WO1996033171A1 - 1h-pyrrol-1-yl and 1h-indol-1-yl aryl sulphones, processes for their preparation and use for the therapy of hiv-1 infections - Google Patents

1h-pyrrol-1-yl and 1h-indol-1-yl aryl sulphones, processes for their preparation and use for the therapy of hiv-1 infections Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
aryl
alkyl
compounds
hiv
halogen
Prior art date
Application number
PCT/EP1996/001642
Other languages
French (fr)
Inventor
Marino Artico
Silvio Massa
Romano Silvestri
Anna Giulia Loi
Antonella De Montis
Paolo La Colla
Original Assignee
Istituto Superiore Di Sanitá
Universita' Degli Studi Di Cagliari
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Istituto Superiore Di Sanitá, Universita' Degli Studi Di Cagliari filed Critical Istituto Superiore Di Sanitá
Priority to AU56901/96A priority Critical patent/AU5690196A/en
Publication of WO1996033171A1 publication Critical patent/WO1996033171A1/en

Links

Classifications

    • 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).

Abstract

This invention relates to new 1H-Pyrrol-1-yl and 1H-Indol-1-yl Aryl Sulphones of Formula (I) that may by useful in the medical therapy of retrovirus infections and in particular of HIV-1 infections. The compounds reported herein may be used alone or in combination with other antiretroviral compounds, preferably chosen among reverse transcriptase inhibitors such as, for example, nucleoside analogues, wherein: R1 = NO2, NH2, halogen, NHCH2Z(Z = H, alkyl, aryl, heteroaryl), NHCOW (W = H, alkyl, aryl, heteroaryl); R2 = H, halogen; R3 = R4 = H, NO¿2?, NH2, CH3, halogen; R?5¿ = H, (2)-COX, (3)-COX, (X = OR, alkyl, aryl, CCl¿3?, N(alkyl2); R = alkyl cycloalkyl, aryl arylmethyl; (2)-CONHY (Y = H, alkyl, aryl); R?6¿ = H, halogen, NO¿2?, NH2, OCH3; A = H, phenyl; K = H, CHO, CH2NC5H11, CH2NC4H8NCH3.

