WO1999025327A2 - Small molecule intervention in hiv-1 replication - Google Patents
Small molecule intervention in hiv-1 replication Download PDFInfo
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- WO1999025327A2 WO1999025327A2 PCT/US1998/019358 US9819358W WO9925327A2 WO 1999025327 A2 WO1999025327 A2 WO 1999025327A2 US 9819358 W US9819358 W US 9819358W WO 9925327 A2 WO9925327 A2 WO 9925327A2
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- alkyl
- hydrogen
- aralkyl
- cycloalkyl
- nitro
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- IHOXDMBFBQKIBB-PRTVBDMESA-N COC([C@H](CC1)NC1C1CC2NCCCC2CC1)=O Chemical compound COC([C@H](CC1)NC1C1CC2NCCCC2CC1)=O IHOXDMBFBQKIBB-PRTVBDMESA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Definitions
- HIV-1 human immunodeficiency virus- 1
- AIDS acquired immune deficiency syndrome
- HIV-1 encodes two regulatory proteins, Tat and Rev, to control the viral gene expression by interacting with unique sequences in the viral RNA genome. Intervention of these protein-RNA interactions interferes with the transcriptional process of the virus in the host and subsequently, the synthesis of both the RNA genome and viral proteins which are essential for HIV-1 replication.
- Tat is an HIV-1 transcriptional trans-activators that acts upon a RNA target sequence in the HIV-1 long terminal repeat promoter region to induce high levels of transcription. Tat specifically recognizes TAR RNA with an arginine residue in its RNA binding domain.
- the RNA target, transactivation responsive element (TAR) possesses unique structural and functional features that are crucial for the viral replication.
- the unique stem-loop structure of TAR contains a highly conserved six-nucleotide loop and a three-nucleotide bulge flanked by two double- stranded stems. While the 5'-uridine residue in the bulge serves as the recognition code for Tat, the hairpin loop provides a homing site for other cellular protein factors. Both of these domains and the associated protein-RNA interactions are important for the formation of processive complexes for HIV-1 transcription. It bulge residues of TAR seriously impairs the transcription, and subsequently, the replication of HIV. HIV-1 Tat-TAR interaction, therefore, represents a potential target for therapeutic intervention.
- Monoclonal antibodies that recognize the Tat sequences have been shown to neutralize the functions of Tat and to block the HIV-1 transcription.
- Transdominant Tat proteins or decoy molecules of TAR RNA expressed in situ have also been demonstrated to possess anti -viral activities in HIV-1 infected cells.
- Nucleic acid molecules, such as anti-sense and ribozyme oligonucleotides, with sequences complementary to that of TAR can also efficiently suppress Tat-TAR mediated HIV-1 transcription.
- derivatives of Tat either Tat- derived peptides or peptoids, have also been shown to interfere with HIV replication in virally infected cell lines.
- aminoglycoside antibiotics represent the only examples of small molecule Tat-TAR inhibitors.
- Tat-TAR inhibitors include analogs of 2,3-quinoxalinediones, 1 ,4-diaminoquinazolines, and Indeno[7,l-fg]quinoxaline-
- the compounds of the present invention show very favorable and valuable pharmaceutical characteristics, especially with regard to the therapeutic and/or diagnostic treatment of retro viral infections, particularly AIDS.
- the compounds of the invention are structures with a low molecular weight which are effective in the treatment of HIV infection, especially HIV-1 infection.
- the compounds of the invention represent a class of molecules that have the ability to interfere with the Tat-TAR formations, with the following advantageous characteristics:
- the compounds of the invention are believed to act through a mechanism that provides them with an incomparable therapeutic potential to complement or replace existing, specific or less specific anti-viral treatments, with particular value for the treatment against variants of HIV, especially such variants that have become resistant to other kinds of treatment.
- the compounds of the invention have use, in particular pharmacological use. Surprisingly, it has been found that the compound of the invention are able to inhibit the propagation of HIV, especially HIV-1, in infected human lymphocytes and show a particularly potent, specific inhibition on the binding of the Tat protein to TAR, mainly by binding to TAR. They thus represent a totally new class of inhibitors and therapeutics.
- the invention relates the treatment or prevention of (prophylaxis against) a disease that responds to inhibition of retroviral Tat-TAR interaction retroviral protease; especially inhibition of HIV, more preferably HIV-1, Tat-TAR interaction; for example, a retroviral infection such as HIV infection, more especially AIDS, comprising an amount of a compound of the invention or a pharmaceutically acceptable salt thereof, effective for the inhibition of the Tat-TAR interaction, especially for the treatment of HIV infection, together with at least one pharmaceutically acceptable carrier.
- the instant invention provides compounds useful in the treatment and/or prevention of HIV- 1 infection.
- the compounds are useful in inhibiting the Tat-TAR interaction. Advantages of the methods are selectivity, there are no cellular counterparts; regulation of both chronic and acute infection; and the fact that the development of resistance is unlikely.
- the compounds of the invention can be used alone in a monotherapy or the compounds used in the invention can be administered in combination with other agents useful in combating HIV-1 infections. Such agents include: reverse transcriptase inhibitors, e.g., zidovudine (AZT), and protease inhibitors, e.g., saquinavir (SQV).
- the invention includes a method of treating HIV-1 infection comprising administering to a mammal in need of said treatment a compound of formula
- A is a saturated or unsaturated ring; R is -H, -NH 2 , or -NHCH ; and R 1 is -NH 2 ,
- the invention includes a method of inhibiting the TatTAR interaction comprising administering to a mammal in need of said treatment a compound of formula
- A is a saturated or unsaturated ring
- R is -H, -NH , or -NHCH3;
- R 1 is -NH 2 ,
- the invention includes a method of treating HIV-1 infection and a method of inhibiting the Tat-TAR interaction comprising administering:
- the invention also includes a method of administering a quinoxalinedione of formula
- Z is an alicyclic fused ring having 5 to 7 carbon atoms
- R! is hydrogen, an alkyl or an arylalkyl
- X and Y are independently hydrogen, halogen, nitro, cyano, COOH, CONR ⁇ R J , SONR2R3 wherein R ⁇ and R- are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or aralkyl; and
- A is 0, NR 4 , CH 2 NR 4 , CN, tetrazole or CO wherein R 4 is hydrogen, alkyl having
- B when A is CO then B is hydroxy, alkoxy, aralkoxy, alkyl having 1 to 6 carbon atoms, aralkyl, NR?R° wherein R' is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or NR is a cyclic amine, and
- R8 is alkyl, aryl, or aralkyl. Especially preferred are:
- the invention also includes a method of administering a quinoxalinedione of formula
- R is hydrogen or hydroxy; R! is hydrogen, alkyl, arylalkyl, (CH 2 ) n OH, or
- (CH 2 ) n NR?R 8 ; R5 and R" are each independently hydrogen, halogen, NO 2 ,
- NHCOR 1 1 wherein R 7 and R 8 are each independently hydrogen or alkyl or together R 7 and R 8 form a ring of from three to seven atoms, R9 is hydrogen or alkyl,
- RIO is hydrogen or alkyl
- A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b, and formed by the following bivalent radicals: a-NR 12 -CHR 13 -CHR 14 -b, a-CHR 13 -CHR 14 -NR 1 -b, a-CHRl3_NRl2-CHR 1 -b, a-CHR 14 -CH 2 -NR 1 -CHR 13 -b, a-CHRl3_NRl2-CH 2 -CHR 14 -b, a-CH 2 -CH -CHR 13 -NR 12 -b, a-NR 12 -CHR 13 -CH 2 -CH -b, a-CH 2 -CH -NR!
