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WO1996033171A1 - Sulfones de 1h-pyrrol-1-yle et de 1h-indol-1-yle aryle, leurs procedes de preparation et leur utilisation dans la therapie des infections a vih-1 - Google Patents

Sulfones de 1h-pyrrol-1-yle et de 1h-indol-1-yle aryle, leurs procedes de preparation et leur utilisation dans la therapie des infections a vih-1 Download PDF

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Publication number
WO1996033171A1
WO1996033171A1 PCT/EP1996/001642 EP9601642W WO9633171A1 WO 1996033171 A1 WO1996033171 A1 WO 1996033171A1 EP 9601642 W EP9601642 W EP 9601642W WO 9633171 A1 WO9633171 A1 WO 9633171A1
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WO
WIPO (PCT)
Prior art keywords
aryl
alkyl
compounds
hiv
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1996/001642
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English (en)
Inventor
Marino Artico
Silvio Massa
Romano Silvestri
Anna Giulia Loi
Antonella De Montis
Paolo La Colla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istituto Superiore di Sanita ISS
Universita degli Studi di Cagliari
Original Assignee
Istituto Superiore di Sanita ISS
Universita degli Studi di Cagliari
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Priority to AU56901/96A priority Critical patent/AU5690196A/en
Publication of WO1996033171A1 publication Critical patent/WO1996033171A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to new 1H-Pyrrol-1-yl and 1H-Indol-1-yl Aryl Sulphones that may be usefull in the medical therapy of retrovirus infections and in particular of H3V-1 infections.
  • Viral infections represent health problems whose solution depends on the development of vaccines and/or selective antiviral drags, i.e. drags that inhibit the multiplication of viruses without interfering with the growth of normal cells.
  • HIV human immunodeficiency viruses
  • RT reverse transcriptase
  • the first group consists of nucleoside analogues such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), 2',3'-didehydro- 2'.3'-dideoxythymidine (D4T) which, upon activation by cellular kinases, compete with natural substrates and efficiently inhibit the reverse transcription of both HIV-1 and HIV-2.
  • ZAT 3'-azido-3'-deoxythymidine
  • ddl 2',3'-dideoxyinosine
  • ddC 2',3'-dideoxycytidine
  • D4T 2',3'-didehydro- 2'.3'-dideoxythymidine
  • the second group comprises non-nucleoside RT inhibitors (NNRTI) such as 1-[(2- hydroxy-ethoxy) methyl]-6-phenylthio)thymine (HEPT), tetrahydroimidazo-[4,5,1- jk]-[1-4]-benzodiazepine-2(lH)-one and thione (TTBO), 6,11-dihydro-11- cyclopropyl-4-methyldipyrido-[2-3-b:2',3'-e]-[1,4]-diazepin-6-one (neviparine), bis-heteroaryl-piperazine (B ⁇ AP), which do not need activation by cellular enzymes, do not compete for the dNTP substrate site and specifically inhibit the multiplication of ⁇ TV-1 but neither of HIV-2 nor of other retro, RNA or DNA viruses.
  • NRTI non-nucleoside RT inhibitors
  • This invention relates to new compounds of general formula (I)
  • R 2 H, halogen
  • R 6 H, halogen, NO 2 , NH 2 , OCH 3 ;
  • A H, phenyl.
  • K H, CHO, CH 2 NC 5 H n , CH 2 NC 4 H 8 NCH 3
  • the compounds of the invention may be usefull in the therapy of retrovirus infections, and in particular ofHIV -1. They may be used alone or in combination with other antiretroviral compounds, such as reverse transcriptase inhibitors and, in particular, nucleoside analogues.
  • Figures 1A and 1B represent the behaviour of p24 antigen by various types of treatment.
  • Figures 2 A and 2B represent the behaviour of HIV-1 gag sequences by various types of treatment.
  • R 2 H, halogen
  • R 6 H, halogen, NO 2 , NH 2 , OCH 3 ;
  • A H, phenyl.
  • K H, CHO, CH 2 NC 5 H 11 , CH 2 NC 4 H 8 NCH 3
  • Nitroaryl pyrrolyl sulfones 1-35 were synthesized by reaction of respective benzenesulfonyl chlorides with alkyl pyrrole-2-carboxylates and 2-acetylpyrrole in the presence of potassium tert-butoxide and 18-crown-6 (Scheme 1).
  • Nitroaryl indolyl sulfones 79-83 were obtained by phase transfer-reaction of respective benzenesulfonyl chlorides with indole or ethyl indole-2-carboxylate in the presence of n -tetrabutylammonium hydrogen sulfate in benzene - aqueous 50% potassium hydroxide medium (Scheme 2).
  • Iron powder reduction of nitro derivatives in glacial acetic acid by heating at 60oC for 2 h furnished the related anilines 36-61, 67-71 and 84-88.