Description

1H-PYRROL-1-YL AND 1H-INDOL-1-YL ARYL SULPHONES, PROCESSES FOR THEIR PREPARAΗON AND USE FOR THE THERAPY OF HIV -1 INFECTIONS.
TECHNICAL HELD
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.
BACKGROUND ART
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.
Among viral infections, the AIDS pandemic has rised widespread concern and, following the identification of human retroviruses as its causative agents, several targets susceptible of selective inhibition have been identified in the multiplication cycle of human immunodeficiency viruses (HIV). One of these targets is the reverse transcriptase (RT), a virus-coded enzyme that can be inhibited by two different groups of compounds. 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. Compounds of this group have been described by Mitsuya et al., PNAS 82, 7096-7100, 1985; Yarchoan et al, Science 245, 412-415, 1989; Mitsuya et al, PNAS 83, 1911-1915, 1986; Lin. et al., Biochem.Pharmacol.36, 2713-2718, 1987.
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 (BΗAP), which do not need activation by cellular enzymes, do not compete for the dNTP substrate site and specifically inhibit the multiplication of ΗTV-1 but neither of HIV-2 nor of other retro, RNA or DNA viruses. Compounds of this group have been described by Miyasaka et al, J. Med. Chem. 32, 2507-2509. 1989; Pauwels et al, Nature 343, 470-474, 1990; Merluzzi et al, Science, 250, 1411-1413,
1990; Romero et al, PNAS, 88, 8806-8810, 1991.
The development of toxicity, which is a major problem with the nucleoside analogues, and the emergence of resistant mutants, which is of major concern with the NNRTI, are the most significant clinical limits of the above RT inhibitors. For this reason, the search for new antiviral compounds and the development of suitable therapeutic strategies aimed at reducing toxicity and preventing drug resistance is still a priority in the fight against AIDS.
S U M M A R Y
This invention relates to new compounds of general formula (I)
Figure imgf000004_0001
wherein:
R1 = NO2, NH2, halogen, NHCH2Z (Z = H, alkyl, aryl, heteroaryl), NHCOW (W = H, alkyl, aryl, heteroaryl);
R2 = H, halogen;
R3 = R4 = H, NO2, NH2, CH3, halogen;
R5 = H, (2)-COX, (3)-COX, (X = OR, alkyl, aryl, CCl3, N(alkyl2)); R = alkyl, cycloalkyl, aryl, arylmethyl; (2)-CONHY (Y= H, alkyl, aryl);
R6 = H, halogen, NO2, NH2, OCH3;
A = H, phenyl.
K = H, CHO, CH2NC5Hn, CH2NC4H8NCH3
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.
BRIEF DESCRIPTION OF THE DRAWINGS
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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention allows to circumvent the prior art limits through the use of compounds of general formula (I)
Figure imgf000005_0001
wherein:
R1 = NO2, NH2, halogen, NHCH2Z (Z = H, alkyl, aryl, heteroaryl), NHCOW (W = H, alkyl, aryl, heteroaryl);
R2 = H, halogen;
R3 = R4 = H, NO2, NH2, CH3, halogen;
R5 = H, (2)-COX, (3)-COX, (X = OR, alkyl, aryl, CCl3, N(alkyl2)); R = alkyl, cycloalkyl, aryl, arylmethyl; (2)-CONHY (Y= H, alkyl, aryl);
R6 = H, halogen, NO2, NH2, OCH3;
A = H, phenyl.
K = H, CHO, CH2NC5H11, CH2NC4H8NCH3
Compounds of formula (I) and their chemical and physical charcteristics are reported in tables 1 and 2, respectively.
Compounds of general formula (I) may be prepared by the processes described below.
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).
Figure imgf000006_0001
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).
Figure imgf000007_0001
Displacement of trichloromethyl group of 1-(2-nitrobenzenesulfonyl)-2- trichloroacetyl-1H-pyrrole by amines afforded the corresponding amides 62-66.
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.
Reaction of ethyl 1-(2-amino-5-chlorobenzenesulfonyl)-1H-pyrrole-2-carboxylate with formaldehyde in the presence of sodium cyanoborohydride in methanol- hydrochloric acid afforded the required N-methyl derivative 76. In a similar way were prepared the N-alkyl derivatives 75, 77 and 78.
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).
The processes for the preparation of the compounds according to the present invention are illustrated by the following examples.
Example 1