- R 12 is hydrogen, CH 2 CH 2 OH, or alkyl
- R 13 and R 14 are each independently hydrogen, CN, CONH 2 , CH NH , CH 2 OH, alkyl, arylalkyl, alkenyl, or CO R ⁇ 5 wherein R 5 is hydrogen or alkyl.
- the invention also includes administering a compound of Formula I
- R is a secondary or tertiary amine
- R ⁇ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl
- R 2 is hydrogen, hydroxy, or amino
- R3 and R4 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, nitro, cyano, SO 2 CF 3 ,
- Rg is hydroxy, alkoxy, , alkyl, haloalkyl, aryl, aralkyl, and R7 and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, or aryl;
- R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, nitro, cyano,
- R5 may be at the a-position and at the b-position on the ring; and R1 1 and R1 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
- Rl4 wherein q is an integer of from 0 to 3 and R ⁇ 3 and R ⁇ 4 are each independently selected from hydrogen, alkyl, aralkyl, cycloalkyl, and heteroalkyl and R15 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and
- R15 and R17 are each independently selected from hydrogen, alkyl, and aryl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl,
- p and p' are each independently an integer selected from 0 and 1 and wherein in the second ring 1 or 2 carbon atoms can be replaced by 1 or 2 heteroatoms selected from N, O, or S.
- the invention also includes administering a compound of Formula I
- R is an amino acid derivative
- n is an integer of from 1 to 4.
- R ⁇ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl;
- R 2 is hydrogen or hydroxy;
- R 3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, halogen, haloalkyl, nitro, cyano, SO 2 CF 3 , C(O)Rg wherein Rg is hydroxy, alkoxy, / R 7
- NHCORg wherein m is an integer of from 0 to 4 and R7 and R 8 are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, heteroaralkyl, aralkyl, heteroaryl, nitro, cyano,
- NHCORg wherein m is as defined above and R7 and R 8 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl; and R5 may be at the b-position and R-(CH 2 ) n - at the a-position on the ring.
- the invention also includes administering a compound of Formula I
- R is an amide
- n is an integer of from 1 to 4.
- R ⁇ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl;
- R 2 is hydrogen, hydroxy, or amino
- R 3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, halogen, haloalkyl, nitro, cyano, SO 2 CF 3 , CH 2 SO 2 R6, (CH 2 ) m CO 2 R 6 , (CH 2 ) m CONR 7 R 8 , (CH 2 ) m SO 2 NR 7 R 8 , or
- NHCOR fj wherein m is an integer of from 0 to 4, and Rg, R7, and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R5 is hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, SO CF 3 , (CH 2 ) m CO 2 R9,
- Preferred is a method wherein indeno[7,l-fg]quinoxaline-8,9-diol is administered.
- Tat-TAR inhibitors thus identified are then submitted to a secondary cell-based assay in which the expression of a reporter gene is driven by Tat-TAR interaction.
- the construct of the reporter system includes a HIV-1 LTR domain which contains the TAR sequence and a lacZ reporter gene.
- production of the reporter proteins indicates the extent of the Tat-TAR interaction.
- the cellular activity of Tat-TAR inhibitors can then be determined by measuring the ⁇ -galactosidase expression in the presence of these inhibitors compared with that determined in the absence of any inhibitors.
- Tat-TAR inhibitors are investigated in a similar cellular assay in which reporter gene expression is TAR-independent. The only difference is that the expression of the reporter gene is driven by a cytomegalovirus immediate early promoter region which does not include the TAR sequence. Compounds active only in the TAR-dependent Tat-transactivation assays are considered as selective Tat-TAR inhibitors. Compounds that inhibit both TAR- dependent or TAR-independent reporter gene expression may interfere with a transcriptional process that is not specific to HIV-1. Small molecules that are active in both Tat-TAR inhibition and Tat- transactivated cellular assays are further examined in HIV-1 infection assays.
- Tat-TAR inhibitors To evaluate the anti -viral activities of the Tat-TAR inhibitors, cell-lines that were infected by HIV-1 were used. Laboratories adopted cell-lines or primary cell-lines obtained from patients are either acutely or chronically infected with various HIV-1 strains.
- the anti-viral activities of the Tat-TAR inhibitors can be determined by measuring the production of viral proteins such as reverse transcriptase and p24 coat proteins or the synthesis of viral RNA. Tat-TAR inhibitors that exhibit antiviral activities represent drug candidates that interfere with HIV-1 replication with a unique mechanism.
- Table 1 shows chemical structures and IC50 values of small molecule which are Tat-TAR inhibitors. IC50 values were obtained using gel mobility shift assays as described in Mei H.-Y., et al., Biiorg. & Med. Chem.. 1997;5:1173.
- Tat 40 contains the first 40 amino acids of HIV- 1 Tat protein.
- TAR 3 1 5'-GGCCAGAUCUGAGCCUGGGAGCUCUCUGGCC-3', contains residues 18 to 44 of HI-1 mRNA.
- the binding characteristics of Tat4o and TAR 3 j have been found to resemble the interaction of the full length Tat protein and TAR RNA.