  • Amides 72-74 were obtained by refluxing l-(2-amino-5-chlorobenzenesulfonyl)-1H- pyrrole-2-carboxylate with acyl chlorides in pyridine (73 and 74) or by treating with aceto formic anhydride (72).
  • Iron powder (5.2 g) was added over a period of 15 min to a stirred solution of 1-(2- nitro-4-chlorobenzenesulfonyl)-1H-pynole (5.00 g, 0.017 mol) in glacial acetic acid (50 mL) while heating at 60oC, then the mixture was maintained at 60oC for 2 h. After evaporation of the solvent, the residue was shaken between ethyl acetate and water. Organic extracts were separated, washed with brine and dried. The residue was purified on alumina column (chloroform). Yield 83%, mp 167-168oC (toluene/ligroin).
  • CD4 + T-cell lines purchased from the American Type Culture Collection (ATCC). Cells were grown in RPMI-1640 medium supplemented with 10% FCS, 100 units/mL penicillin and 100 ⁇ g/mL streptomycin. The cultures were incubated at 37 oC in a humidified, 5% CO 2 atmosphere. The absence of mycoplasma contamination was checked periodically by the Hoechst staining method.
  • Human immunodeficiency viruses type-1 HTV-1, III B strain
  • type 2 HTV-2, CBL-20 and ROD strains
  • H9/III B and CEM cells were used. Additional laboratory strains (MN, RF and 105/F, the latter an AZT-resistant strain) and a clinical isolate (CAMAS) were used. The HIV stock solutions were titrated in C8166 cells and kept at -80oC until use.
  • Anti-HIV activity is, spectrum and mode of action.
  • the activity of compounds against the HIV-1 multiplication in acutely infected cells was based on inhibition of the virus-induced cytopathogenicity (CPE) in MT-4 cells.
  • CPE virus-induced cytopathogenicity
  • MT-4 cells After 4 days incubation at 37oC, the number of viable MT-4 cells was determined by the 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl-tetrazolium bromide (MTT) method (Pauwels R. et al., J. Virol. Meth. 20, 309-321, 1988). Alternatively, cell-free culture supematants were assayed by the HIV- 1 p24 antigen enzyme-linked immunosorbent assay (ELISA, Abbott). Cytotoxicity of compounds was evaluated in parallel with their antiviral activity and was based on the viability of mock-infected cells, as monitored by the MTT method. As shown in Table 3.
  • Data represent mean values for three separate experiments. Variation among triplicate samples was less than 12%.
  • dSelectivity index CC 50 /EC 50 ratio.
  • the anti-HIV activity of compounds 41, 42 and 72 was evaluated also against additional HIV-1 laboratory strains (MN, RF), an highly AZT-resistant strain (105/F), a clinical isolate (CAMAS) and two HIV-2 strains (CBL 20, ROD). All the HIV-1 strains resulted sensitive (Table 4), whereas the HIV-2 strains were both unsusceptible to inhibition by compounds of formula (I).
  • dCompound dose ( ⁇ M) required to reduce p24 levels by 50%.
  • the activity of compounds 41, 42 and 72 was evaluated in cultures infected at different multiplicities by measuring p24 antigen levels.
  • Nevirapine, AZT ddl and ddC were used as reference drugs.
  • the compounds of the invention were inhibitory to HIV-1 also in cells acutely infected at high multiplicities of infection (m.o.i.). In this respect they behaved similarly to nevirapine and AZT, but differently from ddl and ddC. In fact, at m.o.i. > 1.0 the later were unable to prevent the viral breakthrough even when used at high concentrations.
  • PBL peripheral blood lymphocytes
  • CFU-GM bone marrow granulocyte/monocyte precursors from healthy individuals.
  • AZT was used as reference drug.
  • PBL and CFU-GM were obtained by separation on Fycoll-Hypaque gradients. After extensive washings, cells were resuspended (1x10 6 cells/mL) in RPMI-1640 with 10% FCS and incubated overnight to allow adhesion of the macrophages to the plastic.
  • ⁇ M aCompound dose required to reduce the level of p 24 antigen by 50% at day 4 post infection. Data represent mean values for two separate experiments. Variation among duplicate samples was less than 15%.
  • Cytotoxicity of compounds for activated PBL was evaluated by resuspending non- adherent cells at 1x10 6 cells/mL in growth medium and stimulating with PHA (2.5 ⁇ g/mL) for 24 hrs before dilution to 1x10 5 cells/mL in medium containing PHA (2.5 ⁇ g/mL), TL-2 (50 U/mL) and various concentrations of the test compounds. Viable cell numbers were determined six days later. Under these conditions, untreated PBL were able to undergo exponential growth for up to four cell cycles, as determined by viable cell counts. For cytotoxicity evaluations in resting PBL, non-adherent cells were resuspended at high density (1x10 6 cells/mL) and were treated for 3 days with the test compounds.