Condensation of arylsulfonyl chlorides with 1H -pyrrole-2-carboxylic esters and 2- acetylpyrrole. Methyl 1-(2-Nitrobenzenesulfonyl)1H -pyrrole-1-carboxylate. A solution of 2-methoxycarbonyl-1H-pyrrole (12.50 g, 0.10 mol) in dry TΗF (210 mL) was added dropwise to a well-stirred mixture of potassium tert-butoxide (13.46 g, 0.10 mol) and 18-crown-6 (2.83 g, 0.01 mol) in the same solvent (210 mL). After 15 min the suspension was cooled on an ice-bath and then treated by dropping with a solution of 2- nitrobenzenesulfonyl chloride (22.16, 0.10 mol) in dry TΗF (210 mL). Stirring was continued at room temperature for 3.5 h, then the mixture was concentrated to a small volume and the residue was shaken between ethyl acetate and water. The organic layer was separated, washed with brine and dried. Removal of the solvent furnished the crude product which was purified by chromatography on alumina (chloroform). Yield 58%, mp 143ºC (toluene/cyclohezane). 1Η-NMR (DMSO-d6): δ 3.61 (s, 3Η), 6.56 (t, 1H), 7.26
(m, 1H), 7.75-8.05 (m, 4H), 8.16 ppm (dd, 1H). IR: v 1720 cm-1 (CO). Anal. C12H10N2O6S (310.28) C, H, N, S. Example 2
Condensation of benzenesulfonyl chlorides with indole and ethyl 2- indolecarboxylate. 1-(2-Nitrobenzenesulfonyl)-1H -indole.
50% KOH (20 mL) was dropped while stirring into a solution of indole (2.34 g, 0.02 mol) and n-tetrabutylammonium hydrogen sulfate (0.68 g, 0.002 mol) in benzene (40 mL). After 5 min a solution of 2-nitrobenzenesulfonyl chloride (4.43 g, 0.02 mol) in benzene (20 mL) was added dropwise. Reaction was stirred at room temperature for 1 h. Every 20 min was added 2-nitrobenzenesulfonyl chloride (2.21 g, 0.01 mol) in the same solvent (10 mL). The mixture was diluted with water and the organic layer separated, washed with brine and dried. Removal of the solvent gave the crude product which was purified by passing through an alumina column (chloroform). Yield 93%, mp 98-100ºC
(toluene/cyclohexane). 1H-NMR (CDCI3): δ 6.74 (d, 1H), 7.22-7.38 (m, 2H), 7.54- 7.78 (m, 6 H), 7.85 ppm (m, 1H). Anal. C14H10N2O4S (302.30) C, H, N, S.
Example 3
Reduction of nitro group into amino. 1-(2-Amino-4-chlorobenzenesulfonyl)-1H - pyrrole.
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). 1H- NMR (DMSO-d6): δ 6.31 (t, 2H), 6.58-6.65 (m, 3H), 6.88 (d, 1H), 7.38 (t, 2H), 7.65 ppm (d, 1H). IR: v 3380, 3480 cm-1 (NH2). Anal. C10H9CIN2O2S (256.71) C, H, N, Cl, S.
Example 4
Aikylation of aminosters. 1-(2-Methylaminobenzenesulfonyl)-1H-pyrrole.
NaBΗ3CN (0.32 g, 0.005 mol) Was carefully added into a mixture of 1-(2- aminobenzenesulfonyl)-1H-pyrrole (1.00 g, 0.0045 mol), 37% aqueous formaldehyde (0.4 mL), 6N HCl / CH3OH 1:1 (0.74 mL), methanol (18 mL), then reaction was stirred at room temperature for 36 h. After concentration to a small volume the mixture was extracted with chloroform, washed with 5% NaHCO3, then with brine and dried. Removal of the solvent furnished a residue which was purified on alumina column
(dichloromethane/petroleum ether 1:1). Yield 45%, mp 134ºC (ligroin). 1H-NMR (CDCl3): δ 2.87 (d, 3H), 6.15-6.35 (m, 3H), 6.67 (m, 2H), 7.15 (t, 2H), 7.40 (m, 1H),
7.72 ppm (dd, 1H). IR: v 3440 cm-1 (NH). Anal. C11H12N2O2S (236.28) C, H, N, S.
Example 5
Acylation of aminosters. Example. Ethyl 1-(2-Acetamido-5-chloro- benzenesulfonyl)-1H -pyrrole-2-carboxylate.
Acetyl chloride (1.17 g, 0.0148 mol) was dropped into an ice cooled solution of 1-(2- amino-5-chlorobenzenesulfonyl)-1H-pyrrole-2-carboxylate (1.00 g, 0.003 mol) in dry pyridine (10 mL), the reaction was refluxed overnight. After cooling mixture was poured on crashed ice, made acid with 12N HCl and shaken with ethyl acetate. Organic layer was separated, washed with brine and dried. After evaporation of the solvent, the crude product was purified on silica gel column (chloroform). Yield 84%, mp 119-121ºC
(cyclohexane). 1H-NMR (CDCI3): δ 1.26 (t, 3H), 2.23 (s, 3H), 4.18 (q, 2H), 6.36 (t, 1H), 7.09 (m, 1H), 7.43-7.55 (m, 2H), 7.71 (m, 1H), 8.42 (d, 1H), 9.47 ppm (br s, 1H). IR: v 1650, 1720 (CO), 3250 cm-1 (NH). Anal. C15H15CIN2O5S (370.80) C, H, N, Cl, S.
BIOLOGICAL ACTIVITY
In order to describe the usefullness of compounds of formula (I) for the treatment of infections caused by retrovirases, herein will be presented the results of experiments aimed at evaluating:
• potency, selectivity, spectrum and mode of anti-HIV activity;
• cytotoxicity for normal human cells;
• efficacy in suppressing the HIV-1 infection in long-term cultures.