- Anti-HIV-1 assays (IC50/TC50) 17 ⁇ M/>100 ⁇ M 3 ⁇ M/19 ⁇ M
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Abstract
The instant invention is a series of small molecules which are inhibitors of HIV-1 Tat-TAR interaction. The compounds are useful in the treatment of HIV-1 infections.
Description
SMALL MOLECULE INTERVENTION IN HIV-1 REPLICATION
BACKGROUND OF THE INVENTION
The infection of human immunodeficiency virus- 1 (HIV-1) induces a variety of pathogenic effects to the hosts. Following primary infection with HIV-1, new rounds of viral replication proceed with a rate of several millions of copies/day to seriously challenge the host immune system. After a clinical latency, the rapid viral replication in lymphoids or other organs exceeds the capacity of the host immune system and results in the progression of clinical symptoms of acquired immune deficiency syndrome (AIDS). There are several unique features of this infectious virus. HIV-1 is characterized as retro viruses by their ability to reverse transcribe a single-stranded RNA genome into a double-stranded DNA intermediate that is then integrated into the host cell chromosome. The viral gene expression, either at the transcription or post-transcription level, involves RNA- sequence-mediated processes. HIV-1 encodes two regulatory proteins, Tat and Rev, to control the viral gene expression by interacting with unique sequences in the viral RNA genome. Intervention of these protein-RNA interactions interferes with the transcriptional process of the virus in the host and subsequently, the synthesis of both the RNA genome and viral proteins which are essential for HIV-1 replication. Tat is an HIV-1 transcriptional trans-activators that acts upon a RNA target sequence in the HIV-1 long terminal repeat promoter region to induce high levels of transcription. Tat specifically recognizes TAR RNA with an arginine residue in its RNA binding domain. The RNA target, transactivation responsive element (TAR), possesses unique structural and functional features that are crucial for the viral replication. The unique stem-loop structure of TAR contains a highly conserved six-nucleotide loop and a three-nucleotide bulge flanked by two double- stranded stems. While the 5'-uridine residue in the bulge serves as the recognition code for Tat, the hairpin loop provides a homing site for other cellular protein factors. Both of these domains and the associated protein-RNA interactions are important for the formation of processive complexes for HIV-1 transcription. It
bulge residues of TAR seriously impairs the transcription, and subsequently, the replication of HIV. HIV-1 Tat-TAR interaction, therefore, represents a potential target for therapeutic intervention.
There has been significant amount of anti-HIV-1 studies focusing on transcription competition with macromolecules such as proteins and nucleic acids.
Monoclonal antibodies that recognize the Tat sequences have been shown to neutralize the functions of Tat and to block the HIV-1 transcription. Transdominant Tat proteins or decoy molecules of TAR RNA expressed in situ have also been demonstrated to possess anti -viral activities in HIV-1 infected cells. Nucleic acid molecules, such as anti-sense and ribozyme oligonucleotides, with sequences complementary to that of TAR can also efficiently suppress Tat-TAR mediated HIV-1 transcription. Recently, derivatives of Tat, either Tat- derived peptides or peptoids, have also been shown to interfere with HIV replication in virally infected cell lines. There has been, however, few reports for small molecule intervention in HIV-1 following a mechanism of Tat-TAR inhibition. To the best of our knowledge, aminoglycoside antibiotics represent the only examples of small molecule Tat-TAR inhibitors.
We have now found small organic compounds capable of blocking Tat from binding to TAR. These Tat-TAR inhibitors include analogs of 2,3-quinoxalinediones, 1 ,4-diaminoquinazolines, and Indeno[7,l-fg]quinoxaline-
8,9-diol. All of these compounds are active in the Tat-TAR inhibition studies. The molecular mechanism of these molecules have been demonstrated using nuclease or chemical protection assays. The target of action and the location of interaction for these Tat-TAR inhibitors have been determined. This invention relates to the use of these Tat-TAR inhibitors as anti-HIV-1 agents for treating clinical symptoms such as AIDS.
SUMMARY OF THE INVENTION
Surprisingly, it has been found that the compounds of the present invention show very favorable and valuable pharmaceutical characteristics, especially with
regard to the therapeutic and/or diagnostic treatment of retro viral infections, particularly AIDS.
More specifically, the compounds of the invention are structures with a low molecular weight which are effective in the treatment of HIV infection, especially HIV-1 infection. The compounds of the invention represent a class of molecules that have the ability to interfere with the Tat-TAR formations, with the following advantageous characteristics:
• protease resistance and useful stability in biological fluids;
• low molecular weight; • in vivo activity in two different cellular systems at non-cytotoxic concentrations (epithelioid cells co-cultured with constitutively expressing lymphoid cells, as well as human peripheral lymphocytes following an HIV-1 adsorption phase); and/or
• the ability to permeate into cells, which can be demonstrated by a Fusion Induced Gene Stimulation Assay that excludes cell surface effects as the underlying mechanism of action. The compounds of the invention are believed to act through a mechanism that provides them with an incomparable therapeutic potential to complement or replace existing, specific or less specific anti-viral treatments, with particular value for the treatment against variants of HIV, especially such variants that have become resistant to other kinds of treatment.
The compounds of the invention have use, in particular pharmacological use. Surprisingly, it has been found that the compound of the invention are able to inhibit the propagation of HIV, especially HIV-1, in infected human lymphocytes and show a particularly potent, specific inhibition on the binding of the Tat protein to TAR, mainly by binding to TAR. They thus represent a totally new class of inhibitors and therapeutics.
The invention relates the treatment or prevention of (prophylaxis against) a disease that responds to inhibition of retroviral Tat-TAR interaction retroviral protease; especially inhibition of HIV, more preferably HIV-1, Tat-TAR interaction; for example, a retroviral infection such as HIV infection, more especially AIDS, comprising an amount of a compound of the invention or a
pharmaceutically acceptable salt thereof, effective for the inhibition of the Tat-TAR interaction, especially for the treatment of HIV infection, together with at least one pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention provides compounds useful in the treatment and/or prevention of HIV- 1 infection. The compounds are useful in inhibiting the Tat-TAR interaction. Advantages of the methods are selectivity, there are no cellular counterparts; regulation of both chronic and acute infection; and the fact that the development of resistance is unlikely. The compounds of the invention can be used alone in a monotherapy or the compounds used in the invention can be administered in combination with other agents useful in combating HIV-1 infections. Such agents include: reverse transcriptase inhibitors, e.g., zidovudine (AZT), and protease inhibitors, e.g., saquinavir (SQV).