  • the cells were extensively washed to remove the inhibitors and were stimulated with PHA for 24 hrs before being diluted to 1x10 5 cells/mL in medium containing PHA and IL-2.
  • Cell viability was determinee after incubation at 37oC for six days.
  • CFU/GM (2x10 5 /mL) were resuspended in Iscove medium containing 0.3% agar and growth factors from the supernatant of 5637 cells. After ten days at 37oC, colonies (of about 40 cells) were scored under the light microscope.
  • ⁇ M aCom pound dose required to reduce cell g rowth (PBL) or colony formation (CFU-GM) by 50%.
  • bPHA-stimulated were resuspended in IL 2 -containing medium in the presence of the drugs.
  • C PBL were treated with the test drugs for 3 days and then were stimulated with PHA and allowed to grow in drug-free medium.
  • dCFU-GM colony forming units of bone marrow hematopoietic progenitors of granulocytes / macrophages.
  • PCR analyses of the experiment in Fig. 1 were in agreement with the above observations.
  • the HIV-1 DNA was checked (as described by Bagnarelli et al, J. Med. Virol. 34, 89- 95. 1991; Menzo et al, J. Clinical Microbiol. 30, 1752-1757, 1992) by using the set of primers SK38 and SK39, which amplify an internal, highly conserved fragment (115 bp) of the gag gene.
  • the reaction mixture was subjected to 35 cycles of denaturation at 93oC for 15 seconds, annealing at 60 oC for 15 seconds, extension at 72 oC for 30 seconds.
  • the extension step of the last cycle was 10 minutes longer to ensure full completion of the newly synthesized strains.
  • Amplified products were analyzed by electrophoresis on low melting point agarose gel and visualized by ethidium bromide staining.
  • Fig.2A the treatment with AZT 2.5 ⁇ M was unable to prevent the synthesis of HIV-1 gag sequences, that could be evidenced from day 4 through day 32, no matter whether p24 antigen was barely detectable and infectious virus was absent.
  • the cultures treated with the 42-AZT combination remained free of gag DNA sequences starting from day 8 on. The same was true for the samples from which the drugs were removed by day 4 p.i. (Fig.2B).
  • the compounds according to the present invention find a useful use in the therapy of retrovirus infections, used both alone or in combination with other antiretroviral compounds.
  • the present invention refers also to pharmaceutical compositions containing as active substance a compound having formula (I) as well as to a therapeutic method for treating the retrovirus infections.
  • Said pharmaceutical compositions are characterized by containing as active substance a pharmacologically effective amount of a substance of formula (I) in mixture with pharmacologically acceptable diluents and excipients.
  • Said therapeutic method consists in administering by oral route a dose of 10 mg per day and per Kg. of body weight of a compound of formula (I).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des nouvelles sulfones de 1H-pyrrol-1-yle et de 1H-indol-1-yle aryle de la formule (I) qui peuvent être utiles en thérapie médicale dans les infections à rétrovirus, et notamment dans les infections à VIH-1. On peut utiliser les composés de l'invention seuls ou en combinaison avec d'autres composés antirétroviraux, préférablement choisis parmi des inhibiteurs de la transcriptase inverse, tels que des analogues de nucléosides, par exemple. Dans cette formule, R1 représente NO¿2, NH?2, halogène, NHCH¿2?Z (où Z représente H, alkyle, aryle, hétéroaryle), NHCOW (où W représente H, alkyle, aryle, hétéroaryle); R?2¿ représente H, halogène; R3 = R4 et ils représentent H, NO¿2?, NH2, CH3, halogène; R?5¿ représente H, (2)-COX, (3)-COX (où X représente OR, alkyle, aryle, CCl¿3?, N(alkyle2)); R représente alkyle, cycloalkyle, aryle, arylméthyle; (2)-CONHY (où Y représente H, alkyle, aryle); R?6¿ représente H, halogène, NO¿2?, NH2, OCH3; A représente H, phényle et K représente H, CHO, CH2NC5H11, CH2NC4H8NCH3.
PCT/EP1996/001642 1995-04-21 1996-04-19 Sulfones de 1h-pyrrol-1-yle et de 1h-indol-1-yle aryle, leurs procedes de preparation et leur utilisation dans la therapie des infections a vih-1 Ceased WO1996033171A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56901/96A AU5690196A (en) 1995-04-21 1996-04-19 1h-pyrrol-1-yl and 1h-indol-1-yl aryl sulphones, processes f or their preparation and use for the therapy of hiv-1 infect ions

