, for example, by the intravenous injection of
a 0.1 to 25% solution of the active ingredient, optionally in
saline, or administered as a bolus of the active ingredient.
[0455] The concentration of active compound in the drug composition
will depend on absorption, distribution, metabolism and excretion
rates of the drug as well as other factors known to those of skill
in the art. It is to be noted that dosage values will also vary
with the severity of the condition to be alleviated. It is to be
further understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
composition. The active ingredient may be administered at once, or
may be divided into a number of smaller doses to be administered at
varying intervals of time.
[0456] A preferred mode of administration of the active compound is
oral. Oral compositions will generally include an inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches, or capsules.
Pharmaceutically compatible bind agents, and/or adjuvant materials
can be included as part of the composition.
[0457] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a
disintegrating agent such as alginic acid, Primogel, or corn
starch; a lubricant such as magnesium stearate or Sterotes; a
glidant such as colloidal silicon dioxide; a sweetening agent such
as sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate or orange flavoring. When the dosage unit form is
a capsule, it can contain, in addition to material of the above
type, a liquid carrier such as a fatty oil. In addition, dosage
unit forms can contain various other materials which modify the
physical form of the dosage unit, for example, coatings of sugar,
shellac, or other enteric agents.
[0458] The compounds can be administered as a component of an
elixir, suspension, syrup, wafer, chewing gum or the like. A syrup
may contain, in addition to the active compounds, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
[0459] The compounds or their pharmaceutically acceptable
derivative or salts thereof can also be mixed with other active
materials that do not impair the desired action, or with materials
that supplement the desired action, such as antibiotics,
antifungals, antiinflammatories, protease inhibitors, or other
nucleoside or non-nucleoside antiviral agents, as discussed in more
detail above. Solutions or suspensions used for parental,
intradennal, subcutaneous, or topical application can include the
following components: a sterile diluent such as water for
injection, saline solution, fixed-oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium: bisulfite; chelating
agents such as ethylenediaminetetraacetic acid; buffers such as
acetates, citrates or phosphates and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The parental
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic.
[0460] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[0461] Liposomal suspensions (including liposomes targeted to
infected cells with monoclonal antibodies to viral antigens) are
also preferred as pharmaceutically acceptable carriers. these may
be prepared according to methods known to those skilled in the art,
for example, as described in U.S. Pat. No. 4,522,811 (which is
incorporated herein by reference in its entirety). For example,
liposome formulations may be prepared-by dissolving appropriate
lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl
phosphatidyl choline, arachadoyl phosphatidyl choline, and
cholesterol) in an inorganic solvent that is then evaporated,
leaving behind a thin film of dried lipid on the surface of the
container. An aqueous solution of the active compound or its
monophosphate, diphosphate, and/or triphosphate derivatives is then
introduced into the container. The container is then swirled by
hand to free lipid material from the sides of the container and to
disperse lipid aggregates, thereby forming the liposomal
suspension.
[0462] VI. Process of Preparation of the Active Compounds
[0463] The phenylindoles can be synthesized using any means known
in the art. In particular, the methods disclosed in U.S. Pat. No.
5,527,819, hereby incorporated by reference in its entirety for its
disclosure of relevant synthetic methods, can be used to synthesize
the compounds of the present invention. In general, the compounds
of the present invention can be synthesized via the general methods
disclosed in FIGS. 1-4. In particular, the following species can by
synthesized by the following methods.
[0464] a) Ethyl Indole-2-caboxylates-2a-i (Scheme 1, Examples
1-3)
[0465] Ethyl 5,6-dichloroindole-2-carboxylate 2a was prepared
according to literature (j. Med. Chem., 1998, 41, 1568-1573). Ethyl
indole-2-caboxylates 2b-i were synthesized starting from proper
anilines or phenylhydrazines which were transformed into the
related phenylhydrazones 1 and then cyclized to indoles (Fischer
indole synthesis, Robinson, "The Fischer indole synthesis", Wiley,
New York, 1983. The Japp-Klingemann reaction, Org. Reactions, 1959,
10, 143-178). 21
[0466] b) 3-Arylsulfonylindole-2-carboxyamides-5a-g (Scheme 2,
Examples 4-7)
[0467] The reaction of ethyl indole-2-caboxylates 2a-i with
N-(3,5-dimethylphenylthio)-succinimide in the presence of sodium
hydride afforded the ethyl 3-(3,5-5
dimethylphenylthio)indole-2-caboxylates 3a-i which were oxidized to
the related sulfones 4a-i by treatment with 3-chloroperoxybenzoic
acid. Transformation of esters 3a-i into related amides 4a-i was
reached by heating in a sealed tube with ammonium hydroxide. 22
[0468] c) 3-Arylsulthioindole-2-carboxyhydrazides-6a-d, f and 7a-f-
and 3-aryl-sulfonylindole-2-carboxyhydrazides-8a, b, d-f, 9a-f, 10
and 11 (Schemes 3 and 4, Examples 8-10)
[0469] Treatment of ethyl 3-aryllthioindole-2-caboxylates or
3-arylsulfonylindole-2-caboxylates with proper hydrazines afforded
3-arylsulthioindole-2-carboxyhydrazides (6a-d, f and 7a-f) and
3-arylsulfonylindole-2-carboxyhydrazides (8a, b, d-f and 9a-f, 10),
respectively. Reaction of 7e with acetone in the presence of sodium
cyanoborohydride gave 11. 23 24
[0470] d)
1-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carbonyl]-4-me-
thyl-piperazine-13 (Scheme 5, Examples 11 and 12)
[0471] Lithium hydroxide hydrolysis of 41 gave
5-chloro-3-(3,5-dimethylphe- nyl-sulfonyl)indole-2-carboxylic acid
(12) with was converted to 13 by reaction with N-methylpiperazine
in the presence of
benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium
hexafluorophosphate (BOP reagent) and triethylamine in DMF as a
solvent at room temperature. 25
[0472] e)
3-trans-15-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]prope-
namide-18 (Scheme 6, Examples 13-18)
[0473] Acid (12) was transformed into N-methyl,N-methoxy
5-chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (14)
by reacting with N,O-dimethyl-hydroxylamine hydrochloride,
benzotriazol-1-yloxy-tris(dimeihylamino)phosphonium
hexafluoro-phosphate (BOP reagent) in the presence of
triethylamnine and then into
5-chloro-3-(3,5-di-methylphenylsulfonyl)indole-2-carboxyaldehyde
acid (15) by lithium aluminium hydride reduction. Reaction of 15
with triethyl phosphono acetate in the presence of potassium
carbonate gave ethyl
3-trans-[5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indol-2-yl]propenoate
(16), which was transformed to
3-trans-[5-chloro-3-(3,5-dimethylphenylsul-
fonyl)indol-2-yl]propenoic acid (17) by lithium aluminium
hydrolysis and subsequently converted to amide 18 with ammonia in
the presence of 1,1'-carbonyldiimidazole. Reaction of acid 17 with
the gyicine ethyl ester hydrochloride in the presence of BOP and
triethylamine afforded
2-[N-[3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propenam-
ido]]-acetic acid ethyl ester) (19) which was transformed into the
related amide 20 with ammonium hydroxide at 60.degree. C. 26
[0474] f)
2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxyamid-
o]]-5 acetamide-21 (Scheme 7, Examples 19-22)
[0475] Reaction of the acid 12 with the glycine ethyl ester
hydrochloride in the presence of BOP and triethylamine afforded
2-[N-[5-Chloro-3-(3,5-d-
imethylphenylsulfonyl)indol-2-carboxy-amido]]-acetic acid ethyl
ester (21) which was transformed into anide 22 by heating with
ammonium hydroxide. By the same way were prepared arnides 23 and 24
by heating with cyclopropylamine or morpholine, respectively.
