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WO1991015200A2 - Utilisation trinitrobenzenes ou d'acide carminique pour le traitement du cancer ou de maladies virales - Google Patents

Utilisation trinitrobenzenes ou d'acide carminique pour le traitement du cancer ou de maladies virales Download PDF

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Publication number
WO1991015200A2
WO1991015200A2 PCT/GB1991/000517 GB9100517W WO9115200A2 WO 1991015200 A2 WO1991015200 A2 WO 1991015200A2 GB 9100517 W GB9100517 W GB 9100517W WO 9115200 A2 WO9115200 A2 WO 9115200A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
formulation
optionally
carminic acid
prophylaxis
Prior art date
Application number
PCT/GB1991/000517
Other languages
English (en)
Other versions
WO1991015200A3 (fr
Inventor
Washington Odur Ayuko
Original Assignee
Radopath Limited
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
Priority claimed from GB909007453A external-priority patent/GB9007453D0/en
Priority claimed from GB909012166A external-priority patent/GB9012166D0/en
Priority claimed from GB919103075A external-priority patent/GB9103075D0/en
Application filed by Radopath Limited filed Critical Radopath Limited
Priority to AU75604/91A priority Critical patent/AU662883B2/en
Priority to BR919106310A priority patent/BR9106310A/pt
Priority to MC91GB9100517D priority patent/MC2246A1/fr
Priority to JP3506514A priority patent/JPH06501449A/ja
Publication of WO1991015200A2 publication Critical patent/WO1991015200A2/fr
Publication of WO1991015200A3 publication Critical patent/WO1991015200A3/fr
Priority to NO92923824A priority patent/NO923824L/no
Priority to FI924475A priority patent/FI924475L/fi
Priority to LVP-92-149A priority patent/LV10574B/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates generally to compounds and therapeutic formulations based on trinitrobenzene and/or carminic acid (or their derivatives) which in certain low concentrations exhibit anti-cancer or anti-viral activity.
  • Immunotherapy is designed to strengthen the innate ability of the patient's immune system to fight cancer.
  • the present invention approaches these problems through the low dose use of readily available trinitrobenzene compounds and/or carminic acid (either singularly or in combination). It has now been found, most surprisingly, that such compounds are efficacious as anti-cancer or anti-viral agents when administered at low concentrations, regardless of patient bodyweight. Toxicity and expense problems associated with the prior art thus do not apply.
  • the invention provides for use in the therapy or prophylaxis of neoplasm or viral infection in human and non-human animals, a formulation comprising a compound dissolved or dispersed in an aqueous medium at a concentration of 10 -3 to 10 -15 moles per litre and having the general formula:
  • X is selected from OH, NH 2 halogen, a sulfo group, a carboxyl group, OCH 3 or a substituted or unsubstituted hydrazyl group of the formula:
  • A is hydrogen or an unpaired electron of the nitrogen atom
  • Y is hydrogen or an organic group and Z is an organic group, or Y and Z together with the adjacent nitrogen atom form a nitrogen-containing heterocycle; provided that when X is a substituted or unsubstituted hydrazyl group as aforesaid one of the NO 2 groups may be replaced by a sulfo group.
  • the sulfo group is preferably a sulphonate salt group, optionally, sodium or potassium sulphonate (SO 3 Na or SO 3 K) and the carboxyl group is preferably a carboxylate salt group, optionally, sodium or potassium carboxylate.
  • the invention provides for use in the therapy or prophylaxis of neoplasm or viral infection in human and non-human animals, a formulation comprising:
  • P is a nitrophenyl
  • X is selected from OH, NH 2 halogen, a sulfo group, a carboxyl group, OCH 3 or a substituted or unsubstituted hydrazyl group of the formula:
  • A is hydrogen or an unpaired electron of the nitrogen atom
  • Y is hydrogen or an organic group and Z is an organic group, or Y and Z together with the adjacent nitrogen atom form a nitrogen-containing heterocycle; provided that when X is a substituted or unsubstituted hydrazyl group as aforesaid one of the NO 2 groups may be replaced by a sulfo group; and
  • a further aspect of the invention is a pharmaceutical or veterinary formulation wherein a compound as defined above is dissolved or dispersed in an aqueous medium at a concentration of from about 10 -3 to 10 -15 moles per litre.