Compounds were solubilized in DMSO at an initial concentration of 100 mM and then were serially diluted in RPMI 1640.
The following cell lines were used in cytotoxicity and antiviral assays: C8166 and MT- 4. human 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 μg/mL streptomycin. The cultures were incubated at 37 ºC in a humidified, 5% CO2 atmosphere. The absence of mycoplasma contamination was checked periodically by the Hoechst staining method.
Human immunodeficiency viruses type-1 (HTV-1, IIIB strain) and type 2 (HIV-2, CBL-20 and ROD strains) were obtained from the supernatant of persistently infected
H9/IIIB and CEM cells, respectively. 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, 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. Brielfly, 50 μL of culture medium additioned of 10% FCS and containing 1x104 MT-4 cells were added to each well of flat bottomed microtitre trays containing 50 μL of medium without or with serial concentrations of the test compounds. 20 μL of a viral suspension were then added to give 100 CCID50/well. 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. representative compounds of the invention were found non-cytotoxic for MT-4 cells at concentrations higher than 100 μM (see CC50 column). Many of them were active against the HIV -1 multiplication at concentrations ranging from 1 to 20 μM (see EC50 column), whereas five compounds turned out highly potent showing EC50 in the submicromolar range.
In order to determine whether these compounds were targeted at the RT, they were tested against theHIV -1 recombinant reverse transcriptase (rRT). Assays were performed at 37º for 30 min. in a 50 μL reaction mixture containing 50 mM Tris-HCl (pH 7.8), 1 mM dithiothreitol, 80 mM KCl, 6 mM MgCl2, 0.1 mg/mL BSA, 10 mM [3H]-dTTP (1 Ci/mmol), 0.05 OD260 units/mL of Poly(rA)-oligo(dT)ιo and 1.6x10-3 units of enzyme (a unit was defined as the amount of enzyme necessary to incorporate 1 nmol of [3H]-dTMP into the Poly(rA)-oligo(dT)10 template in 1 min. at 37º). 40 μL aliquots were spotted on glass fiber filters (Whatman GF/A) and processed for determination of trichloroacetic acid-insoluble radioactivity. With the exception of 72, 73 and 74 (Table 3), all compounds resulted inhibitory to the rRT at concentrations (see IC50 column) comparable to those active in cell culture-based assays. This confirmed that compounds of formula (I) with R1 = NH2/NO2 interfere with the HIV-1 multiplication by inhibiting the RT activity.
Figure imgf000012_0001
aCompound dose (μM) required to reduce we viability of mock-infected MT-4 cells by 50%, as determined by the MTT method.
bCompound dose (μM) required to achieve 50% protection of MT-4 cells from the HIV-induced cytopathicity, as determined by the MTT method. Data represent mean values for three separate experiments. Variation among triplicate samples was less than 12%.
cCompound dose (μM) required to inhibit the HIV-1 rRT activity by 50% + standard deviation. dSelectivity index: CC50/EC50 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).
Figure imgf000013_0001
aData represent mean values for two separate experiments. Variation among duplicate samples was less than 15%.
bCompound dose (μM) required to achieve 50% protection of C8166 cells from the HIV-2- induced cytopathicity.
cCompound dose (μM) required to reduce the number of syncytia by 50%. Untreated cultures contained 80 syncytia/field.
dCompound dose (μM) 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. Interestingly, 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.
Cytotoxicity for normal human cells.
In order to get more insights into the cytotoxic potential of compounds of formula (I), 41, 42 and 72 were tested in vitro against peripheral blood lymphocytes (PBL) from HIV- negative donors and bone marrow granulocyte/monocyte (CFU-GM) 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 (1x106 cells/mL) in RPMI-1640 with 10% FCS and incubated overnight to allow adhesion of the macrophages to the plastic.
Figure imgf000014_0001