27
[0476] g)
5-(1H-Pyrrol-1-yl)-3-(3,5-dimethylphenylsulfonyl)indole-2-carbox-
yamide-25b (Scheme 8, Example 23)
[0477] 5-Nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide
(5k) was reduced
5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide with
hydrogen in the presence of PtO.sub.2 (Adams' catalyst) as a
catalyst. Transformation into
5-(1H-pyrrol-1-yl)-3-(3,5-dimethyl-phenylsu-
lfonyl)indole-2-carboxylate (25a) was performed by heating with
2,5-dimethoxy-tetrahydrofuran in glacial acetic acid (Acta Chem.
Scand. 1952, 6, 667-670; Acta Chem. Scand, 1952, 6, 867-874).
28
[0478] The following working examples provide a further
understanding of the method of the present invention. These
examples are of illustrative purpose, and are not meant to limit
the scope of the invention. Equivalent, similar, or suitable
solvents, reagents or reaction conditions may be substituted for
those particular solvents, reagents or reaction conditions
described herein without departing from the general scope of the
method of synthesis.
EXAMPLES
[0479] All melting points (mp) were taken on a Buchi 510 apparatus
(uncorrecte). Infrared spectra (IR): Perkin-Elmer 1310
spectrophotometer. Proton nuclear magnetic resonance (1H NMR)
spectra: Bruker AM-200 (200 MHz) FT spectrometer. Column
chromatographies: alumina Merck (70-230 mesh) and silica gel Merck
(70-230 mesh). TLC: Aluminum oxide TLC cards Fluka (aluminum oxide
precoated aluminum cards with fluorescent indicator at 254 nm) and
silica gel TLC cards Fluka (silica gel precoated aluminum cards
with fluorescent indicator at 254 nm). Developed plates were
visualized by spectroline ENF 260C/F UV apparatus. Organic
solutions were dried over anhydrous sodium sulfate. Concentration
and evaporation of the solvent after reaction or extraction: rotary
evaporator Buchi Rotavapor operating at reduced pressure. Elemental
analyses (.+-.0.4% of the theoretical values): laboratories of Dr.
M. Zancato, Dipartimento di Scienze Farmaceutiche, University of
Padova (Italy).
Example 1
[0480] Synthesis of Ethyl Pyruvate
4-Chloro-3-Fluorophenylhydrazone
[0481] A solution of sodium nitrite (4.76 g, 0.069 mol) in water
(6.3 mL) was added dropwise to an ice cooled mixture of
4-chloro-3-fluoroaniline (J. Am. Chem. Soc., 1996, 61, 5130-5133)
(10.00 g, 0.069 mol), water (167 mL) and 37% hydrochloric acid (167
mL). After 20 minutes potassium acetate (9.81 g, 0.10 mol) was
added, and then a solution of ethyl 2-methylacetoacetate (9.95 g,
0.069 mol), potassium acetate (9.81 g, 0.10 mol) in methanol (67
mL) was dropped while cooling on the ice bad. Reaction was stirred
at 0.degree. C. for 3 hours, then extracted with diethyl ether.
Organic layer was washed with brine and dried. Removal of the
solvent furnished a red oily residue that was treated with ethanol
(100 mL) and stirred at room temperature overnight. The solid which
formed was filtered a recrystallized from ethanol to give 5.4 g
(30%) of title compound, mp 161-163.degree. C. (from ethanol).
[0482] Ethyl pyruvate 2,4-difluorophenylhydrazone, yield 40%, mp
153-156.degree. C. (from ethanol).
[0483] Ethyl pyruvate 3-chloro-4-fluorophenylhydrazone, yield 17%,
mp 89-91.degree. C. (from aqueous ethanol).
[0484] Ethyl pyruvate 3,4-difluorophenylhydrazone, yield 53%, mp
112-114 (from ethanol).
Example 2
[0485] Synthesis of Ethyl pyruvate 2,4-dichlorophenylhydrazone
[0486] A mixture of 2,4-dichlorophenylhydrazine (16.00 g, 0.075
mol), ethyl pyruvate (14.47 g, 10.3 mL, 0.12 mol), glacial acetic
acid (0.9 mL), absolute ethanol (105 mL) was refluxed for 2 hours.
After cooling at room temperature, the solid which formed was
filtered and recrystallized from ethanol to give 17.0 g (83%) of
the title compound, mp 118-120.degree. C. (from ethanol).