Some of the compound of the instant invention are prepared according to the chemical syntheses in United States Serial Numbers 08/534,526 filed
October 23, 1995; 60/019,377 filed June 5, 1996; 08/443,507 filed May 18, 1995; and United States Patent Numbers 5,654,303 and 5,614,508. These applications and patents are hereby incorporated by reference.
The invention includes a method of treating HIV-1 infection comprising administering to a mammal in need of said treatment a compound of formula
or a pharmaceutically acceptable salt thereof wherein
A is a saturated or unsaturated ring; R is -H, -NH2, or -NHCH ; and
R1 is -NH2,
-NH-C-NH2,
O
The invention includes a method of inhibiting the TatTAR interaction comprising administering to a mammal in need of said treatment a compound of formula
or a pharmaceutically acceptable salt thereof wherein
A is a saturated or unsaturated ring;
R is -H, -NH , or -NHCH3; and
R1 is -NH2,
-NH-C-NH2,
II O
-N ^ ^naphthyl, or
N6,N6 -(1 ,4-Phenylenedimethyl)bis-2,4,6-quinazolinetriamine;
6,6'-[l,3-Propanediylbis(oxy)]bis-2,4-quinazolinediamine;
Quinazoline-2,4,5,6-tetraamine;
5,6,7,8-Tetrahydro-quinazoline-2,4,6-triamine;
2,4,6-Quinazolinetriamine;
N5-Methyl-quinazoline-2,4,5,6-tetraamine;
2,4,6-Quinazolinetriamine, Ng-( 1 -phenylethylidene);
(2,4-Diamino-quinazolin-6-yl)-urea; and N6-Naphthalen-2-ylmethylene-quinazoline-2,4,6-triamine.
The invention also includes a method of administering a quinoxalinedione of formula
or a pharmaceutically acceptable salt thereof, wherein Z is an alicyclic fused ring having 5 to 7 carbon atoms;
R! is hydrogen, an alkyl or an arylalkyl;
X and Y are independently hydrogen, halogen, nitro, cyano, COOH, CONR^RJ, SONR2R3 wherein R^ and R- are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or aralkyl; and
A is 0, NR4, CH2NR4, CN, tetrazole or CO wherein R4 is hydrogen, alkyl having
1 to 6 carbon atoms or aralkyl, wherein
(i) when A is 0 or NR4 then B is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkylheterocyclic, alkylcarbonyl, aralkylcarbonyl,
alkylheterocyclic-carbonyl, CONR^R6 wherein R^ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or NR^ is a cyclic amine, and R6 is alkyl, aryl or aralkyl, or when A is NR4 then B is a common amino acid moiety joined by an amide bond, provided that when Z is a fused cyclohexyl ring and R4 is hydrogen then B is not hydrogen; (ii) when A is CN then B is not present and Z is not a fused cyclohexyl ring; (iii) when A is tetrazole then B is hydrogen or alkyl having 1 to 6 carbon atoms; and
(iv) when A is CO then B is hydroxy, alkoxy, aralkoxy, alkyl having 1 to 6 carbon atoms, aralkyl, NR?R° wherein R' is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or NR is a cyclic amine, and
R8 is alkyl, aryl, or aralkyl. Especially preferred are:
6-Nitro-8-(lH-tetrazol-5-yl)-4,7,8,9-tetrahydro-lH- cyclopenta[fj quinoxaline-2 ,3 -dione ;
8-(lH-Tetrazol-5-yl)-4,7,8,9-tetrahydro-lH-cyclopenta[f]quinoxaline-2,3- dione; 8-(lH-Tetrazol-5-ylmethyl)-4,7,8,9-tetrahydro-lH- cyclopenta[fJquinoxaline-2,3-dione;
6-Nitro-8-(lH-tetrazol-5-ylmethyl)-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione;
6-Nitro-8-[2-(lH-tetrazol-5-yl)-ethyl]-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione; or
8-[2-(lH-Tetrazol-5-yl)-ethyl]-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione.
The invention also includes a method of administering a quinoxalinedione of formula
or a pharmaceutically acceptable salt thereof wherein
R is hydrogen or hydroxy; R! is hydrogen, alkyl, arylalkyl, (CH2)nOH, or
(CH2)nNR?R8; R5 and R" are each independently hydrogen, halogen, NO2,
CN, CF3,
SO NR7R8>
PO3R9R10, alkyl, alkenyl, alkynyl,
(CH2)nCONR7R8, (CH2)nCO2RlO,
NHCOR1 1, wherein R7 and R8 are each independently hydrogen or alkyl or together R7 and R8 form a ring of from three to seven atoms,
R9 is hydrogen or alkyl,
RIO is hydrogen or alkyl,
R! MS hydrogen or alkyl, and n is an integer of from zero to four; A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b, and formed by the following bivalent radicals: a-NR12-CHR13-CHR14-b, a-CHR13-CHR14-NR1 -b, a-CHRl3_NRl2-CHR1 -b, a-CHR14-CH2-NR1 -CHR13-b, a-CHRl3_NRl2-CH2-CHR14-b, a-CH2-CH -CHR13-NR12-b, a-NR12-CHR13-CH2-CH -b, a-CH2-CH -NR! 2-CH2-CH2-b, a-CH2-CH2-CH -NR12-CH2-b, a-CH^NR1 -CH-CH-CH-b, a-CH -CH2-CH -CH2-NR12-b, a-NR12-CH2-CH2-CH2-CH2-b, wherein R12 is hydrogen, CH2CH2OH, or alkyl, and R13 and R14 are each independently hydrogen, CN, CONH2, CH NH , CH2OH, alkyl, arylalkyl, alkenyl, or CO R^5 wherein R 5 is hydrogen or alkyl.
Especially preferred are:
5-Nitro-l, 4,7,8,9,10-hexahydro-pyrido[2,3-f]quinoxaline-2,3-dione; 2-Methyl-2,3 ,6,9-tetrahydro- 1 H-2,6,9-triaza-cyclopenta[a]naphthalene-
7,8-dione;
4-(6-Nitro-2,3-dioxo-l,2,3,4,7,10-hexahydro-8H-pyrido[3,4-f]quinoxalin- 9-yl)-butyronitrile;
2-(6-Nitro-2,3-dioxo-l,2,3,4,7,10-hexahydro-8H-pyrido[3,4-f]quinoxalin- 9-yl)-N-phenethyl-acetamide;
Indeno[7,l-fg]quinoxaline-8,9-diol; and
6-Nitro-8-(lH-tetrazol-5-yl)-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione.
The invention also includes administering a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein R is a secondary or tertiary amine; R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl;
R2 is hydrogen, hydroxy, or amino;
R3 and R4 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, nitro, cyano,
SO2CF3,
C(O)R6,
CH2SO2R6,
(CH2)mCO2R9 wherein R9 is hydrogen, alkyl, aralkyl, or cycloalkyl,
(CH2)mCONR7R8,
(CH2)mSO2NR7R8, or
NHCORg wherein m is an integer of from
0 to 4, Rg is hydroxy, alkoxy, ,
alkyl, haloalkyl, aryl, aralkyl, and R7 and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, or aryl;
R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, nitro, cyano,
SO2CF3,
C(O)R6, (CH2)mCO2R9,
(CH2)mCONR7R8, SONR7R8, or
NHCORg wherein m, R7, and R8 are as defined above;
R5 may be at the a-position and at
the b-position on the ring; and R1 1 and R12 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
Rl3 θ
I II
-( C)q-C-R15
I Rl4 wherein q is an integer of from 0 to 3 and Rι 3 and Rι 4 are each independently selected from hydrogen, alkyl, aralkyl, cycloalkyl, and heteroalkyl and R15 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and
NR1 gRi 7 wherein R15 and R17 are each independently selected from hydrogen, alkyl, and aryl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl,
r^ \ .alkyl
— N X
\ / / alkyl
wherein p and p' are each independently an integer selected from 0 and 1 and wherein in the second ring 1 or 2 carbon atoms can be replaced by 1 or 2 heteroatoms selected from N, O, or S.
The invention also includes administering a compound of Formula I
R.
R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl; R2 is hydrogen or hydroxy;
R3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, halogen,
haloalkyl, nitro, cyano, SO2CF3, C(O)Rg wherein Rg is hydroxy, alkoxy, /R7
^ \ , alkyl, haloalkyl, aryl, aralkyl, R8
CH2SO2R6,
(CH2)mCO2R9 wherein R9 is hydrogen, alkyl, aralkyl, or cycloalkyl, (CH2)mCONR7R8, (CH2)mSO NR7R8, or
NHCORg wherein m is an integer of from 0 to 4 and R7 and R8 are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, heteroaralkyl, aralkyl, heteroaryl, nitro, cyano,
SO2CF3,
C(O)R6, (CH2)mCO2R9,
(CH2)mCONR7R8,
SONR7R8, or
NHCORg wherein m is as defined above and R7 and R8 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl; and R5 may be at the b-position and R-(CH2)n- at the a-position on the ring.
The invention also includes administering a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein R is an amide; n is an integer of from 1 to 4;
R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl;
R2 is hydrogen, hydroxy, or amino;
R3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, halogen, haloalkyl, nitro, cyano, SO2CF3, CH2SO2R6, (CH2)mCO2R6, (CH2)mCONR7R8, (CH2)mSO2NR7R8, or
NHCORfj wherein m is an integer of from 0 to 4, and Rg, R7, and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R5 is hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, SO CF3, (CH2)mCO2R9,
(CH2)mCONR9R10, SONR9R10, or NHCOR9; m is an integer of from 0 to 4;
R9 and R10 are each independently hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; and R5 may be at the a-position and R-(CH2)n- at the b-position on the ring.
Preferred is a method wherein indeno[7,l-fg]quinoxaline-8,9-diol is administered.
METHODOLOGIES USED FOR IDENTIFYING HIV-1 TAT-TAR INHIBITORS
We have previously reported a drug discovery approach which was designed to identify small organic molecules that intervene IN HIV-1 replication by blocking the specific interaction between Tat protein and TAR RNA (Mei, et al., Discovery of selective, small molecule inhibitors of RNA Complexes- 1. The Tat Protein/TAR RNA Complexes for HIV-1 Transcription. Bioorganic & Medicinal Chemistry, 1997;6:1178-1184. The first step of this approach utilizes methodologies such as gel mobility shift, membrane filtration, and scintillation proximity assays to identify inhibitors for HIV-1 Tat-TAR interaction. These inhibition assays are amenable to automation and are capable of screening large number of compounds with a high throughput. Tat-TAR inhibitors thus identified are then submitted to a secondary cell-based assay in which the expression of a reporter gene is driven by Tat-TAR interaction. The construct of the reporter system includes a HIV-1 LTR domain which contains the TAR sequence and a lacZ reporter gene. When Tat is expressed in the same cellular environment, production of the reporter proteins (β-galactosidase) indicates the extent of the Tat-TAR interaction. The cellular activity of Tat-TAR inhibitors can then be determined by measuring the β-galactosidase expression in the presence of these inhibitors compared with that determined in the absence of any inhibitors.
Furthermore, Tat-TAR inhibitors are investigated in a similar cellular assay in which reporter gene expression is TAR-independent. The only difference is that the expression of the reporter gene is driven by a cytomegalovirus immediate early promoter region which does not include the TAR sequence.
Compounds active only in the TAR-dependent Tat-transactivation assays are considered as selective Tat-TAR inhibitors. Compounds that inhibit both TAR- dependent or TAR-independent reporter gene expression may interfere with a transcriptional process that is not specific to HIV-1. Small molecules that are active in both Tat-TAR inhibition and Tat- transactivated cellular assays are further examined in HIV-1 infection assays. To evaluate the anti -viral activities of the Tat-TAR inhibitors, cell-lines that were infected by HIV-1 were used. Laboratories adopted cell-lines or primary cell-lines obtained from patients are either acutely or chronically infected with various HIV-1 strains. The anti-viral activities of the Tat-TAR inhibitors can be determined by measuring the production of viral proteins such as reverse transcriptase and p24 coat proteins or the synthesis of viral RNA. Tat-TAR inhibitors that exhibit antiviral activities represent drug candidates that interfere with HIV-1 replication with a unique mechanism.
Table 1 below shows chemical structures and IC50 values of small molecule which are Tat-TAR inhibitors. IC50 values were obtained using gel mobility shift assays as described in Mei H.-Y., et al., Biiorg. & Med. Chem.. 1997;5:1173.