Applications Claiming Priority (2)

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IT95MI000812A IT1282797B1 (it) 1995-04-21 1995-04-21 Pirril-(indolil)-aril-sulfoni e relativo processo di produzione ed impiego nella terapia delle infezioni da virus dell'aids
ITMI95A000812 1995-04-21

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IT (1) IT1282797B1 (fr)
WO (1) WO1996033171A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2765222A1 (fr) * 1997-06-27 1998-12-31 Fournier Ind & Sante Nouveaux composes de n-benzenesulfonyl-l-proline, procede de preparation et utilisation en therapeutique
US6225309B1 (en) 1994-09-26 2001-05-01 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US6288103B1 (en) 1997-08-07 2001-09-11 Zeneca Limited Indole derivatives as MCP-1 receptor antagonists
US6291507B1 (en) 1998-02-17 2001-09-18 Astrazeneca Uk Limited Chemical compounds
US6300330B1 (en) 1996-11-08 2001-10-09 Zeneca Limited Heterocycle derivatives which inhibit factor Xa
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
WO2002032863A1 (fr) * 2000-10-20 2002-04-25 Biovitrum Ab N1-(benzensulfonyl)indoles substitues en 2, 3, 4 ou 5 et leur utilisation a des fins de traitement
US6391880B1 (en) 1997-02-13 2002-05-21 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6441004B1 (en) 1997-08-07 2002-08-27 Zeneca Limited Monocyte chemoattractant protein-1 inhibitor compounds
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6486154B1 (en) 1997-07-29 2002-11-26 Zeneca Limited (Hetero) aryl-sulfonamide derivatives, their preparation and their use as factor XA inhibitors
US6569888B1 (en) 1999-02-05 2003-05-27 Astrazeneca Ab Anti-inflammatory indole derivatives
US6613760B1 (en) 1999-02-05 2003-09-02 Astrazeneca Ab Indole derivatives and their use as MCP-1 receptor antagonists
US6723723B1 (en) 1999-02-11 2004-04-20 Astrazeneca Heterocyclic derivatives as inhibitors of factor Xa
US6737435B1 (en) 1999-02-05 2004-05-18 Astrazeneca Ab Indole derivatives and their use as MCP-1 antagonist
US6833387B1 (en) 1999-02-05 2004-12-21 Astrazeneca Ab Chemical compounds
EP1568698A1 (fr) * 2004-02-27 2005-08-31 Aventis Pharma Deutschland GmbH Dérivés de pyrrole en tant qu'inhibiteurs du facteur xa
US6984657B1 (en) 2000-01-13 2006-01-10 Astrazeneca Ab Indole derivatives as MCP-1 receptor antagonists
US8912136B2 (en) 2009-12-18 2014-12-16 Sanford-Burnham Medical Research Institute Methods and compositions related to clot-binding compounds
US9101671B2 (en) 2007-01-03 2015-08-11 Sanford-Burnham Medical Research Institute Methods and compositions related to clot binding compounds
WO2025132542A1 (fr) 2023-12-19 2025-06-26 Idorsia Pharmaceuticals Ltd Agonistes macrocycliques de l'orexine