Example 3
[0487] Synthesis of Ethyl 5-chloro-6-fluoroindole-2-carboxylate
(2j) and ethyl 5-chloro-4-fluoroindole-2-carboxylate (2g)
[0488] Ethyl pyruvate 4-chloro-3-fluorophenylhydrazone (5.00 g,
0.0193 mol) was added by portions to PPA (50 g) pre-heated at
110.degree. C., then reaction was stirred for 30 minutes. After
cooling at room temperature, ice water was added while stirring.
The solid which formed was filtered, washed with water, dried and
passed by a silica gel column chromatography (n-hexane : ethyl
acetate 1:2 as eluent). First fractions furnished ethyl
5-chloro-6-fluoroindole-2-carboxylate (2f), (1.85 g, 40%), mp
160-164.degree. C. (ethanol). Further elution with the same eluent
gave ethyl 5-chloro4-fluoroindole-2-carboxylate (2g) (0.9 g, 19%),
mp 186-190.degree. C. (ethanol).
[0489] Ethyl 5,7-dichloroindole-2-carboxylate (2b), yield 37%, mp
143-145.degree. C. (from ethanol).
[0490] Ethyl 4,5-difluoroindole-2-carboxylate (2c), yield 15%, mp
166-168.degree. C. (from ethanol).
[0491] Ethyl 4,5-difluoroindole-2-carboxylate (2d), yield 22%, mp
171-173.degree. C. (from ethanol).
[0492] Ethyl 5,7-difluoroindole-2-carboxylate (2e), yield 9%, mp
175-177.degree. C. (from ethanol).
[0493] Ethyl 4-chloro-5-fluoroindole-2-carboxylate (2h), yieldl8%,
mp 183-16.degree. C. (from ethanol).
[0494] Ethyl 6-chloro-5-fluoroindole-2-carboxylate (2i), yield 61%,
mp 198-200.degree. C. (from ethanol).
Example 4
[0495] Synthesis of Ethyl
5-chloro-3-(3,5-dimeihylphenylthio)-6-fluoroindo- le-2-carboxylate
(3f)
[0496] Boron trifluoride ethyl etherate (0.135 g, 0.12 mL, 0.001
mol) was added to a mixture of ethyl
5-chloro-6-fluoroindole-2-carboxylate (0.75 g, 0.0031 mol),
N-(3,5-dimethylphenylthio)-succinimide (0.78 g, 0.0033 mol) and
anhydrous dichloromethane (20 mL) under dry argon atmosphere. After
stirring at room temperature for 2 hours was added boron
trifluoride ethyl etherate (0.27 g, 0.24 mL, 0.002 mol) and then
reaction was heated at 45.degree. C. for 2 hours. After cooling
reaction was diluted chloroform and brine while shaking. Organic
layer was separated, washed with saturated solution of sodium
hydrogen carbonate, then with brine and dried. The solvent was
evaporated to give 1.2 g (100%) of satisfactory pure title
compound, mp 170-173.degree. C. (from ethanol).
[0497] Ethyl
5,6-dichloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate (3a),
yield 96%, mp 192-195.degree. C. (from ethanol).
[0498] Ethyl
5,7-dichloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate (3b),
not purified.
[0499] Ethyl
3-(3,5-dimethylphenylthio)4,5-difluoroindole-2-carboxylate (3c),
yield 97%, mp 148-150.degree. C. (from ethanol).
[0500] Ethyl
3-(3,5-dimethylphenylthio)-5,6-difluoroindole-2-carboxylate (3d),
yield 98%, mp 171-174.degree. C. (from ethanol).
[0501] Ethyl
3-(3,5-dimethylphenylthio)-5,7-difluoroindole-2-carboxylate (3e),
not purified.
[0502] Ethyl
5-chloro-3-(3,5-dimethylphenylthio)-4-fluoroindole-2-carboxyl- ate
(3g), yield 51%, mp 149-151.degree. C. (from ethanol).
[0503] Ethyl
4-chloro-3-(3,5-dimethylphenylthio)-5-fluoroindole-2-carboxyl- ate
(3h), yield 77%, mp 184-186.degree. C. (from ethanol).
[0504] Ethyl
6-chloro-3-(3,5-dimethylphenylthio)-5-fluoroindole-2-carboxyl- ate
(3i), yield 61%, mp 186-190.degree. C. (from ethanol).
[0505] Methyl
5-chloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate (3j), yield
77%, mp 174-175.degree. C. (from toluene/cyclohexane).
[0506] Ethyl 5-nitro-3-(3,5-dimethylphenylthio)indole-2-carboxylate
(3k), yield 46%, mp 212-213.degree. C. (from ethanol).
[0507] Ethyl
5-acetyl-3-(3,5-dimethylphenylthio)indole-2-carboxylate (31), yield
70%, mp 164-166.degree. C. (from ethanol).
Example 5
[0508] Synthesis of Ethyl
5-chloro-3-(3,5-dimethylphenysulfonyl)-6-fluoroi-
ndole-2-carboxylate (4f)
[0509] 3-Chloroperoxybenzoic acid (1.32 g, 0.00766 mol) was added
to an ice cooled solution of ethyl
5-chloro-3-(3,5-dimethylphenylthio)-6-fluoro- indole-2-carboxylate
(3f) (1.0 g, 0.00264 mol) in chloroform (42 mL). Reaction was
stirred at room temperature for 1.5 hours, poured on crushed ice
and extracted with chloroform. Organic solution was shaken with
saturated solution of sodium hydrogen carbonate, then with brine.
After concentration to a small volume, the solution was passed
through a silica gel column chromatography (ethyl acetate as
eluent) to furnish 0.9 g (83%) of title compound, mp
236-240.degree. C. (from ethanol).
[0510] Ethyl
5,6-dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyla- te
(4a), yield 82%, mp 196-197.degree. C. (from aqueous ethanol).
[0511] Ethyl
5,7-dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyla- te
(4b), yield 50%.