IC50 values were obtained as follows: A preformed Tat4()/TAR3ι complex (=100 pM 32P-TAR3 \ and 0.5 nM Tat4ø) and was challenged with varying concentrations (0.1, 1, 10, 100 μM) of drugs. All inhibition studies were performed in a buffer solution containing 10 mM Tris-HCI (pH 7.5), 70 mM NaCI, 0.2 mM EDTA, 0.01% Nonidet P-40, 5% glycerol. The mixtures were equilibrated for 2 to 20 minutes before submitted to gel electrophoresis. Samples were loaded on a 20% w/v acrylamide and 75 : 1 acrylamide/bis(acrylamide) and electrophoresed in a running buffer containing 45 mM Tris-borate/0.5 mM EDTA for 2 hours at 25 V/cm constant voltage.
Tat40, YGRKKRRQRRRPPQGSQTHQVSLSKQPTSQPRGDPTGPKE, contains the first 40 amino acids of HIV- 1 Tat protein. TAR31 , 5'-GGCCAGAUCUGAGCCUGGGAGCUCUCUGGCC-3', contains residues
18 to 44 of HI-1 mRNA. The binding characteristics of Tat4o and TAR3j have been found to resemble the interaction of the full length Tat protein and TAR RNA.
Tar/TAR Inhibition (IC50) lμM 0.5 μM 10 μM 50 μM
Anti-Tat-Transactivation lμM/>100μM >100μM 15μM/>100μM 2μM/15μM
(IC50/TC50)
Anti-HIV-1 assays: (IC50/TC50) 17μM/>100μM 3μM/19μM
CEM Cells
OM 10.1 Cells 20μM/>100μM 4 μM/40 μM 50μM/>100μM I Ul Cells 13μM/>100μM 62μM/>100μM 17μM/40μM 51 μM/>100μM
0.1 - 1 μM 1-lOμM 10-lOOμM >100μM
H COOH CH2COOH NH2
NHCOPh NH(CH3) N(CH3)2
NHCOCH2N(CH CH OH)
N(CH.)CO NHC(S)NH— ^ /
N(CH3)COPh
NHCO K NHCO s-
1 -10μM 10-lQOμM >100μM
CH2(i-Bu) H CH3
CH2CONH(CH2) Ph CH(CH3)(C2H5) C2H5
CH2COOCH3 CH2CONH(CH )3CO2CH3 CH2Ph(CF3)
(CH2)3CN C(S)NHPh COCH Ph coxfl COCH2N(C2H5)2
1 t t
CO(CH2)2N(C2H5)2 I
CO
O' co¬
CO y \ -OCH
1 -lOμM 10-lOOμM >100μM
NHCOCH3
NHCONHPh N(CH3)COPh
1-lOμM 10-lOOμM >100μM
NH2 OH N(CH3)2
N
NH(CH2)2CH3 N(CH3)CO(CH2)2CON(CH3)2
Claims
1. A method of treating HIV-1 infection comprising administering to a mammal in need of said treatment a quinoxalinedione or a diaminoquinazoline or a pharmaceutically acceptable salt thereof to said mammal.
2. A method of inhibiting the Tat-TAR interaction comprising administering to a mammal in need of said treatment a quinoxalinedione or a diaminoquinazoline or a pharmaceutically acceptable salt thereof to said mammal.
3. A method of treating HIV- 1 infection comprising administering to a mammal in need of said treatment a compound of formula
or a pharmaceutically acceptable salt thereof wherein A is a saturated or unsaturated ring;
R is -H, -NH , or -NHCH3; and
R1 is -NH2,
-NH-C-NH2,
O ΓÇö N naphthyl, or
^^
4. A method of inhibiting the Tat-TAR interaction comprising administering to a mammal in need of said treatment a compound of formula
or a pharmaceutically acceptable salt thereof wherein
A is a saturated or unsaturated ring;
R is -H, -NH2, or -NHCH3; and
R1 is -NH ,
-NH-C-NH2,
O
ΓÇö N ^ ^naphthyl, or
5. A method of treating HIV-1 infection comprising administering to a mammal in need of said treatment the compound N",N" -(1,4- phenylenedimethyl)bis-2,4,6-quinazolinetriamine.
6. A method of inhibiting the Tat-TAR interaction comprising administering to a mammal in need of said treatment the compound N",N" -(1,4- phenylenedimethyl)bis-2,4,6-quinazolinetriamine.
7. A method for treating HIV-1 infection comprising administering to a mammal in need of said treatment the compound 6,6'-[ 1 ,3- propanediylbis(oxy)]bis-2,4-quinazolinediamine.
8. A method inhibiting the Tat-TAR interaction comprising administering to a mammal in need of said treatment the compound 6,6'-[l,3- propanediylbis(oxy)]bis-2,4-quinazolinediamine.
9. A method according to Claim 3 or 4 wherein the compound administered is selected from
Quinazoline-2,4,5,6-tetraamine;
5,6,7,8-Tetrahydro-quinazoline-2,4,6-triamine;
2,4,6-Quinazolinetriamine; N5-Methyl-quinazoline-2,4,5,6-tetraamine;
2,4,6-Quinazolinetriamine, N_5-(l -phenylethylidene);
(2,4-Diamino-quinazolin-6-yl)-urea; and N6-Naphthalen-2-ylmethylene-quinazoline-2,4,6-tri amine.
10. A method according to Claim 1 wherein the quinoxalinedione administered is selected from one or more compounds of formula
or a pharmaceutically acceptable salt thereof, wherein Z is an alicyclic fused ring having 5 to 7 carbon atoms;
Rl is hydrogen, an alkyl or an arylalkyl;
X and Y are independently hydrogen, halogen, nitro, cyano, COOH, CONR2R3, SONR R3 wherein R2 and R3 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl or aralkyl; and
A is 0, NR4, CH2NR4, CN, tetrazole or CO wherein R4 is hydrogen, alkyl having 1 to 6 carbon atoms or aralkyl, wherein (i) when A is 0 or NR4 then B is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkylheterocyclic, alkylcarbonyl, aralkylcarbonyl, alkylheterocyclic-carbonyl, CONR^Ro wherein R^ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or NR^ is a cyclic amine, and R" is alkyl, aryl or aralkyl, or when A is NR4 then B is a common amino acid moiety joined by an amide bond, provided that when Z is a fused cyclohexyl ring and R4 is hydrogen then B is not hydrogen; (ii) when A is CN then B is not present and Z is not a fused cyclohexyl ring;
(iii) when A is tetrazole then B is hydrogen or alkyl having 1 to
6 carbon atoms; and (iv) when A is CO then B is hydroxy, alkoxy, aralkoxy, alkyl having 1 to 6 carbon atoms, aralkyl, NR^R8 wherein R^ is hydrogen, alkyl having 1 to 6 carbon atoms, aralkyl or NR^ is a cyclic amine, and R8 is alkyl, aryl, or aralkyl.