  • carminic acid has been found to exhibit anti-viral effects when used alone at low molar concentrations according to the invention.
  • an important aspect of the invention is the use of carminic acid and its derivatives in the preparation of a medicament for the prophylaxis or therapy of viral disease such as AIDS
  • Such derivatives have the following general formula:
  • R is COOH (i.e., carminic acid) or some other organic or inorganic functional group such as NH 2 , SO 3 [K, H or Na], and the C-glycoside is any sugar.
  • the anthraquinone may optionally be a benzoquinone (single ring) or napthaquinone (double ring).
  • Preferred formulations according to the invention comprise a trinitrobenzene derivative (such as picryl chloride or diphenyl picrylhydrazine (DPPH)), an anthraquinone having a glycosidic moiety (such as carminic acid or a derivative thereof), or an admixture of one or more trinitrobenzene derivatives and an anthraquinone glycoside.
  • a trinitrobenzene derivative such as picryl chloride or diphenyl picrylhydrazine (DPPH)
  • an anthraquinone having a glycosidic moiety such as carminic acid or a derivative thereof
  • Carminic acid has been used in the laboratory for staining nucleic acids and, interestingly, its effect on DNA is inhibited by, inter alia, free radical scavengers (Lown et al., Bioorganic Chem. 8 (1979), 17-24).
  • such a formulation contains the active ingredients dissolved or suspended in an aqueous medium at a concentration in the range from 10 -3 to 10 -15 moles per litre, and may be administered orally or parenterally.
  • Carminic acid is especially useful for anti-viral treatment.
  • FIGURE 1 is a plot of the average survival time in days of NMRI mice transplanted with MAC16 colon carcinoma cells after treatment with various therapeutically-effective concentrations of picryl chloride according to the teachings of the present invention
  • FIGURE 2 is a plot of the dose response of a GM892 cell line to diphenyl picrylhydrazyl (DPPZ) and diphenyl picrylhydrazine (DPPH) according to the teachings of the invention.
  • DPPZ diphenyl picrylhydrazyl
  • DPPH diphenyl picrylhydrazine
  • a compound capable of initiating and propagating a free radical mechanism may be dissolved or dispersed in an aqueous medium at a therapeutically-effective concentration in the range of from about 10 -3 - 10 -15 moles per litre.
  • Such compounds catalytically trigger free radical chain reactions, thereby producing active chemical species that selectively attack abnormal cells.
  • One such set of compounds include derivatives of nitrobenzene of the following general formula:
  • X is selected from OH, NH 2, halogen, a sulfo group, a carboxyl group, OCH 3, or a substituted or unsubstituted hydrazyl group.
  • X is the hydroxyl radical
  • the compound is picric acid.
  • X is chloride, picryl chloride is formed, and so forth.
  • the sulfo group is preferably a sulphonate salt group, optionally, sodium or potassium sulphonate (SO 3 Na or SO 3 K) and the carboxyl group is preferably a carboxylate salt group, optionally, sodium or potassium carboxylate.
  • the halogen is Cl, Br or F.
  • the hydrazyl group or derivative is a radical of the following general formula:
  • A is hydrogen or the unpaired electron of one nitrogen atom
  • Y is hydrogen or an organic group and Z is an organic group, or Y znd Z together with the adjacent nitrogen atom form a nitrogen-containing heterocycle (e.g., a carbazyl group); provided that when X is a substituted or unsubstituted hydrazyl group as aforesaid one of the NO 2 groups may be replaced by a sulfo group.
  • A is hydrogen and Y and Z are phenyl groups
  • the overall compound becomes diphenyl picrylhydrazine (DPPH).
  • DPPZ diphenyl picrylhydrazyl
  • Carbazyl picrylamine (CPZ) is formed when A is hydrogen and Y and Z are paired phenyl groups, thus forming a nitrogen-containing heterocycle.
  • One particularly desirable water-soluble derivative has the following structural formula for the hydrazyl-derived group:
  • Y and Z are phenyl groups, and potassium is optionally hydrogen or sodium.
  • DDSH diphenyl dinitrosulfonate phenylhydrazyl
  • SO 3 K sulfonate potassium salt group SO 3 K (substituted for the 5-NO 2 group) and is preferably synthesized by the interaction of diphenylhydrazine with the potassium salt of 2-chloro-3, 5-dinitro-benzene sulfonic acid in dilute alcohol or dilute dioxane, with subsequent oxidation of the resulting hydrazine by lead dioxide. Additional details concerning the synthesis of the DDSH radical are set forth in Investigation ln The Field Of The Chemistry Of Free Radicals Of The
  • FIGURE 1 is a plot of the average survival time in days of NMRI mice transplanted with MAC16 colon carcinoma cells after treatment by subcutaneous injection with various therapeutically-effective concentrations of picryl chloride according to the teachings of the present invention.
  • the untreated control animals lived an average of less than 10 days, whereas animals treated with the various specified concentrations of picryl chloride had significant survival rates.
  • the best results were obtained at 10 -12 molar concentration when the animals were injected subcutaneously for five (5) days (one injection per day). At this concentration, most of the treated animals were tumor-free on day 60.
  • FIGURE 2 is a plot of the dose response of a GM892 cell line to diphenyl picrylhydrazyl (DPPZ) and diphenyl picrylhydrazine (DPPH). The figure represents an average of 3-6 different experiments, with a Coulter counter used to determine the cell count. As seen in FIGURE 2 , both agents provide significant in-vitro anti-tumor effects on this cell line when administered in a substantially pure aqueous solution/suspension ranging at dilutions between about 10 -3 - 10 -15 molar concentration.
  • DPPZ diphenyl picrylhydrazyl
  • DPPH diphenyl picrylhydrazine
  • carminic acid alone (or a derivative thereof) is especially useful as an anti-viral agent.
  • Carminic acid has a C-glycoside (C 6 H 11 O 5 ) side-linked to a polyhydroxyanthraquinone as evidenced by the following formula:
  • one preferred composition is an admixture of one or more trinitrobenzene derivatives and an anthraquinone having a glycosidic moiety, optionally carminic acid.
  • one such composition is an admixture of picryl chloride (or picryl sulfonate) and carminic acid.
  • picryl chloride or picryl sulfonate
  • the preferred ratio of picryl chloride to carminic acid is preferably between 1:1 and 1:2 but with the concentration of the active ingredients being in a therapeutically-effective concentration of between about 10 -3 - 10 -15 molar concentration.
  • a therapeutically-effective amount of the pharmaceutically composition in solution or suspension is between 2.0-5.0 mis, and this amount is apparently substantially independent of the bodyweight of the host animal .
  • more than one trinitrobenzene can be advantageously incorporated into the admixture.
  • these trinitrobenzenes may act synergistically in generating free radicals and a free radical chain reaction mechanism.
  • the quinone if used, can also be a source of OH free radicals.
  • predetermined amounts of picric acid, DPPH and carminic acid are mixed in a substantially pure aqueous solution/suspension ranging at dilutions giving between about 10 -3 - 10 -15 molar concentration.
  • the DPPH has the highest dilution, followed by the carminic acid and then the picric acid.
  • a pharmaceutical or veterinary composition may be formed by first dissolving the hydrazine derivative in double-distilled, deionized water in a clean glass container under sterile conditions. Thereafter, the carminic acid is added and mixed into the solution. The picric acid is then added and the solution throughly mixed. Serial dilution can then be used to obtain the desired molar concentration. Alternatively, the three constituents are mixed together prior to dissolution in the carrier.
  • the efficacy of a free radical chain reaction mechanism may be enhanced through administration of iron or any other transitional metal, especially copper.
  • the anti-tumor agents described above can be administered to the host subcutaneously, intravenously or using an acceptable carrier or excipient.
  • double-distilled, deionized water is the preferred solution/suspension liquid
  • other dilutants such as a dimethylsulfoxide/water solution, arachis oil, olive oil, vegetable oil or corn oil
  • Yet another useful catalyst for the free radical mechanism is a (low concentration) polyunsaturated fatty acid, which is a long chain free carboxylic acid typically found in a lipid.
  • trinitrobenzene derivatives useful in accordance with the present invention are picric acid, picryl chloride, picryl sulfonate, diphenyl picrylhydrazine and diphenyl picrylhydrazyl, other trinitrobenzene compounds are also suitable catalysts for the free radical mechanism. Such compounds are included within the above general formula.
  • Z when A is hydrogen and Y is a phenyl group, Z may be, for example, any aromatic group such as shown in appendix Table I or an aliphatic group as shown in appendix Table II. Alternatively, Y and Z may be any of the aromatic compounds shown in appendix Table III. Another set of "phenyl” derivatives is derived from the compounds shown in appendix Table IV and a set of “carbazyl” derivatives is defined by the formulae set forth in appendix Table V.
  • the preferred hydrazine derivatives are diphenyl picrylhydrazine (DPPH) and derivatives thereof such as diphenyl picrylhydrazyl (DPPZ), phenyl picrylhydrazine (PPH), carbazyl picrylamine (CPZ) and 2-sulfophenyl, 2-sulfophenyl, picrylhydrazine.
  • DPPH diphenyl picrylhydrazine
  • DPPZ diphenyl picrylhydrazyl
  • PPH phenyl picrylhydrazine
  • CPZ carbazyl picrylamine
  • 2-sulfophenyl 2-sulfophenyl, 2-sulfophenyl, picrylhydrazine.
  • DDSH diphenyl dinitrosulfonate phenylhydrazyl
  • carminic acid has evidenced significant anti-viral effects when dissolved in an aqueous medium at low concentrations.
  • a thirty seven year old male was diagnosed as HIV positive by the standard ELISA test.
  • the patient had oral thrush, very severe herpes zooster of the left facial nerve with involvement of the left orbital region, hard bilateral cervical lymph nodes, and an enlarged liver and spleen.
  • the patient was treated with carminic acid, dissolved in double-distilled, deionized water at 10 -6 molar concentration, via subcutaneous injections. For five days, the patient received a single 2.0 ml. injection per day.
  • carminic acid in therapeutically-effective concentrations as described, appears to stimulate the immune system. It is believed that other quinones having side-chained sugars (and derivatives thereof) may also exhibit anti-viral activity when administered according to the teachings herein.
  • an important aspect of the invention is the use of carminic acid and its derivatives in the preparation of a medicament for the prophylaxis or therapy of viral disease such as AIDS.
  • Such derivatives have the following genaral formula:
  • R is COOH (carminic acid) or other organic or inorganic functional group such as NH 2 , SO 3 [K, H or Na], and the C-glycoside is any sugar.
  • the anthraquinone may optionally be a benzoguinone (single ring) or napthaquinone (double ring).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de radicaux à base de trinitrobenzène, acide carminique et ses dérivés, utilisables comme agents anti-cancer et anti-virus. Ces composés et les formules basées sur ceux-ci, peuvent s'administrer par voie orale ou parentérale à un malade humain ou animal, en solution/suspension aqueuse pratiquement pure dans une plage de dilutions située entre 10?-3 et 10-15¿ en concentrations molaires. Selon une application préférentielle de l'invention, on utilise un ou davantage desdits composés et un anthraquinone (comme l'acide carminique). L'acide carminique seul présente des effets anti-virus notoires.
PCT/GB1991/000517 1990-04-03 1991-04-03 Utilisation trinitrobenzenes ou d'acide carminique pour le traitement du cancer ou de maladies virales WO1991015200A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU75604/91A AU662883B2 (en) 1990-04-03 1991-04-03 Use of trinitrobenzenes or carminic acid in the treatment of cancer or viral diseases
BR919106310A BR9106310A (pt) 1990-04-03 1991-04-03 Formulacao para terapia ou profilaxia de neoplasma ou infeccao viral formulacao farmaceutica ou veterinaria,radial ou composto,formulacao para a terapia de infeccao viral e glicosido de anfraquinona
MC91GB9100517D MC2246A1 (fr) 1990-04-03 1991-04-03 Utilisation de trinitrobenzenes ou d'acide carminique dans le traitement du cancer ou des maladies virales
JP3506514A JPH06501449A (ja) 1990-04-03 1991-04-03 癌またはウイル性疾患の治療におけるトリニトロベンゼン類またはカルミン酸の使用
NO92923824A NO923824L (no) 1990-04-03 1992-10-01 Bruk av trinitrobenzener eller karminsyre ved behandling av kreft eller virussykdommer
LVP-92-149A LV10574B (en) 1990-04-03 1992-10-05 The therapeutic use of low concentrations of trinitrobenzene, carminic acid and their derivatives as anti-cancer and anti-viral agents
FI924475A FI924475L (fi) 1990-04-03 1992-10-05 Anvaendning av trinitrobensener och karminsyra vid behandling av canceroch virusbetingade sjukdomar

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB909007453A GB9007453D0 (en) 1990-04-03 1990-04-03 Tumour therapy
GB9007453.5 1990-04-03
GB909012166A GB9012166D0 (en) 1990-05-31 1990-05-31 Hydrazine derivatives for cancer therapy
GB9012166.6 1990-05-31
GB9103075.9 1991-02-13
GB919103075A GB9103075D0 (en) 1991-02-13 1991-02-13 Trinitrobenzene derivatives and their therapeutic use

Publications (2)

Publication Number Publication Date
WO1991015200A2 true WO1991015200A2 (fr) 1991-10-17
WO1991015200A3 WO1991015200A3 (fr) 1992-03-05

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PCT/GB1991/000517 WO1991015200A2 (fr) 1990-04-03 1991-04-03 Utilisation trinitrobenzenes ou d'acide carminique pour le traitement du cancer ou de maladies virales

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EP (1) EP0524212A1 (fr)
JP (1) JPH06501449A (fr)
AU (1) AU662883B2 (fr)
BR (1) BR9106310A (fr)
CA (1) CA2079803A1 (fr)
FI (1) FI924475L (fr)
HU (1) HUT62785A (fr)
LV (1) LV10574B (fr)
MC (1) MC2246A1 (fr)
NO (1) NO923824L (fr)
WO (1) WO1991015200A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499467A2 (fr) * 1991-02-13 1992-08-19 Radopath Limited Utilisation de quinones dans le traitement du cancer ou du SIDA
WO1994027584A2 (fr) * 1993-05-21 1994-12-08 Radopath Limited Medicaments d'arylation
US5412123A (en) * 1993-02-08 1995-05-02 Glycomed Incorporated Anthraquinone and anthracene derivatives as inhibitors of the cell-adhesion molecules of the immune system
GB2284153A (en) * 1993-05-21 1995-05-31 Radopath Ltd Therapeutic arylating agents
WO1995024897A1 (fr) * 1994-03-17 1995-09-21 Radopath Limited Agents antiviraux et anticancereux
LT3609B (en) 1993-05-21 1995-12-27 Radopath Ltd Arylating agents, used in the treatment of cancerand disease caused by viral infection
WO1996029067A1 (fr) * 1995-03-17 1996-09-26 Radopath Limited Agents antiviraux et anticancereux
WO1997034593A1 (fr) * 1996-03-18 1997-09-25 Radopath Limited AGONISTES UTILES DANS LA COSTIMULATION DE LYMPHOCYTES T INDUITS PAR TcR/CD3
WO1999029706A2 (fr) * 1997-12-08 1999-06-17 Glycomed Incorporated IMITATEURS DE L'OLIGOSACCHARIDE SIALYL-LEWISx A BASE D'ANALOGUES DE DISALICYLATE
CN112424291A (zh) * 2018-07-17 2021-02-26 皮利公司 蒽醌衍生物及其作为着色剂的用途

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EP0314580A1 (fr) * 1987-10-30 1989-05-03 Institut Pasteur Application de groupes nitrophényles à la stimulation des capacités d'incorporation d'un médicament dans les cellules sensibles de l'hôte

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US4032659A (en) * 1969-03-20 1977-06-28 American Home Products Corporation Method of viral chemoprophylaxis
US4724230A (en) * 1982-09-17 1988-02-09 Therapeutical Systems Corp. Method for producing oncolysis
EP0314580A1 (fr) * 1987-10-30 1989-05-03 Institut Pasteur Application de groupes nitrophényles à la stimulation des capacités d'incorporation d'un médicament dans les cellules sensibles de l'hôte

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014454A1 (fr) * 1991-02-13 1992-09-03 Radopath Limited Utilisation de quinones dans le traitement du cancer ou du sida
EP0499467A3 (en) * 1991-02-13 1992-12-16 Radopath Limited Use of quinones in the treatment of cancer or aids
EP0499467A2 (fr) * 1991-02-13 1992-08-19 Radopath Limited Utilisation de quinones dans le traitement du cancer ou du SIDA
LT3197B (en) 1991-02-13 1995-03-27 Radopath Ltd Use of quinones in the treatmet of cancer or aids
US5412123A (en) * 1993-02-08 1995-05-02 Glycomed Incorporated Anthraquinone and anthracene derivatives as inhibitors of the cell-adhesion molecules of the immune system
LT3609B (en) 1993-05-21 1995-12-27 Radopath Ltd Arylating agents, used in the treatment of cancerand disease caused by viral infection
GB2312375A (en) * 1993-05-21 1997-10-29 Radopath Ltd Therapeutic arylating agents
GB2284153A (en) * 1993-05-21 1995-05-31 Radopath Ltd Therapeutic arylating agents
GB2284153B (en) * 1993-05-21 1998-02-25 Radopath Ltd Substances for use in treatment of HIV-infection in HIV-infected patients
WO1994027584A3 (fr) * 1993-05-21 1995-05-26 Radopath Ltd Medicaments d'arylation
WO1994027584A2 (fr) * 1993-05-21 1994-12-08 Radopath Limited Medicaments d'arylation
GB2312375B (en) * 1993-05-21 1998-02-25 Radopath Ltd Agents for treatment of cancer
EP0677292A1 (fr) * 1994-03-17 1995-10-18 Radopath Limited Médicaments antiviraux et anticancer
AP575A (en) * 1994-03-17 1997-01-31 Radopath Ltd Anti viral and anti cancer agents.
WO1995024897A1 (fr) * 1994-03-17 1995-09-21 Radopath Limited Agents antiviraux et anticancereux
WO1996029067A1 (fr) * 1995-03-17 1996-09-26 Radopath Limited Agents antiviraux et anticancereux
WO1997034593A1 (fr) * 1996-03-18 1997-09-25 Radopath Limited AGONISTES UTILES DANS LA COSTIMULATION DE LYMPHOCYTES T INDUITS PAR TcR/CD3
WO1999029706A2 (fr) * 1997-12-08 1999-06-17 Glycomed Incorporated IMITATEURS DE L'OLIGOSACCHARIDE SIALYL-LEWISx A BASE D'ANALOGUES DE DISALICYLATE
WO1999029706A3 (fr) * 1997-12-08 1999-08-12 Glycomed Inc IMITATEURS DE L'OLIGOSACCHARIDE SIALYL-LEWISx A BASE D'ANALOGUES DE DISALICYLATE
CN112424291A (zh) * 2018-07-17 2021-02-26 皮利公司 蒽醌衍生物及其作为着色剂的用途

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LV10574B (en) 1995-08-20
CA2079803A1 (fr) 1991-10-04
WO1991015200A3 (fr) 1992-03-05
FI924475A0 (fi) 1992-10-05
NO923824D0 (no) 1992-10-01
AU7560491A (en) 1991-10-30
EP0524212A1 (fr) 1993-01-27
NO923824L (no) 1992-11-26
AU662883B2 (en) 1995-09-21
MC2246A1 (fr) 1993-03-25
LV10574A (lv) 1995-04-20
FI924475L (fi) 1992-10-05
BR9106310A (pt) 1993-04-20
HU9203148D0 (en) 1992-12-28
HUT62785A (en) 1993-06-28
JPH06501449A (ja) 1994-02-17

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