[0512] Ethyl
3-(3,5-dimethylphenylsulfonyl)-4,5-difluoroindole-2-carboxyla- te
(4c), yield 27%, mp 176-178.degree. C. (from ethanol).
[0513] Ethyl
3-(3,5-dimethylphenylsulfonyl)-5,6-difluoroindole-2-carboxyla- te
(4d), yield 100%, mp 232-235.degree. C. (from ethanol).
[0514] Ethyl
3-(3,5-dimethylphenylsulfonyl)-5,7-difluoroindole-2-carboxyla- te
(4e), yield 100%, mp 208-210.degree. C. (from ethanol).
[0515] Ethyl
5-chloro-3-(3,5-dimethylphenylsulfonyl)-4-fluoroindole-2-carb-
oxylate (4g), yield 89%, mp 224-226.degree. C. (from ethanol).
[0516] Ethyl
4-chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carb-
oxylate (4h), yield 54%, mp 232-234.degree. C. (from ethanol).
[0517] Ethyl
6-chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carb-
oxylate (4i), yield 100%, mp 233-235.degree. C. (from ethanol).
[0518] Methyl
5-chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2-carboxylate (4j),
yield 74%, mp 234-236.degree. C. (from toluene/cyclohexane).
[0519] Ethyl
5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylate (4k),
yield 100%, mp 255-256.degree. C. (from ethanol).
[0520] Ethyl
5-acetyl-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylate (4l),
yield 61%, mp 193-195.degree. C. (from ethanol). 29
Example 6
[0521] Synthesis of
5-Chloro-3-(3,5-dimethylphenysulfonyl)-6-fluoroindole--
2-carboxyamide (5f)
[0522] Ethyl
5-chloro-3-(3,5-dimethylphenysulfonyl)-6-fluoroindole-2-carbo-
xylate (4f) was heated with 30% ammonium hydroxide (25 mL) and
ammonium chloride (40 mg) in a sealed tube at 100.degree. C.
overnight. After cooling reaction mixture was poured on ice water
and stirred for 15 minutes and extracted with ethyl acetate.
Organic layer was washed with brine, dried and the solvent
evaporated to afford a residue which was purified on silica gel
column chromatography (chloroform-ethanol 95:5). Removal of the
solvent gave 0.28 g (65%) of title compound, mp 270-270.degree. C.
(from ethanol).
[0523]
5,6-Dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide
(5a), yield 43%, mp 280-282.degree. C. (from ethanol).
[0524]
5,7-Dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide
(5b), yield 90%, mp>300.degree. C. (from ethanol).
[0525]
3-(3,5-Dimethylphenylsulfonyl)-4,5-difluoroindole-2-carboxyamide
(5c), yield 43%, mp 298-300.degree. C. (from ethanol).
[0526]
3-(3,5-Dimethylpbenylsulfonyl)-5,6-difluoroindole-2-carboxyamide
(5d), yield 65%, mp 266-269.degree. C. (from aqueous
dimethylformamide).
[0527]
3-(3,5-Dimethylphenylsulfonyl)-5,7-difluoroindole-2-carboxyamide
(5e), yield 75%, mp>300.degree. C. (from aqueous
dimethylformamide).
[0528]
5-Chloro-3-(3,5-dimethylphenylsulfonyl)-4-fluoroindole-2-carboxyami-
de (5g), yield 31%, mp 268-270.degree. C. (from ethanol).
[0529]
4-Chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carboxyami-
de (5h), yield 46%, mp 279-280.degree. C. (from ethanol).
[0530]
6-Chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carboxyami-
de (5i), yield 50%, mp 262-264.degree. C. (from ethanol).
[0531]
5-Chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2-carboxyamide (5j),
yield 64%, mp 280-284.degree. C. (from ethanol).
[0532] 5-Nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide
(5k), yield 57%, mp 270-272.degree. C. (from ethanol).
[0533] 5-Acetyl-3-(3,5-dimethylphenylthio)indole-2-carboxyamide
(5l), yield 54%, mp>300.degree. C. (from ethanol).
Example 7
[0534] Synthesis of N-(3,5-Dimethylphenylthio)succinimide
[0535] 3,5-Dimethylthiophenol (2.76 g, 0.02 mol) was added by a
syringe to an ice cooled mixture of N-chlorosuccinimide (3.34 g,
0.025 mol) and anhydrous dichloromethane (30 mL) under argon
atmosphere. After 1 hour, N-chlorosuccinimide (0.4 g, 0.003 mol)
was added, then reaction was stirred for 2.5 hours. Triethylamine
(3.9 mL, 0.028 mol) was added while stirring for 15 minutes, then
dichloromethane and 1N HCl were added. After shaking, organic layer
was dried, concentrated to a small volume and passed through a
Celite.RTM. column. After evaporation of the solvent, the residue
was triturated with diethyl ether to give 3.0 g (64%) of title
compound, mp 131-134.degree. C. (from diethyl ether).
Example 8
[0536] Synthesis of
5-Chloro-3-(3,5-;dimethylphenylsulfonyl)indole-2-carbo-
xy-hydrazide (7e)
[0537] A mixture of ethyl
5-chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2- -carboxylate
(1.00 g, 0.0026 mol), hydrazine hydrate (5 mL) and ethanol (5 mL)
was stirred at room temperature for 2 hours. After quenching on
crushed ice, the solid which formed was filtered, washed with water
and dried to give 0.77 (82%) of title compound, mp>300.degree.
C. (from aqueous dimethylformamide).
[0538] 5-Chloro-3-phenylthioindole-2-carboxyhydrazide (6a), yield
80%, mp 231.degree. C. (from ethanol).
[0539] 5-Chloro-3-(4-methylphenylthio)indole-2-carboxyhydrazide
(6b), yield 90%, mp 249-250.degree. C. (from ethanol).
[0540]
5-Chloro-3-(4-fluoromethylphenylthio)indole-2-carboxyhydrazide
(6c), yield 90%, mp 235-236.degree. C. (from ethanol).
[0541] 5-Chloro-3-(4-chlorophenylthio)indole-2-carboxyhydrazide
(6d), yield 100%, mp 247-248.degree. C. (from ethanol).