11. A method according to Claim 1 or 2 wherein the compound administered is
6-Nitro-8-(lH-tetrazol-5-yl)-4,7,8,9-tetrahydro-lH- cyclopenta[f] quinoxaline-2,3 -dione; 8-(lH-Tetrazol-5-yl)-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione;
8-( 1 H-Tetrazol-5 -ylmethyl)-4,7, 8,9-tetrahydro- 1 H- cyclopenta[f]quinoxaline-2,3-dione;
6-Nitro-8-(lH-tetrazol-5-ylmethyl)-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione;
6-Nitro-8-[2-(lH-tetrazol-5-yl)-ethyl]-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione; or
8-[2-(lH-Tetrazol-5-yl)-ethyl]-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione.
12. A method according to Claim 1 or 2 wherein the quinoxalinedione administered is selected from one or more compounds of formula
or a pharmaceutically acceptable salt thereof wherein
R is hydrogen or hydroxy;
R! is hydrogen, alkyl, arylalkyl, (CH2)nOH, or
(CH2)nNR7R8;
R and R^ are each independently hydrogen, halogen, NO2, CN, CF3,
SO2NR?R8>
PO3R9R10, alkyl, alkenyl, alkynyl,
(CH )nCONR?R8, (CH2)nCO2Rl , NHCOR1 1, wherein R ' and R8 are each independently hydrogen or alkyl or together R' and R8 form a ring of from three to seven atoms, R┬░ is hydrogen or alkyl, R 10 is hydrogen or alkyl,
R! 1 is hydrogen or alkyl, and n is an integer of from zero to four; A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b, and formed by the following bivalent radicals: a-NR12-CHR13-CHR14-b, a-CHR13-CHR14-NR12-b, a-CHR13-NR12-CHR14-b, a-CHR14-CH -NR12-CHR13-b, a-CHR13-NR1 -CH2-CHR14-b, a-CH2-CH2-CHR13-NR1 -b, a-NR12-CHR13-CH2-CH2-b, a-CH2-CH2-NR12-CH2-CH2-b, a-CH2-CH2-CH2-NR! 2-CH2-b, a-CH2-NR! 2-CH-CH-CH-b, a-CH2-CH2-CH2-CH2-NRl 2-b, a-NR12-CH2-CH2-CH2-CH2-b, wherein R12 is hydrogen, CH2CH2OH, or alkyl, and R13 and R14 are each independently hydrogen, CN, CONH , CH NH , CH2OH, alkyl, arylalkyl, alkenyl, or CO2Rl5, wherein R!5 1S hydrogen or alkyl.
13. A method according to Claim 1 or 2 wherein the compound administered is 5-Nitro- 1,4,7,8, 9,10-hexahydro-pyrido[2,3-f]quinoxaline-2,3- dione;
2-Methyl-2,3,6,9-tetrahydro-lH-2,6,9-triaza- cyclopenta[a]naphthalene-7,8-dione;
4-(6-Nitro-2,3 -dioxo- 1 ,2,3 ,4,7, 10-hexahydro-8H-pyrido [3 ,4- f]quinoxalin-9-yl)-butyronitrile; and
2-(6-Nitro-2,3 -dioxo- 1 ,2,3,4,7, 10-hexahydro-8H-pyrido[3,4- f]quinoxalin-9-yl)-N-phenethyl-acetamide.
14. A method according to Claim 1 or 2 wherein the quinoxalinedione administered is Indeno[7,l-fg]quinoxaline-8,9-diol.
15. A method according to Claim 1 or 2 wherein the quinoxalinedione administered is 6-nitro-8-(lH-tetrazol-5-yl)-4,7,8,9-tetrahydro-lH- cyclopenta[f]quinoxaline-2,3-dione.
16. A method according to Claim 1 or 2 wherein the compound administered is selected from a compound of Formula I 
or a pharmaceutically acceptable salt thereof wherein R is a secondary or tertiary amine; R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl; R2 is hydrogen, hydroxy, or amino;
R and R4 are each independently hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, nitro, cyano,
SO CF3,
C(O)R6,
CH2SO2R6,
(CH2)mCO2R9 wherein R9 is hydrogen, alkyl, aralkyl, or cycloalkyl,
(CH2)mCONR7R8, (CH2)mSO2NR7Rg, or
NHCOR wherein m is an integer of from
/-R7
0 to 4, Rg is hydroxy, alkoxy, \D
R8
alkyl, haloalkyl, aryl, aralkyl, and R7 and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, or aryl;
R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, nitro, cyano,
SO2CF3,
C(O)R6, (CH2)mCO2R9,
(CH2)mCONR7R8, SONR7R8, or
NHCORg wherein m, R7, and Rg are as defined above;
R5 may be at the a-position and (CH2 at 
the b-position on the ring; and
R1 1 and R^2 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, R13 O
-( C)q- C-R15
R14 wherein q is an integer of from 0 to 3 and R╬╣ 3 and R14 are each independently selected from hydrogen, alkyl, aralkyl, cycloalkyl, and heteroalkyl and R]5 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heteroaryl and
NR^gRi 7 wherein Ri g and R\ are each independently selected from hydrogen, alkyl, and aryl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, thioalkyl,
17. A method according to Claim 1 or 2 wherein the compound administered is selected from a compound of Formula I
R
or a pharmaceutically acceptable salt thereof wherein R is an amino acid derivative; n is an integer of from 1 to 4; R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl; R2 is hydrogen or hydroxy;
R3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, halogen, haloalkyl, nitro, cyano,
SO CF3,
C(O)Rg wherein Rg is hydroxy, alkoxy, ^R7
\ _ , alkyl, haloalkyl, aryl, aralkyl, R8
CH2SO2R6,
(CH2)mCO2R9 wherein R9 is hydrogen, alkyl, aralkyl, or cycloalkyl, (CH2)mCONR7Rg,
(CH2)mS02NR7Rg, or
NHCORg wherein m is an integer of from 0 to 4 and R7 and
Rg are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, heteroaralkyl, aralkyl, heteroaryl, nitro, cyano,
SO2CF3,
C(O)R6, (CH2)mCO2R9,
(CH2)mCONR7R8, SONR7R8, or
NHCORg wherein m is as defined above and R7 and R8 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl; and R5 may be at the b-position and R-(CH2)n- at the a-position on the ring.