aCompound dose (μM) required to reduce the level of p24 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 1x106 cells/mL in growth medium and stimulating with PHA (2.5 μg/mL) for 24 hrs before dilution to 1x105 cells/mL in medium containing PHA (2.5 μg/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 (1x106 cells/mL) and were treated for 3 days with the test compounds. Then, the cells were extensively washed to remove the inhibitors and were stimulated with PHA for 24 hrs before being diluted to 1x105 cells/mL in medium containing PHA and IL-2. Cell viability was determinee after incubation at 37ºC for six days. CFU/GM (2x105 /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.
Table 6. Cytotoxicity of compound 41, 42 and 72 for human cells.
Figure imgf000015_0001
aCom pound dose (μM ) required to reduce cell g rowth (PBL) or colony formation (CFU-GM) by 50%.
bPHA-stimulated were resuspended in IL2-containing medium in the presence of the drugs.
CPBL 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.
e Data represent mean values for two separate experiments. Variation among duplicate samples was less than 14%.
As shown in Table 6, 41, 42 and 72 proved non-cytotoxic (CC50 > 100 μM) for both PHA-stimulated and resting PBL, whereas AZT resulted cytotoxic for activated PBL. Moreover, when the cytotoxicity of each compound for myeloid precursor cells was evaluated, compounds of formula (I) resulted non-cytotoxic, whereas AZT showed a CC50 of 2.4 μM.
Efficacy in suppressing the HIV-1 infection.
The long-term anti-HIV-1 activity of compound 42 and AZT, alone and in combination, was evaluated in cultures of MT-4 cells and was based on both evaluation of p24 antigen levels and protection from the HIV-1 -induced CPE, as monitored by the Elisa test and the MTT method, respectively. Briefly, 1x106 MT-4 cells were infected with 1x106 CCID50 (1 CCID50 = 25 -250 infectious virions) at 20 ºC for 1 hr, washed three times, resuspended at 2x105 cells/mL as such (m.o.i. > 1) or after dilution 1:10 (m.o.i. = 0.1) or 1:100 (m.o.i. = 0.01) with medium containing 2x105 uninfected cells/mL. 1x104 cells/well were seeded in 96 multiwell plates and grown at 37ºC in a humidified 5% CO2 atmosphere in the absence or presence of the drags, alone or in combination. 4 days later, the whole sample (0.1 mL) was resuspended in 0.9 mL of fresh medium containing the given drag concentrations and seeded in 24 multiwell plates. After 4 more days, the whole culture (1.0 mL) was resuspended in 9 mL of fresh medium (containing the given drag concentrations) in a 25-cm2 flask. Starting at day 12, only one-tenth (in 25-cm2 flasks) or one hundreth (in 24 multiwell plates) of each culture was further transplanted. It is worth noting that the above procedure, while settling conditions suitable for continuous exponential growth of the cultures, on the other hand allowed to keep all the cells which were originally infected (or the virus produced by them) up to day 12 post infection (p.i.).
When used alone at 10 μM, 42 delayed up to day 12 the rise of p24 antigen (Fig. 1A) and the development of the virus-induced CPE (Fig. 1B). Under the same conditions, AZT 2.5 μM reduced to very low (although still detectable) levels the p24 antigen, prevented the virus-induced CPE and allowed exponential growth of the culture up to day 32 post infection (p.i.). However, when AZT was removed, the HIV-1 multiplication resumed within few days, as evidenced by the rise of p24 levels, production of infectious virus (1.2x106 CCID50/mL) and cell death. In the experiment of Fig. 1 removal of AZT was carried out 20 days p.i., but analogous results were obtained when AZT was removed as early as 4 days p.i. and as late as 28 days p.i..
On the contrary, when the cells were treated with compound 42, 10 μM, in combination with AZT, 2.5 μM (Fig.1), total lack of both p24 antigen and HIV-1- induced CPE was observed for as long as 32 days. Interestingly, when HIV-1 -infected cultures that had been treated with the above combination for 4 days were further transplanted in drag- free medium, no signs of resumption of viral multiplication became evident up to day 32 p.i..
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.
As shown in Fig.2A, the treatment with AZT 2.5 μM 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. By contrast, 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).
Due to their characteristics, 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.
Therefore 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).
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001