[0542] 5-Chloro-3-phenylsulfonylindole-2-carboxyhydrazide (7a),
yield 100%, mp>300.degree. C. (from ethanol).
[0543]
5-Chloro-3-(4-methyhlphenylsulfonyl)indole-2-carboxyhydrazide (7b),
yield 100%, mp>300.degree. C. (from ethanol).
[0544] 5-Chloro-3-(4-fluorophenylsulfonyl)indole-2-carboxyhydrazide
(7c), yield 55%, mp 252-253.degree. C. (from ethanol).
[0545] 5-Chloro-3-(4-chlorophenylsulfonyl)indole-2-carboxyhydrazide
(7d), yield 90%, mp>300.degree. C. (from ethanol).
Example 9
[0546] Synthesis of
5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-[N'-(2-
-hydroxy-ethyl)]-carboxyhydrazide (9f)
[0547] A mixture of ethyl
5-chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2- -carboxylate
(1.00 g, 0.0026 mol), 2-hydroxyethylhydrazine (5 mL) and ethanol (5
mL) was stirred at room temperature overnight. After quenching on
crushed ice, the solid which formed was filtered, washed with water
and dried to give 0.95 (90%) of title compound, mp 228-230.degree.
C. (from ethanol).
[0548]
5-Chloro-3-phenylthioindole-2-[N'-(2-hydroxyethyl)]carboxyhydrazide
(8a), yield 88%, mp 178-180.degree. C. (from ethanol).
[0549]
5-Chloro-3-(2-methylphenylthio)indole-2-[N'-(2-hydroxyethyl)]carbox-
yhydrazide (8b), yield 70%, mp 190-192.degree. C. (from
ethanol).
[0550]
5-Chloro-3-(4-methylphenylthio)indole-2-[N'-(2-hydroxyethyl)]carbox-
yhydrazide (8d), yield 65%, mp 211-213.degree. C. (from aqueous
ethanol).
[0551]
5-Chloro-3-(2,4-dimethylphenylthio)indole-2-[N'-(2-hydroxyethyl)]ca-
rboxyhydrazide (8e), yield 59%, mp 170-172.degree. C. (from
toluene/cyclohexane).
[0552]
5-Chloro-3-(3,5-dimethylphenylthio)indole-2-[N'-(2-hydroxyethyl)]ca-
rboxyhydrazide (8f), yield 52%, mp 215-217.degree. C. (from
ethanol).
[0553]
5-Chloro-3-phenylsulfonylindole-2-[N'-(2-hydroxyethyl)]carboxyhydra-
zide (9a), yield 88%, mp 178-180.degree. C. (from ethanol).
[0554]
5-Chloro-3-(2-methylphenylsulfonyl)indole-2-[N'-(2-hydroxyethyl)]ca-
rboxyhydrazide (9b), yield 83%, mp 220-221.degree. C. (from
ethanol).
[0555]
5-Chloro-3-(3-methylphenylsulfonyl)indole-2-[N'-(2-hydroxyethyl)]ca-
rboxyhydrazide (9c), yield 98%, mp 210-215.degree. C. (from
ethanol).
[0556]
5-Chloro-3-(4-methylphenylsulfonyl)indole-2-[N'-(2-hydroxyethyl)]ca-
rboxyhydrazide (9d), yield 84%, mp 281-283.degree. C. (from
ethanol).
[0557]
5-Chloro-3-(2,4-dimethylphenylsulfonyl)indole-2-[N'-(2-hydroxyethyl-
)]carboxyhydrazide (9e), yield 94%, mp 141-143.degree. C. (from
ethanol).
[0558]
5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-(N'-methyl)carboxyh-
ydrazide (10), yield 16%, mp 284-287.degree. C. (aqueous
dimethylformamide).
Example 10
[0559] Synthesis of
5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-(N'-is-
opropyl)-carboxy-hydrazide (11)
[0560] Sodium cyanoborohydride (0.19 g, 0.0031 mol) was added to an
ice cooled solution of
5-chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carbox- yhydrazide
(7e) (0.98 g, 0.0026 mol), acetone (0.15 g, 0.0026 mol),
tetrahydrofuran (32.5 mL) and methanol (32.5 mL) containing 6N
HCl-CH.sub.3OH 1:1 (0.44 mL). Reaction was stirred at 0.degree. C.
for 2 hours, then at room temperature overnight. After
concentration to a small volume, water and ethyl acetate were added
while shaking. Organic layer was separated, washed with brine and
dried. Removal of the solvent gave a residue which was purified by
passing through a silica gel column chromatography
(chloroform-ethanol 95:5 as eluent) to afford 0.68 g (63%) of title
compound, mp 248-250.degree. C. (from ethanol).
Example 11
[0561] Synthesis of
5-Chloro-3-(3,5-dimethylphenylsutfonyl)indole-2-carbox- ylic acid
(12)
[0562] Lithium hydroxide monohydrate (0.33 g, 0.0079 mol) was added
to a solution of methyl
5-chloro-3-(3,5-dimethylphenylthio)indole-2-carboxylat- e (1.0 g,
0.0026 mol) in tetrahydrofuran (30 mL) and water (30 mL), then
reaction was stirred at room temperature for 4 days. After dilution
with water the mixture was acidified with 1N HCl and extracted with
ethyl acetate. Organic reaction was washed with brine and dried.
Evaporation of the solvent furnished 0.94 (100%) of title compound,
mp 277-278.degree. C. (from ethanol).
Example 12
[0563] Synthesis of
1-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-car-
bonyl]-4-methyl-piperazine (13)
[0564] Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP reagent) (1.22 g, 0.00275 g) was added to
a solution of
5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indole-2-carboxylic acid
(12) (1.00 g, 0.00275 mol), N-methylpiperazine (0.55 g, 0.0055
mol), triethylamine (0.55 g, 0.0055 mol) in anhydrous DMF (50 mL).
Reaction was stirred at room temperature for 72 hours, then diluted
with water and extracted with ethyl acetate. Organic extracts were
washed with brine, dried and the solvent evaporated to give 1.20 g
(98%) of pure title compound, mp 281-283.degree. C. (from aqueous
ethanol).