18. A method according to Claim 1 or 2 wherein the compound administered is selected from a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein
R is an amide; n is an integer of from 1 to 4;
R\ is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl ; R2 is hydrogen, hydroxy, or amino;
R3 and R4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, halogen, haloalkyl, nitro, cyano, SO2CF3,
CH2SO2Rg, (CH2)mCO2Rg, (CH2)mCONR7R8,
(CH2)mSO2NR7R8, or NHCORg wherein m is an integer of from 0 to 4, and Rg, R7, and Rg are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R5 is hydrogen, alkyl, alkenyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitro, cyano, SO2CF3, (CH2)mCO2R9, (CH2)mCONR9R1o, SONR9R10, or NHCOR9; m is an integer of from 0 to 4;
R9 and R10 are each independently hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; and R╬╢ may be at the a-position and R-(CH )n- at the b-position on the ring.
19. A method of treating HIV-1 infection in comprising administering to a mammal in need of said treatment a compound which inhibits the TatTAR interaction.
20. A compound Indeno[7, 1 -fg]quinoxaline-8,9-diol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU93182/98A AU9318298A (en) | 1997-11-14 | 1998-09-16 | Small molecule intervention in hiv-1 replication |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6555997P | 1997-11-14 | 1997-11-14 | |
| US60/065,559 | 1997-11-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1999025327A2 true WO1999025327A2 (en) | 1999-05-27 |
| WO1999025327A3 WO1999025327A3 (en) | 1999-09-23 |
Family
ID=22063554
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/019358 WO1999025327A2 (en) | 1997-11-14 | 1998-09-16 | Small molecule intervention in hiv-1 replication |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU9318298A (en) |
| WO (1) | WO1999025327A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002002516A2 (en) * | 2000-06-30 | 2002-01-10 | Thomas Jefferson University | Inhibitors of hiv integrase |
| JP2002338552A (en) * | 2001-05-15 | 2002-11-27 | Takeda Chem Ind Ltd | Quinoxaline-based compound and industrial germicidal composition |
| WO2002094796A2 (en) * | 2001-05-18 | 2002-11-28 | Axxima Pharmaceuticals Ag | Benzo[g]quinoxaline derivatives as effective compounds against infectious diseases |
| EP2928459A4 (en) * | 2012-12-06 | 2016-10-26 | Baruch S Blumberg Inst | Functionalized benzamide derivatives as antiviral agents against hbv infection |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0657166A1 (en) * | 1993-12-09 | 1995-06-14 | Hoechst Aktiengesellschaft | Combination containing a quinoxaline and a nucleoside |
| EP0708093A1 (en) * | 1994-10-19 | 1996-04-24 | Hoechst Aktiengesellschaft | Quinoxalines, process for their preparation, and their use |
| WO1996017832A1 (en) * | 1994-12-07 | 1996-06-13 | Warner-Lambert Company | Novel glutamate receptor antagonists: fused cycloalkylquinoxalinediones |
| WO1996040759A1 (en) * | 1995-06-07 | 1996-12-19 | Novartis Ag | Antiviral peptoid compounds |
| WO1997027179A2 (en) * | 1996-01-26 | 1997-07-31 | Novartis Ag | Antiretroviral bases |
-
1998
- 1998-09-16 WO PCT/US1998/019358 patent/WO1999025327A2/en active Application Filing
- 1998-09-16 AU AU93182/98A patent/AU9318298A/en not_active Abandoned
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0657166A1 (en) * | 1993-12-09 | 1995-06-14 | Hoechst Aktiengesellschaft | Combination containing a quinoxaline and a nucleoside |
| EP0708093A1 (en) * | 1994-10-19 | 1996-04-24 | Hoechst Aktiengesellschaft | Quinoxalines, process for their preparation, and their use |
| WO1996017832A1 (en) * | 1994-12-07 | 1996-06-13 | Warner-Lambert Company | Novel glutamate receptor antagonists: fused cycloalkylquinoxalinediones |
| WO1996040759A1 (en) * | 1995-06-07 | 1996-12-19 | Novartis Ag | Antiviral peptoid compounds |
| WO1997027179A2 (en) * | 1996-01-26 | 1997-07-31 | Novartis Ag | Antiretroviral bases |
Non-Patent Citations (3)
| Title |
|---|
| H.-Y- MEI ET AL.: "Discovery of Selective, Small-Molecule Inhibitors of RNA Complexes - I. The Tat Protein/TAR RNA Complexes Required for HIV-1 Transcription" BIOORGANIC & MEDICINAL CHEMISTRY, vol. 5, no. 6, 1997, pages 1173-1184, XP002096444 * |
| H.-Y. MEI ET AL.: "INHIBITION OF AN HIV-1 TAT-DERIVED PEPTIDE BINDING TO TAR RNA BY AMINOGLYCOSIDE ANTIBIOTICS" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 5, no. 22, 1995, pages 2755-2760, XP004135228 * |
| H.-Y.MEI ET AL.: "Inhibitors of Protein-RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules" BIOCHEMISTRY, vol. 37, no. 40, 17 September 1998 (1998-09-17), pages 13204-14212, XP002096445 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002002516A2 (en) * | 2000-06-30 | 2002-01-10 | Thomas Jefferson University | Inhibitors of hiv integrase |
| WO2002002516A3 (en) * | 2000-06-30 | 2002-10-24 | Univ Jefferson | Inhibitors of hiv integrase |
| JP2002338552A (en) * | 2001-05-15 | 2002-11-27 | Takeda Chem Ind Ltd | Quinoxaline-based compound and industrial germicidal composition |
| WO2002094796A2 (en) * | 2001-05-18 | 2002-11-28 | Axxima Pharmaceuticals Ag | Benzo[g]quinoxaline derivatives as effective compounds against infectious diseases |
| WO2002094796A3 (en) * | 2001-05-18 | 2003-12-04 | Axxima Pharmaceuticals Ag | Benzo[g]quinoxaline derivatives as effective compounds against infectious diseases |
| EP2928459A4 (en) * | 2012-12-06 | 2016-10-26 | Baruch S Blumberg Inst | Functionalized benzamide derivatives as antiviral agents against hbv infection |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999025327A3 (en) | 1999-09-23 |
| AU9318298A (en) | 1999-06-07 |
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