Claims

1. Compounds having general formula (I) )
Figure imgf000023_0001
wherein:
R1 = NO2, NH2, halogen, NHCH2Z (Z = H, alkyl, aryl, heteroaryl), NHCOW (W = H, alkyl, aryl, heteroaryl);
R2 = H, halogen;
R3 = R4 = H. NO2, NH2, CH3, halogen;
R3 = H, (2)COX, (3)-COX, (X = OR, alkyl, aryl, CCl3, N(alkyl2)); R = alkyl, cycloalkyl, aryl, arylmethyl; (2)-CONHY (Y= H, alkyl, aryl);
R6 = H, halogen, NO2, NH2, OCH3;
A = H, phenyl.
K = H, CHO, CH2NC5H11, CH2NC4H8NCH3
2. Compounds according to claim 1, wherein: R1 = NH2; R2 = H; R = Cl; R = H; R = (2)COX with X = OCH3 and A = H
3. Compounds according to claim 1, wherein: R1 = NH2; R2 = H; R = Cl; R = H; R = (2)COX with X = OC2H5 and A = H
4. Compounds according to claim 1, wherein: R1 = NHCHO; R2 = H; R3 = Cl; R4 = H; R5 = (2)COX with X = OC2H5 and A = H
5. Process for the preparation of compounds having general formula (I) according to claim 1, characterized by the steps of the following scheme (1).
Figure imgf000024_0001
6. Process for the preparation of compounds having general formula (I), characterized by the steps of the following steps (2).
Figure imgf000025_0001
7. Pharmaceutical composition usefull in the medical therapy of retrovirus infections characterized by containing as active substance a pharmacologically effective amount of a substance according to claim 1 in mixture with pharmacologically acceptable diluents and excipients.
8. Therapeutic method for the medical treatment of retrovirus infections consisting of administering by oral route a dose of 10 mg per day and per Kg. of body weight of a compound according to claim 1.
PCT/EP1996/001642 1995-04-21 1996-04-19 1h-pyrrol-1-yl and 1h-indol-1-yl aryl sulphones, processes for their preparation and use for the therapy of hiv-1 infections WO1996033171A1 (en)

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)

Application Number Priority Date Filing Date Title
IT95MI000812A IT1282797B1 (en) 1995-04-21 1995-04-21 PYRRYL-(INDOLYL)-ARIL-SULFONES AND RELATED PRODUCTION PROCESS AND USE IN THE THERAPY OF AIDS VIRUS INFECTIONS
ITMI95A000812 1995-04-21

Publications (1)

Publication Number Publication Date
WO1996033171A1 true WO1996033171A1 (en) 1996-10-24

Family

ID=11371406

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/001642 WO1996033171A1 (en) 1995-04-21 1996-04-19 1h-pyrrol-1-yl and 1h-indol-1-yl aryl sulphones, processes for their preparation and use for the therapy of hiv-1 infections

Country Status (3)

Country Link
AU (1) AU5690196A (en)
IT (1) IT1282797B1 (en)
WO (1) WO1996033171A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2765222A1 (en) * 1997-06-27 1998-12-31 Fournier Ind & Sante NOVEL N-BENZENESULFONYL-L-PROLINE COMPOUNDS, PREPARATION METHOD AND THERAPEUTIC USE
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 (en) * 2000-10-20 2002-04-25 Biovitrum Ab 2-, 3-, 4-, or 5-substituted-n1-(benzensulfonyl)indoles and their use in therapy
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 (en) * 2004-02-27 2005-08-31 Aventis Pharma Deutschland GmbH Pyrrole-derivatives as factor Xa inhibitors
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

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ARTICO, MARINO ET AL: "2-Sulfonyl-4-chloroanilino moiety: A potent pharmacophore for the anti-human immunodeficiency virus Type 1 activity of pyrrolyl aryl sulfones.", J. MED. CHEM. (1996), 39(2), 522-30 CODEN: JMCMAR;ISSN: 0022-2623, 19 January 1996 (1996-01-19), XP000576074 *
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 *
ARTICO, MARINO ET AL: "Synthesis of pyrryl aryl sulfones targeted at the HIV-1 reverse transcriptase", ARCH. PHARM. (WEINHEIM, GER.) (1995), 328(3), 223-9 CODEN: ARPMAS;ISSN: 0365-6233, March 1995 (1995-03-01), XP000576697 *
CHIMENTI, F. ET AL: "Compounds with antiblastic activity. LVII. Anthramycin and related compounds. VI. Synthesis of pyrrolo[1,2-b][1,2,5]benzothiadiazepine derivatives", FARMACO, ED. SCI. (1974), 29(8), 589-97 CODEN: FRPSAX, 1974, XP000576049 *
SILVESTRI, ROMANO ET AL: "Heterocycles with a benzothiadiazepine moiety. 3. Synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide", J. HETEROCYCL. CHEM. (1994), 31(4), 1033-6 CODEN: JHTCAD;ISSN: 0022-152X, 1994, XP002009323 *
WASLEY, JAN W. F. ET AL: "Synthesis of 1-arylsulfonylpyrroles", SYN. COMMUN. (1973), 3(4), 303-4 CODEN: SYNCAV, 1973, XP000576672 *