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ARTICO, MARINO ET AL: "Heterocycles with a benzothiadiazepine moiety. 1. Synthesis of pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine 5,5-dioxide", SYNTH. COMMUN. (1992), 22(10), 1433-9 CODEN: SYNCAV;ISSN: 0039-7911, 1992, XP000576666 *
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6225309B1 (en) 1994-09-26 2001-05-01 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US6730672B2 (en) 1994-09-26 2004-05-04 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US6300330B1 (en) 1996-11-08 2001-10-09 Zeneca Limited Heterocycle derivatives which inhibit factor Xa
US6936610B2 (en) 1996-11-08 2005-08-30 Astrazeneca Uk Limited Heterocyclic derivatives
US6391880B1 (en) 1997-02-13 2002-05-21 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6384222B1 (en) 1997-06-27 2002-05-07 Fournier Industrie Et Sante N-benzenesulfonyl-L-proline compounds, preparation method and method for using the compounds in therapy
WO1999000387A1 (fr) * 1997-06-27 1999-01-07 Fournier Industrie Et Sante Nouveaux composes de n-benzenesulfonyl-l-proline, procede de preparation et utilisation en therapeutique
FR2765222A1 (fr) * 1997-06-27 1998-12-31 Fournier Ind & Sante Nouveaux composes de n-benzenesulfonyl-l-proline, procede de preparation et utilisation en therapeutique
US6486154B1 (en) 1997-07-29 2002-11-26 Zeneca Limited (Hetero) aryl-sulfonamide derivatives, their preparation and their use as factor XA inhibitors
US6953809B2 (en) 1997-08-07 2005-10-11 Zeneca Limited Monocyte chemoattractant protein-1 inhibitor compounds
US6288103B1 (en) 1997-08-07 2001-09-11 Zeneca Limited Indole derivatives as MCP-1 receptor antagonists
US6441004B1 (en) 1997-08-07 2002-08-27 Zeneca Limited Monocyte chemoattractant protein-1 inhibitor compounds
US6291507B1 (en) 1998-02-17 2001-09-18 Astrazeneca Uk Limited Chemical compounds
US6613760B1 (en) 1999-02-05 2003-09-02 Astrazeneca Ab Indole derivatives and their use as MCP-1 receptor antagonists
US6737435B1 (en) 1999-02-05 2004-05-18 Astrazeneca Ab Indole derivatives and their use as MCP-1 antagonist
US6833387B1 (en) 1999-02-05 2004-12-21 Astrazeneca Ab Chemical compounds
US6569888B1 (en) 1999-02-05 2003-05-27 Astrazeneca Ab Anti-inflammatory indole derivatives
US6723723B1 (en) 1999-02-11 2004-04-20 Astrazeneca Heterocyclic derivatives as inhibitors of factor Xa
US6984657B1 (en) 2000-01-13 2006-01-10 Astrazeneca Ab Indole derivatives as MCP-1 receptor antagonists
WO2002032863A1 (fr) * 2000-10-20 2002-04-25 Biovitrum Ab N1-(benzensulfonyl)indoles substitues en 2, 3, 4 ou 5 et leur utilisation a des fins de traitement
US7087750B2 (en) 2000-10-20 2006-08-08 Biovitrum Ab Compounds, their use and preparation
KR100823908B1 (ko) 2000-10-20 2008-04-21 바이오비트럼 에이비(피유비엘) 2-, 3-, 4-, 또는 5-치환-ｎ1-(벤젠술포닐)인돌 및 이의치료 용도
US7524839B2 (en) 2000-10-20 2009-04-28 Biovitrum Am (Publ.) Compounds, their use and preparation
EP1568698A1 (fr) * 2004-02-27 2005-08-31 Aventis Pharma Deutschland GmbH Dérivés de pyrrole en tant qu'inhibiteurs du facteur xa
US9101671B2 (en) 2007-01-03 2015-08-11 Sanford-Burnham Medical Research Institute Methods and compositions related to clot binding compounds
US8912136B2 (en) 2009-12-18 2014-12-16 Sanford-Burnham Medical Research Institute Methods and compositions related to clot-binding compounds
WO2025132542A1 (fr) 2023-12-19 2025-06-26 Idorsia Pharmaceuticals Ltd Agonistes macrocycliques de l'orexine

Also Published As

Publication number Publication date
ITMI950812A0 (it) 1995-04-21
AU5690196A (en) 1996-11-07
IT1282797B1 (it) 1998-03-31
ITMI950812A1 (it) 1996-10-21

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