[0565] N-Methyl,N-methoxy
5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-c- arboxyamide (14),
was prepared using N,O-dimethylhydroxylamine hydrochloride. Yield
70%, mp 264-267.degree. C. (ethanol).
Example 13
[0566] Synthesis of
5-Chloro-3-(3,5-dimethylphenylsutfonyl)indol-2-carboxy- -oldehyde
(15)
[0567] A 1M solution of lithium aluminium hydride (1.6 mL, 0.0015
mol) was slowly added via syringe to a solution of 14 (0.6 g,
0.0015 mol) in anhydrous tetrahydrofuiran (40 mL) under argon
atmosphere. Reaction was stirred at room temperature for 1.5 hours,
then quenched by carefully addition of crushed ice. The solid that
formed was filtered, washed with tetrahydrofluran and concentrated
to a small volume. After extraction with ethyl acetate, the organic
layer was washed with brine and dried. Removal of the solvent
furnished 0.5 g (96%) of satisfactory pure title compound, mp
253-255.degree. C. (from aqueous ethanol).
Example 14
[0568] Synthesis of Ethyl
3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)-
indol-2-yl]propionate (16)
[0569] Tri ethyl phosphonoacetate (0.36 g, 0.016 mol) was added in
one portion to a mixture of 15 (0.45 g, 0.0013 mol), potassium
carbonate (0.53 g, 0.0039 mol) and absolute ethanol (10 mL), then
reaction was stirred at 70.degree. C. per 2 hours. After cooling
water and diethyl ether were added while shaking. The organic layer
was separated, washed with brine and dried. After evaporation of
the solvent, the crude product was purified by passing through a
silica gel column chromatography (ethyl acetate as eluent) to give
0.27 g (50%) of pure title compound, mp 236-238.degree. C. (from
ethanol).
Example 15
[0570] Synthesis of
3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)
indol-2-yl]-propionic acid (17)
[0571] Was prepared by lithium hydroxide hydrolysis of 16, as
reported above for acid 12. After 48 hours was obtained
satisfactory pure title compound, yield 89%, mp 155-156.degree. C.
(from aqueous ethanol).
Example 16
[0572] Synthesis of
3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol--
2-yl]-propionamide (18)
[0573] 1,1'-Carbonyldiimidazole (0.24 g, 0.0015 mol) was added by
portions to an ice water cooled solution of 17 in anhydrous
tetrahydrofuran. Reaction was stirred at room temperature for 2
hours, then gaseous ammonia was bubbled through for 30 minutes.
After dilution with water, the mixture was extracted with ethyl
acetate, washed with brine and dried. Removal of the solvent gave a
residue, which was purified by passing through a silica gel column
chromatography (ethyl acetate/ethanol 9:1 as eluent). Evaporation
of the eluent gave 0.19 g (51%) of title compound,
mp>300.degree. C. (from aqueous dimethylformamide).
Example 17
[0574] Synthesis of
2-[N-[3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)-
indol-2-yl]propion-amido]]-acetic acid ethyl ester (19)
[0575] Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP reagent) (0.90 g, 0.0020 mol) was added to
a solution of
3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]pr-
opionic acid (17) (0.80 g, 0.0020 mol), glycine ethyl ester
hydrochloride (0.57 g, 0.0041 mol) and triethylamine (0.62 g,
0.0061 mol) in anhydrous DMF (37 mL). Reaction was stirred at room
temperature for 48 hours, then diluted with water and extracted
with ethyl acetate. Organic layer was separated, washed with brine
and dried. Removal of the solvent furnished 0.8 g (82%) of
satisfactory pure title compound, mp 278-280.degree. C. (from
ethanol).
[0576]
2-[-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]]-
acetic acid ethyl ester (21), was prepared from
5-chloro-3-(3,5-dimethylph- enylsulfonyl)indole-2-carboxylic acid
(12)--after 72 hours at room temperature the reaction mixture was
diluted with water; the solid which formed was filtered, washed
with water and dried to give 0.62 g (80%) of satisfactory pure
title compound, mp 209-211.degree. C. (from ethanol).
Example 18
[0577] Synthesis of
2-[N-[3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)-
indol-2-yl]propion-amido]]-acetamide (20)
[0578] A suspension of 19 (0.30 g, 0.0006 mol), in ethanol (28 mL)
and 30% ammonium hydroxide (17 mL) was stirred at 60.degree. C. for
1.5 hours. After cooling the mixture was diluted with water and
extracted with ethyl acetate. Organic layer was separated, washed
with brine and dried. Removal of the solvent furnished 0.2 g (65%)
of pure title compound, mp>300.degree. C. (from ethanol).
[0579]
2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]-
]-acetamide (22), was prepared from
2-[N-[5-chloro-3-(3,5-dimethylphenylsu-
lfonyl)indol-2-carboxyamido]]-acetic acid ethyl ester (21)--the
crude product was passed through a silica gel column chromatography
(ethyl acetate), yield 95%, mp 265-267.degree. C. (aqueous
dimethylformamide).
Example 19
[0580] Synthesis of N-Cyclopropyl
2-[N-[5-Chloro-3-(3,5-dimethylphenylsulf-
onyl)-indol-2-carboxyamido]]acetamide (23)
[0581] A mixture of
2-[N-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-c-
arboxy-amido]]-acetic acid ethyl ester (21), ethanol (5 mL) and
cyclopropylamine (5 mL) was heated at 60.degree. C. for 6hours.
After concentration to a small volume, the residue was extracted
with ethyl acetate, washed with brine and dried. Removal of the
solvent furnished a crude product which was purified by passing
through a silica gel column chromatography (ethyl acetate) to give
0.14 g (69%) of title compound, mp 267-270.degree. C.
(ethanol).
[0582]
N-(1-Morpholin-4-yl)-2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)i-
ndol-2-carboxy-amido]]-acelamide (24), was prepared using
morpholine--after 48 hours. at 60.degree. C., yield 74%,
mp>300.degree. C. (ethanol).
Example 20
[0583] Synthesis of
5-(1H-Pyrrol-1-yl)-3-(3,5-dimethylphenylsulfonyl)indol-
e-2-carboxyamide (25b)
[0584] A solution of
5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carbox- yamide (5k)
(0.25 g, 0.0007 mol) in tetrahydrofuran (40 mL) and methanol (16
mL) was reduced under an atmospheric pressure of hydrogen in the
presence of PtO.sub.2 (50 mg) as a catalyst for 6 hours. Catalyst
was separated by filtration and the solvent evaporated to give
0.227 g (100%) of pure
5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide as a
brown oil. A solution of the last compound (0.227 g, 0.0007 mol),
2,5-dimethoxythetrahydrofuran (0.09 g, 0.0006 mol) in glacial
acetic acid (5 mL) was refluxed for 30 minutes. After evaporation
of the solvent the residue was triturated with ice water and
extracted with ethyl acetate. Organic layer was washed with brine
and dried. Removal of the solvent left the crude product which was
purified by passing through a silica gel column chromatography
(ethyl acetate as eluent) to give 0.15 g (57%) of title compound,
mp 270-272.degree. C. (from ethanol).
[0585] 5-(1H-Pyrrol-1-yl)-3-(phenylsulfonyl)indole-2-carboxyamide
(25a), was prepared from
5-nitro-3-(phenylsulfonyl)indole-2-carboxyamide, yield 71%, mp
250.degree. C. (ethanol).
Example 21
[0586] Synthesis of
5-(1-Hydroxyethyl)-3-(3,5-dimethylphenylsulfonyl)indol-
e-2-carboxyamide (26)
[0587] Sodium borohydride (0.03 g, 0.0008 mol) was added to a
mixture of
5-acetyl-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (51)
(0.30 g, 0.0008 mol) in tetrahydrofuran (8.5 mL) containing 0.1 mL
of water, then reaction was refluxed for 1 hour. After cooling,
water was added while stirring for a few minutes, then the mixture
was extracted with ethyl acetate, washed with brine and dried.
Removal of the solvent fumished 0.25 g (83%) of satisfactory pure
title compound, mp 260-260.degree. C. (ethanol).
Example 22
[0588] Preparation of 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)
indole-2-carboxyserinamide
[0589] 4,5-Difluoro-3-(3,5-dimethylphenylsulphonyl)indole
2-carboxylic acid (3.52g) and L-serinamide hydrochloride (2.77g)
were dissolved in anhydrous dimethylformamide (90ml). Triethylamine
(2.8ml) was added and the mixture stirred for 5min.
Benzotriazol-1-yloxy-tris(dimethylamino)pho- sphosphonium
hexafluorophosphate (BOP) (4.69g) was added and the orange mixture
was stirred overnight at room temperature. The reaction mixture was
diluted with water (350 ml) and the white solid precipitate
collected by filtration, washed with water and dried to afford the
title product (3.86g) as a white powder (97.9% pure by hplc).
[0590] In a similar manner
5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphony- l)
indole-2-carboxyserinamide was prepared from the
5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl)
indole-2-carboxylic acid. The product was obtained as a white
solid.
Example 23
[0591] Preparation of 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)
indole-2-(2-(1-pyrrolo)ethyl)carboxamide
[0592] 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole
2-carboxylic acid (4.22g) and 2-(l-pyrrolo)ethylamine (2.63g) were
dissolved in anhydrous dimethylformamide under an atmosphere of
nitrogen (100 ml) and triethylamine (3.2 ml) was added.
Benzotriazol-1-yloxy-tris(dimethylamino- )phosphosphonium
hexafluorophosphate (BOP)(5.63g) was added and the yellow solution
was stirred at room temperature for 18 hours. The reaction mixture
was diluted with water (350ml) and stirred for 30min.The white
precipitate was collected by filtration, washed with water and
dried to afford the title product (5.18g) as a white powder (97.1%
pure by hplc).
[0593] In a similar manner
5-chloro4-fluoro-3-(3,5-dimethylphenylsulphonyl- )
indole-2-(2-(1-pyrrolo)ethyl)carboxamide was prepared from the
5-chloro4-fluoro-3-(3,5-dimethylphenylsulphonyl)
indole-2-carboxylic acid. The product was obtained as a white
solid.
Example 24
[0594] Preparation of 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)
indole-2-(1-morpholinomethyl)carboxamide
[0595] 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole
2-carboxarnide (670 mg) was mixed with 1,4-dioxan (18 ml) and the
resultant white slurry was heated to reflux temperature. Morpholine
(0.8 ml) and 37% aqueous formaldehyde (0.7 ml) were added and the
mixture rapidly became homogeneous and was refluxed for 24 hours
then allowed to cool and poured into water (75 ml). The white
slurry was stirred at room temperature for 4 hrs and the white
solid was collected by filtration, washed with water and dried to
afford the title product (730 mg) as a white powder.
[0596] In similar fashion
5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl- )
indole-2-(1-morpholinomethyl)carboxamide was prepared from
5-chloro4-fluoro-3-(3,5-dimethylphenylsulphonyl)indole
2-carboxamide. The product was obtained as a white solid.
[0597] VII. Biological Activity Against Drug Resistant Strains of
HIV
[0598] In one embodiment the phenylindoles of the present invention
do not exhibit significant cross resistance with other
non-nucleosides reverse transcriptase inhibitors (NNRTI), in that
it displays an EC.sub.50 (in molar concentrations) in a mutant HIV
strain of less than approximately 50, 25, 10 or 1 micromolar
concentration. In a preferred embodiment, the non-nucleosides
reverse transcriptase inhibitors (NNRTI) displays an EC.sub.50 (in
molar concentrations) in a mutant HIV strain of less than
approximately 5, 2.5, 1 or 0.1 micromolar concentration. The degree
of cross-resistance against a drug resistant strain of HIV can
easily be measured by assessing the EC.sub.50 of the desired indole
in the target mutated i.e., drug resistant, virus.
[0599] Therefore, in another important embodiment of this
invention, a method for treating a patient with a cross-resistant
HIV is provided that includes administering an effective
HIV-treatment amount of a phenylindole or its prodrug or salt.
Example 25
[0600] influence of Phenyl Substitution and Amido Group on
Protein
[0601] Binding in Presence of Glycoprotein or Human Serum
Albumin
[0602] In order to understand how variations in the substituents on
the phenyl ring, and variations at the 2-position of the indole
ring, in this class of compounds influence protein binding, a
number of representative phenylindoles were tested in the presence
of glycoprotein or human serum albumin, and compared to the
prototype NNRTIs efavirenz and nevirapine. The structure of the
tested compound is given below, and the test results presented in
Tables 1 and 2. 30
1 TABLE 1 EC.sub.90 (Nx).sup.d Substituents .sub..alpha.-GP.sup.b
HSA.sup.c Cmpd. R R.sub.1 RPMI.sup.a 1 mg/mL 45 mg/mL 1* H NH.sub.2
0.001 0.002 (2x) 0.01 (10x) 2 3,5 diMe NH.sub.2 0.005 0.01 (2x) 0.2
(40x) 3 3,5 diMe NHNHC.sub.2H.sub.5OH 0.004 0.03 (7x) 0.27 (67x) 4
3,5 diMe NHCH.sub.2CONH.sub.2 0.06 0.2 (3x) 4.8 (80x) EFV 0.01 0.02
(2x) 0.13 (13x) .sup.aCompound concentration (.mu.M) required to
reduce the amount of p24 by 90% in HIV-1-infected MT-4 cells
incubated in RPMI 10% FCS. .sup.bCompound concentration (.mu.M)
required to reduce the amount of p24 by 90% in HIV-1-infected MT-4
cells incubated in RPMI 10% FCS in the presence of 1 mg/mL
.gamma.-acidic glycoprotein (.gamma.GP). .sup.cCompound
concentration (.mu.M) required to reduce the amount of p24 by 90%
in HIV-1-infected MT-4 cells incubated in RPMI 10% FCS in the
presence of 45 mg/mL human serum albumin (HSA). .sup.dProtein
binding shift.
[0603]
2TABLE 2 Compd. Substituents WT.sub.IIIB K103R Y181C K103N-Y181C
(CC.sub.50).sup.a R R.sub.1 EC.sub.50.sup.b EC.sub.90
EC.sub.90.sup.d EC.sub.50 EC.sub.50 4(30) 3,5 NHCH.sub.2CO-- 0.006
0.01 0.1 (10) 0.03 (5) 0.8 (133) diMe NH.sub.2 5 3,5 NHCH.sub.2CO--
0.01 0.03 1 (33) 0.05 (5) 2 (200) (.gtoreq.200) diMe NHNH.sub.2 6
3,5 CH.dbd.CHCO-- 0.06 0.03 >100 0.6 (10) >100 (1666)
(>200) diMe NH.sub.2 7 3,5 NHCH.sub.2CH.sub.2-- 0.01 0.07 7
(100) 0.7 (70) 10 (1000) (71) diMe (2NO.sub.2,5Me imidazole) NVP
0.37 >30 >30 (200) EFV 0.004 0.008 1.8 0.025 0.15 (38) (35)
(225) (6) .sup.aCompound concentration (.mu.M) required to reduce
the viability of mock-infected MT-4 cells by 50%, as determined by
the MTT method. .sup.bCompound concentration [.mu.M] required to a
achieve 50% protection of MT-4 cells from the HIV-1-induced
cytopathogenicity, as determined by the MTT method. .sup.cCompound
concentration [.mu.M] required to reduce the amount of p24 by 90%
in virus-infected C8166 cells. .sup.d(Nx) resistance shift.
Example 26
[0604] Influence of Substituents on the Indole Nucleus
[0605] Example 26 illustrates the influence of substituents at
positions 4, 5, 6, and 7 of the indole ring, in which position 2 of
the indole ring is maintained constant, and the substitution at the
3,5-position of the phenyl ring is either hydrogen or held constant
with a 3,5-dimethyl substitution. Table 3 presents the influence of
these variations on the ability of the compounds to protect cells
from HIV-1 induced pathogenecity. Comparisons are again made to
nevirapine and efavirenz. 31
3TABLE 3 Compd Substituents WT.sub.IIIB K103R Y181C K103N-Y181C
(CC.sub.50).sup.a R R.sub.1 EC.sub.50.sup.b EC.sub.90
EC.sub.90.sup.d EC.sub.50 EC.sub.50 8 (123) H 5,6 Cl 0.14 0.17 16
(94) 2.6 (18) >100 (>714) 9 (19) 3,5 Me 5,6 Cl 0.03 0.07 0.3
(4) 1.7 (57) >100 (>3333) 10 (>200) 3,5 5,7 Cl 1.6 1.2
>100 >100 >100 (>62.5) Me (>83) 11 (17) 3,5 4,5 F
0.02 0.7 (35) >200 Me 12 ( ) 3,5 5,6 F .ltoreq.0.003 0.07 2.6
(.gtoreq.866) Me (.gtoreq.23.3) 13 (>200) 3,5 5,7 F 0.01 0.02
>100 2 (200) >100 (>10000) Me (>5000) NVP (200) 0.37
>30 >30 EFV (35) 0.004 0.008 1.8 (225) 0.025 (6) 0.15 (38)
.sup.aCompound concentration (.mu.M) required to reduce the
viability of mock-infected MT-4 cells by 50%, as determined by the
MTT method. .sup.bCompound concentration [.mu.M] required to a
achieve 50% protection of MT-4 cells from the HIV-1-induced
cytopathogenicity, as determined by the MTT method. .sup.cCompound
concentration [.mu.M] required to reduce the amount of p24 by 90%
in virus-infected C8166 cells. .sup.d(Nx) resistance shift.
[0606] This invention has been described with reference to its
preferred embodiments. Variations and modifications of the
invention, will be obvious to those skilled in the art from the
foregoing detailed description of the invention. It is intended
that all of these variations and modifications be included within
the scope of this invention.
* * * * *