Cited By (28)

* 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 (en) * 1997-06-27 1999-01-07 Fournier Industrie Et Sante Novel n-benzenesulphonyl-l-proline compounds, preparation method and use in therapy
FR2765222A1 (en) * 1997-06-27 1998-12-31 Fournier Ind & Sante NOVEL N-BENZENESULFONYL-L-PROLINE COMPOUNDS, PREPARATION METHOD AND THERAPEUTIC USE
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 (en) * 2000-10-20 2002-04-25 Biovitrum Ab 2-, 3-, 4-, or 5-substituted-n1-(benzensulfonyl)indoles and their use in therapy
US7087750B2 (en) 2000-10-20 2006-08-08 Biovitrum Ab Compounds, their use and preparation
KR100823908B1 (en) 2000-10-20 2008-04-21 바이오비트럼 에이비(피유비엘) 2-, 3-, 4-, or 5-substituted-n1-benzensulfonylindoles and their use in therapy
US7524839B2 (en) 2000-10-20 2009-04-28 Biovitrum Am (Publ.) Compounds, their use and preparation
EP1568698A1 (en) * 2004-02-27 2005-08-31 Aventis Pharma Deutschland GmbH Pyrrole-derivatives as factor Xa inhibitors
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

Also Published As

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

Similar Documents

Publication Publication Date Title
WO1996033171A1 (en) 1h-pyrrol-1-yl and 1h-indol-1-yl aryl sulphones, processes for their preparation and use for the therapy of hiv-1 infections
Merluzzi et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor
US4841039A (en) 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents
US4681933A (en) 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents
Herdewijn et al. 3'-Substituted 2', 3'-dideoxynucleoside analogs as potential anti-HIV (HTLV-III/LAV) agents
US5248672A (en) Polysubstituted benzimidazole nucleosides as antiviral agents
JP2521426B2 (en) Selective inhibitors of gene expression
CA1286991C (en) Medicament for the treatment of virus infections
Sriram et al. Aminopyrimidinimino isatin analogues: Design of novel non-nucleoside HIV-1 reverse transcriptase inhibitors with broad-spectrum chemotherapeutic properties
JPH1180153A (en) 1,3-oxathiolane nucleoside analog
EP0301064A1 (en) 3'-azido-2',3'-dideoxyuridine anti-retroviral composition.
NO300842B1 (en) 1,3-oxathiolane nucleoside analogues
Sriram et al. Synthesis, antiviral and antibacterial activities of isatin mannich bases
Balzarini et al. The 2′, 3′-dideoxyriboside of 2, 6-diaminopurine selectively inhibits human immunodeficiency virus (HIV) replication invitro
Taraporewala et al. HIV-1 neutralization and tumor cell proliferation inhibition in vitro by simplified analogs of pyrido [4, 3, 2-mn] thiazolo [5, 4-b] acridine marine alkaloids
JPH04300834A (en) Synergistic action of hiv reverse transcriptase inhibitor
Sriram et al. Newer aminopyrimidinimino isatin analogues as non-nucleoside HIV-1 reverse transcriptase inhibitors for HIV and other opportunistic infections of AIDS: design, synthesis and biological evaluation
US4835168A (en) Thiadiazole antiviral agents
EP0261595B1 (en) Pharmaceutical composition comprising 2',3'-dideoxycytidin-2'-ene(2',3'-didehydrocytidine) for treating patients infected with retrovirus
US6531476B1 (en) Piperazine derivatives inhibiting human immunodeficiency virus replication
US5672594A (en) L-erythrosyl nucleosides
RU2595038C1 (en) Drug preparation with antiviral activity (versions)
EP0286825A2 (en) Use of 3'-fluro-3' deoxythymidine for the manufacture of a medicament for the treatment of virus infections
EP0475231A1 (en) Benzodiazepines
Sriram et al. Aminopyrimidinimino isatin analogues: design and synthesis of novel non-nucleoside HIV-1 reverse transcriptase inhibitors with broad-spectrum anti-microbial properties

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BB BG BR BY CA CN CZ EE GE HU IS JP KE KG KP KR KZ LK LR LS LT LV MD MG MK MN MW MX NO NZ PL RO RU SD SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i
CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA