WO1992022610A1 - Derives de colorants azoiques presentant une efficacite anti-vih - Google Patents

Derives de colorants azoiques presentant une efficacite anti-vih Download PDF

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Publication number
WO1992022610A1
WO1992022610A1 PCT/US1992/004820 US9204820W WO9222610A1 WO 1992022610 A1 WO1992022610 A1 WO 1992022610A1 US 9204820 W US9204820 W US 9204820W WO 9222610 A1 WO9222610 A1 WO 9222610A1
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WO
WIPO (PCT)
Prior art keywords
azo
compounds
hiv
azo compound
acid
Prior art date
Application number
PCT/US1992/004820
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English (en)
Inventor
Rudiger D. Haugwitz
Leon H. Zalkow
Howard Deutsch
Ewa Gruszecka-Kowalik
Clarita Asibal
Sabiha Qazi
Original Assignee
The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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.)
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Publication date
Application filed by The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services filed Critical The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Publication of WO1992022610A1 publication Critical patent/WO1992022610A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B35/00—Disazo and polyazo dyes of the type A<-D->B prepared by diazotising and coupling
    • C09B35/02—Disazo dyes
    • C09B35/039—Disazo dyes characterised by the tetrazo component
    • C09B35/205—Disazo dyes characterised by the tetrazo component the tetrazo component being a derivative of a diaryl- or triaryl- alkane or-alkene
    • C09B35/215—Disazo dyes characterised by the tetrazo component the tetrazo component being a derivative of a diaryl- or triaryl- alkane or-alkene of diarylethane or diarylethene
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B35/00—Disazo and polyazo dyes of the type A<-D->B prepared by diazotising and coupling
    • C09B35/02—Disazo dyes
    • C09B35/021—Disazo dyes characterised by two coupling components of the same type

Definitions

  • the present invention relates to novel azo compound derivatives which exhibit anti-HIV activity, methods for synthesizing these azo compound derivatives, pharmaceutical compositions containing these azo compound derivatives and methods for treating HIV infections in mammals, especially humans, by administering these derivatives in a pharmacologically acceptable form. More particularly, the present invention is related to substantially pure azo compound derivatives of stilbenes and related compounds wherein the stilbene double bond is replaced with, for example, a methylene-, ethylene-, hetero atom-, amido-, ureido- or thioureido-linkage, as well as pharmacological uses and compositions thereof.
  • compounds which exhibit potential antiherpes activity include the dye Trypan blue (Alarcon et al, "Screening for New Compounds with Antiherpes Activity,” Antiviral Res., 4. (1984), pp. 231-243; and Thome et al, "Inactivation of Measles and Herpes Simplex Viruses by Tripan Blue,” J. Gen. Virol. (1983), 64, pp.
  • Azo and/or azoxy groups are probably the chromophores.
  • the first products of the self condensation of 5-nitro-o-toluenesulfonic acid include 4,4'-dinitro-2,2'- stilbenedisulfonic acid and 4,4'-dinitrobibenzyl-2,2'- disulfonic acid which therefore form convenient starting points for the secondary condensations with arylamines.
  • the largest and probably now the most important class of stilbene dyes consist of such secondary condensations in which the arylamine is an aminoazo compound.
  • the constitutions and therefore the properties of the stilbene dyes vary with the proportions and concentrations of the reactants, and with the temperature and the duration of heating. Probably no two manufacturers use exactly the same conditions for any given dye.”
  • the alkaline condensation of 4- nitrotulene-2-sulfonic acid may be carried in the presence of reducing agents such as glucose or oxidizing agents such as NaOCL.
  • the agents may be added during or after the condensation (H.R. Schweizer, Kunststoffliche Organische Farbstoffe und Strukturbericht. page 406, Springer Verlag, 1964).
  • Reaction conditions, and references for the stilbene dyes have been tabulated (Colour Index, third edition, pages 4365-4373).
  • Zollinger, Color Chemistry, page 101, VCH 1987 except for the primary reaction product, 4,4'-dinitrostilbene-2,2'-disulfonic acid, their structures are not known exactly.
  • R is SO 3 H ⁇ E, CO 2 H ⁇ E or PO(OH) 2 ⁇ E, NO 2 or halogen;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently H, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, CH 3 O, SO 3 H ⁇ E, NO 2 , halogen, CO 2 H ⁇ E and PO(OH) 2 -E;
  • X is -CHCH-, -CH 2 CH 2 -, -CONH-, -NHCONH-, -NHCSNH-, -S-, -SO-, -SO 2 -, -NH-, -CH 2 - or cyclopropyl;
  • ring "A” is an optional benzene ring fused to the phenyl ring to provide a naphthyl ring system or an optional pyridine ring fused to the phenyl ring to provide a quinoline ring system;
  • E represents sodium, potassium, ammonium, magnesium, (HOC 2 H 4 ) 3 N, (CH 3 ) 3 N, CH 3 N(C 2 H 4 OH) 2 , or N-methylglucamine.
  • the present invention further relates to pharmaceutical compositions containing the above-noted compounds of Formula 1 and appropriate pharmaceutically acceptable excipients.
  • a method is provided for treating viral infections of a host by administering to the host an antiviral effective amount of a pharmaceutical composition containing the above-noted azo compound derivatives of Formula 1.
  • Figures 1 and 2 are graphs showing in vitro testing results for anti-HIV activity for Examples 1 and 13.
  • the present invention relates to novel azo compound derivatives of the above-noted Formula 1.
  • azo compounds of structure 1 are prepared by reacting the requisite amine 2, with nitrous acid to give the corresponding arene diazonium ion 3. Coupling of 3. at either acid or basic pH with the appropriate aromatic or heteroaromatic amine, hydroxy or methoxy compound 4 yields compounds of structure 1 as shown in the reaction scheme below.
  • the azo compound derivatives of the present invention may be employed in pharmaceutical compositions and used for treating viral infections, such as Hepatitis B, HTLV-1, HTLV-II, HTLV-IV, HTLV-V, HIV-1, HIV-2, HIV-3 and HIV-4, herpes simplex I, herpes simplex II, herpes zoster, Epstein-Barr virus, cytomegalo viruses and influenza.
  • viral infections such as Hepatitis B, HTLV-1, HTLV-II, HTLV-IV, HTLV-V, HIV-1, HIV-2, HIV-3 and HIV-4, herpes simplex I, herpes simplex II, herpes zoster, Epstein-Barr virus, cytomegalo viruses and influenza.
  • the azo compound derivatives employed in the present invention may be made into pharmaceutical compositions by combination with appropriate pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules ointments. solutions, suppositories, injections, inhalants, and aerosols in the usual ways for their respective route of administration.
  • suitable pharmaceutically acceptable carriers or diluents such as tablets, capsules, powders, granules ointments. solutions, suppositories, injections, inhalants, and aerosols in the usual ways for their respective route of administration.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • the azo compound derivatives employed in the present invention may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the azo compound derivatives may be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, e.g. with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • the azo compound derivatives employed in the present invention may be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • the azo compound derivatives employed in the present invention may be formulated into preparations for injections by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
  • solubilizers isotonic agents
  • suspending agents emulsifying agents, stabilizers and preservatives.
  • the azo compound derivatives employed in the invention in the form of a liquid or minute powder may be filled up in an aerosol container with gas or liquid spraying agents, and if desired, together with conventional adjuvants such as humidifying agents. They may also be formulated as pharmaceuticals for non-pressured preparations such as in a nebulizer or an atomizer.
  • the amount of the azo compound derivatives employed in the present invention to be used varies according to the degree of the infection encountered, and the stages of the disease.
  • a suitable dosage is that which will result in concentration of the azo dye derivative in blood and/or tissues harboring virus which are known to inhibit the virus, e.g. about 1 ⁇ 10 -4 M to 1 ⁇ 10 -6 M, more preferably 1 ⁇ 10 -5 M to 1 ⁇ 10 -6 M.
  • the preferred dosage is that amount sufficient to beneficially affect a host and possibly render the host asymptomatic to the particular viral infection.
  • the dose may vary when the compounds are used prophylactically.
  • Unit dosage forms for oral administration such as syrups, elixirs, and suspensions wherein each dosage unit, e.g., teaspoonful, tablespoonful, contains a predetermined amount of the azo compound derivatives employed in the present invention can be by a pharmaceutically acceptable carrier, such as Sterile Water for Injection, USP, or by normal saline.
  • a pharmaceutically acceptable carrier such as Sterile Water for Injection, USP, or by normal saline.
  • the azo compound derivatives employed in the present invention can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • the azo compound derivatives employed in the present invention can be utilized in aerosol formulation to be administered via inhalation.
  • the azo compound derivatives employed in the present invention can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the azo compound derivatives calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable, diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
  • compositions for example, vehicles, adjuvants, carriers or diluents are readily available to the public.
  • Coupling of 3 at either acid or basic pH with the appropriate aromatic or heteroaromatic amine, hydroxy, or methoxy compound 4 yields compounds of structure 1.
  • the conditions for coupling compound 3 with compound 4 include chilling the freshly prepared diazonium salt solution or suspension to 10-15oC and then with rapid stirring adding it rapidly to the appropriate aromatic or heteroaromatic amine, hydroxy or methoxy compound 4. The mixture is then stirred for a period of about two hours at ice bath temperature and then for about three hours at room temperature. The resulting solid is then filtered off, washed with ice water and repeatedly purified.
  • Sodium, potassium and ammonium salts of 1 are water soluble, but the calcium, barium and lead analogs are much less so and often insoluble. Salts with organic cations such as the S-benzylthiouronium ion have frequently defined melting points and may be used to characterize the acids whose melting points are usually ill defined. Further details regarding the sale formation may be found in Houben-Weyl's Methoden der Organischen Chemie, Vol 9, chapter 16, Thieme Verlag, 1955.
  • Pure compounds of structure 1 are obtained by subjecting the crude reaction mixture to centrifugal partition chromatography which upon repeated cycles will furnish spectrally pure dye.
  • the following examples are provided for illustration purposes only without departing from the spirit or scope of the invention.
  • Example 1 The melting point of Example 1 is over 300oC. TLC
  • Example 2-12 Following the procedures of Example 1 and coupling diazonium salt 3 with the appropriate amine-, hydroxy-, or methoxyquinoline of structure 4 the compounds of Examples 2-12 as shown in Table 1 are obtained.
  • Example 13 Following the procedures of Example 1 and coupling diazonium salt 3 with the appropriate amine-, hydroxy-, or methoxybenzene of structure 4 the compounds of Examples 13- 25 as shown in Table 2 are obtained.
  • Example 26 Following the procedures of Example 1 and coupling diazonium salt 3 with the appropriate amine-, hydroxy- or methoxynaphthalene of structure 4 the compounds of Examples 26-42 as shown in Table 3 are obtained. The structure of Example 26 is indicated below.
  • HIV Human Immunodeficiency Virus
  • Weislow, O.W. et al, "New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS- antiviral activity," J. Natl. Cancer Inst.. 81:577-586, 1989 is designed to detect agents acting at any stage of the virus reproductive cycle.
  • the assay basically involves the killing of T4 lymphocytes by HIV. Small amounts of HIV are added to cells, and a complete cycle of virus reproduction is necessary to obtain the required cell killing. Agents that interact with virions, cells, or virus gene-products to interfere with viral activities will protect cells from cytolysis.
  • the system is automated in several features to accommodate large numbers of candidate agents and is generally designed to detect anti-HIV activity. However, compounds that degenerate or are rapidly metabolized in the culture conditions may not show activity in this screen. All tests are compared with at least one positive (e.g., AZT-treated) control done at the same time under identical conditions.
  • Candidate agent is dissolved in dimethyl sulfoxide (unless otherwise instructed) then diluted 1:100 in cell culture medium before preparing serial half-log 10 dilutions.
  • T4 lymphocytes CEM cell line
  • HIV-1 is added, resulting in a 1:200 final dilution of the compound.
  • Uninfected cells with the compound serve as a toxicity control, and infected and uninfected cells without the compound serve as basic controls.
  • the tetrazolium salt, XTT is added to all wells, and cultures are incubated to allow formazan color development by viable cells. 4. Individual wells are analyzed spectrophotometrically to quantitate formazan production, and in addition are viewed microscopically for detection of viable cells and confirmation of protective activity.
  • Drug-treated virus-infected cells are compared with drug-treated noninfected cells and with other appropriate controls (untreated infected and untreated noninfected cells, drug-containing wells without cells, etc.) on the same plate.
  • Figures 1 and 2 display a plot of the log 10 of the concentrations (as ⁇ g/mL or molar) of the Examples 1 and 13 compounds, respectively, against the measured test values expressed as a percentage of the uninfected, untreated control values.
  • the solid line connecting the diamond symbols depicts the percentage of surviving HIV-infected cells treated with your sample (at the indicated concentration) relative to uninfected, untreated controls.
  • This line expresses the in vitro anti-HIV activity of the Example.
  • the dashed line connecting the triangular syrnbols depicts the percentage of surviving uninfected cells treated with the Example relative to the same uninfected, untreated controls. This line expresses the in vitro growth inhibitory properties of the Example.
  • the viral cytopathic effect in this particular experiment is indicated by a dotted reference line.
  • This line shows the extent of destruction of cells by the virus in the absence of treatment and is used as a quality control parameter. Survival values of this parameter less then 50% are considered acceptable in the current protocol. The percent of protection has been calculated from the data and is presented on the right side of the graph. Approximate values for 50% effective concentration (EC 50 ) have been calculated for each test and are provided for most Examples in Tables 1-3.

Abstract

L'invention décrit des nouveaux dérivés de composés azoïques présentant une efficacité anti-VIH, des procédés de synthèse desdits dérivés, des compositions pharmaceutiques contenant ces dérivés de composés azoïques, ainsi que des procédés servant à traiter les infections dues au VIH chez l'animal et chez l'homme par l'administration desdits dérivés sous une forme acceptable pharmacologiquement.
PCT/US1992/004820 1991-06-14 1992-06-12 Derives de colorants azoiques presentant une efficacite anti-vih WO1992022610A1 (fr)

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US71565291A 1991-06-14 1991-06-14
US715,652 1991-06-14

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050347A1 (fr) * 1997-05-05 1998-11-12 The Regents Of The University Of California Naphtols utilisables dans des methodes antivirales
WO1999037154A1 (fr) * 1998-01-09 1999-07-29 Minnesota Mining And Manufacturing Company Procedes permettant de limiter la croissance des micro-organismes par des composes contenant un metal
US6432396B1 (en) * 2000-07-06 2002-08-13 3M Innovative Properties Company Limiting the presence of microorganisms using polymer-bound metal-containing compositions
US6653321B1 (en) 1999-07-29 2003-11-25 Telik, Inc. Naphthylsulfonic acids and related compounds as glucose uptake agonists
JP2007145995A (ja) * 2005-11-28 2007-06-14 Mitsubishi Chemicals Corp 水溶性色素並びにそれを用いた色素組成物、異方性色素膜及び偏光素子
WO2008042806A2 (fr) * 2006-10-04 2008-04-10 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Dérivés d'acide stilbènedisulfonique comme inhibiteurs de l'intégrase rétrovirale
EP2599480A1 (fr) * 2011-12-03 2013-06-05 Universität Innsbruck Compositions pour le traitement de la grippe
CN110041732A (zh) * 2018-01-16 2019-07-23 天津市宏津盛化工有限公司 皮革用湖蓝染料及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB190211766A (en) * 1902-05-23 1903-02-19 Ernest James Turner Improvements in Guards for Calendars or Cylinders of Laundry Machines and other Machines.
US2489463A (en) * 1946-02-25 1949-11-29 Parker Pen Co Stable blue writing ink and a dye therefor
US4098570A (en) * 1976-04-09 1978-07-04 Ciba-Geigy Corporation Process for dyeing or printing polyamide material

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB190211766A (en) * 1902-05-23 1903-02-19 Ernest James Turner Improvements in Guards for Calendars or Cylinders of Laundry Machines and other Machines.
US2489463A (en) * 1946-02-25 1949-11-29 Parker Pen Co Stable blue writing ink and a dye therefor
US4098570A (en) * 1976-04-09 1978-07-04 Ciba-Geigy Corporation Process for dyeing or printing polyamide material

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 77, No. 12, Abstract 96575e issued 02 October 1992, (Columbus, Ohio, U.S.A.), RAGUZINA, L.M., "Spectrophotometric Determination of Gallium (III)...". *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050347A1 (fr) * 1997-05-05 1998-11-12 The Regents Of The University Of California Naphtols utilisables dans des methodes antivirales
US6140368A (en) * 1997-05-05 2000-10-31 The Regents Of The University Of California Naphthols useful in antiviral methods
WO1999037154A1 (fr) * 1998-01-09 1999-07-29 Minnesota Mining And Manufacturing Company Procedes permettant de limiter la croissance des micro-organismes par des composes contenant un metal
US6248733B1 (en) 1998-01-09 2001-06-19 3M Innovative Properties Company Method for limiting the growth of microorganisms using metal-containing compounds
US6653321B1 (en) 1999-07-29 2003-11-25 Telik, Inc. Naphthylsulfonic acids and related compounds as glucose uptake agonists
US6432396B1 (en) * 2000-07-06 2002-08-13 3M Innovative Properties Company Limiting the presence of microorganisms using polymer-bound metal-containing compositions
JP2007145995A (ja) * 2005-11-28 2007-06-14 Mitsubishi Chemicals Corp 水溶性色素並びにそれを用いた色素組成物、異方性色素膜及び偏光素子
WO2008042806A2 (fr) * 2006-10-04 2008-04-10 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Dérivés d'acide stilbènedisulfonique comme inhibiteurs de l'intégrase rétrovirale
WO2008042806A3 (fr) * 2006-10-04 2008-12-24 Us Gov Health & Human Serv Dérivés d'acide stilbènedisulfonique comme inhibiteurs de l'intégrase rétrovirale
EP2599480A1 (fr) * 2011-12-03 2013-06-05 Universität Innsbruck Compositions pour le traitement de la grippe
CN110041732A (zh) * 2018-01-16 2019-07-23 天津市宏津盛化工有限公司 皮革用湖蓝染料及其制备方法
CN110041732B (zh) * 2018-01-16 2020-09-22 天津市宏津盛化工有限公司 皮革用湖蓝染料及其制备方法

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