AP604A - Substituted indoloquinoxalines and their use as HIV integrase inhibiting compositions. - Google Patents
Substituted indoloquinoxalines and their use as HIV integrase inhibiting compositions. Download PDFInfo
- Publication number
- AP604A AP604A APAP/P/1995/000751A AP9500751A AP604A AP 604 A AP604 A AP 604A AP 9500751 A AP9500751 A AP 9500751A AP 604 A AP604 A AP 604A
- Authority
- AP
- ARIPO
- Prior art keywords
- group
- iodine
- lower alkyl
- formula
- hiv integrase
- Prior art date
Links
- 108010002459 HIV Integrase Proteins 0.000 title claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 4
- NXOVZLREWXNIDP-UHFFFAOYSA-N 7h-pyrazino[2,3-c]carbazole Chemical class N1=CC=NC2=C3C4=CC=CC=C4NC3=CC=C21 NXOVZLREWXNIDP-UHFFFAOYSA-N 0.000 title description 3
- 239000000203 mixture Substances 0.000 title 1
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 229910052736 halogen Chemical class 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 102000004190 Enzymes Human genes 0.000 claims abstract description 4
- 108090000790 Enzymes Proteins 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 4
- 150000007513 acids Chemical class 0.000 claims abstract description 4
- OIVUHPTVQVCONM-UHFFFAOYSA-N 6-bromo-4-methyl-1h-indazole Chemical compound CC1=CC(Br)=CC2=C1C=NN2 OIVUHPTVQVCONM-UHFFFAOYSA-N 0.000 claims abstract description 3
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims abstract description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 102100034343 Integrase Human genes 0.000 abstract description 7
- 108010061833 Integrases Proteins 0.000 abstract description 6
- 208000030507 AIDS Diseases 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 231100000706 no observed effect level Toxicity 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Use of a compound having the formula 1 and the pysiologically acceptable addition products of the compounds with acids and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide, for preparing a medicament for inhibiting the enzyme human immunodeficiency virus integrase (hiv integrase).
Description
INHIBITOR
The present invention relates to use of indolo-2,3b-quinoxalines of the general formula I
c wherein R^ represents hydrogen or one or several, preferably 1 to 4, similar or different substituents in the positions 1-4 and/or 7-10, selected from halogen, preferably Br, lower alkyl/alkoxy group having not more than 4 carbon atoms, trifluoromethyl group, trichloromethyl group;
X is a group -(CH2)n-R2 wherein R2 represents a nitrogen containing basic residue such as NH2, NHR^ or NR^Rg wherein R4 , Rg and Rg independently are lower alkyl or cycloalkyl and n is an integer of from 1 to 4 and
R2 represents hydrogen, lower alkyl/cycloalkyl group having not more than 4 carbon atoms, and the physiologically acceptable addition products of the compounds with acids and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide, as inhibitors of human immunodeficiency virus (HIV) integrase.
AP/P/ 9 5 / 0 0 7 5
AP.00304
Substituted indoloquinoxalines of formula I have previously been demonstrated to possess valuable activity against several types of vira and several of the compounds also have been demonstrated to show a high anti-cancer effect, cf. our previous patents EP 0,238,459 and U.S. 4,990,510. However, they have also been shown to be Inactive as enzyme inhibitors, cf. Harmenberg et al. Antimicrobial Agents and Chemotherapy, November 1988, pp. 1720-1724. These studies included several virus polymerases.
Of the RNA viruses the retroviruses are of particular importance. Retroviruses are a sub-group of RNA viruses which In order to replicate must first reverse transcribe the RNA of their genome into DNA (transcription is a conventional description of the synthesis of RNA from DNA). Once in the form of DNA the viral genome may be incorporated into the host cell genome which allows it to take advantage of the transcription/translation of the host cell for the purposes of replication. Once incorporated in the host cell the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus may persist for the life of the cell.
AP/P/ 9 5 / 0 0 7 5 1
Human Immunodeficiency Virus (HIV) is a species of retrovirus which has been reproducibly isolated from humans with Acquired Immune Deficiency Syndrome (AIDS) or with the symptoms that frequently precede AIDS. AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections. AIDS is characteristically associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the OKT4 surface marker. HIV is cytopathic and seems to preferentially infect and destroy T-cells bearing the OKT4 marker and it is generally recognised that HIV is the etiological agent of AIDS.
AP .0 0 6 0 4
The treatment of human immunodeficiency virus (HIV) is thus an increasing and important problem which needs to be solved.
It has according to the present invention unexpectedly been found that compounds of the general formula I are active against the enzyme human immunodeficiency virus integrase which was a surprising discovery in view of the fact that compounds of the same type previously had been shown to be inactive as enzyme inhibitors, cf. the article of Harmenberg et al cited above.
According to the present invention it has surprisingly been found that these indoloquinoxalines are active against the enzyme human immunodeficiency virus integrase (HIV integrase). This is evidenced from an in vitro assay in accordance with the method described by M.R. Fesen et al in Proc. Natl. Acad. Sci., USA, March 1993, Vol. 90, pp. 23992403.
In this test the sequental cleavage and integration reactions in the retroviral integrase assay can be illustrated by means of the following figure:
AP/P/ 95/00751
The cleavage reaction removes a dinucleotide from the 3' end of one of the strands at the integration site, thereby conOO verting the P-labeled 21-mer to a 19-mer (step 1). Step 2, the integration can occur at several sites in either recipient strand. Reaction products were separated by electrophoresis and analyzed by autoradiography.
AP. Ο Ο 6 0 A
The substances of formula I used according to the present invention generally show low toxicity; thus, e-g- the compound 2,3-dimethyl-6-(N,N-dimethylaminoethyl)-6H-indologuinoxaline having the formula II ,N-
CIL
CH/ CII3 showed the following data when tested as to toxicity:
Acute toxicity
LD p.o. rats > 800 mg/kg
LD i.v. rats > 100 mg/kg
General toxicity after repeated administration NOEL (no observable effect level)
i.v. rats 12.5 mg/kg for 28 days dermal rabbits 200 mg/kg for 28 days (except for local toxicity)
APIPI 9 5 / 0 0 7 5 1
The substances of formula I used according to the present invention are prepared in accordance with the methods described in our above cited previous patents EP 0,238,459 and U.S. 4,990,510.
One compound of the general formula I, viz. the abovementioned compound II, was tested as an inhibitor· human immunodeficiency virus integrase by the method described by M. R. Fesen et al in the above ci ted article in Pro'·. Natl .
Acad. Sci.
AP.00604
The test results have been plotted in Figure 1 wherein % inhibition is shown as a function of concentration.
Compounds of the general structure I form salts with reverse transcriptase inhibiting phosphonoalkanoic acids (e.g. phosphonoformic acid) hence these are interesting possibilities Cor synergistic effects.
Claims (2)
1. Use of a compound having the formula I
AP. 0Q6n 4
CLAIMS wherein R^ represents hydrogen or one or several, preferably 1 to 4, similar or different substituents in the positions 1-4 and/or 7-10, selected from halogen, preferably Br, lower alkyl/alkoxy group having not more than 4 carbon atoms, trifluoromethyl group, trichloromethyl group;
X is a group -(CH2)n-R2 wherein R2 represents a nitrogen containing basic residue such as NH2, NHR4 or NR^Rg wherein r4, Rg and Rg Independently are lower alkyl or cyeloalkyl and n is an Integer of from 1 to 4 and
Rg represents hydrogen, lower alkyl/cyeloalkyl group having not more than 4 carbon atoms,· and the physiologically acceptable addition products of the compounds with acids and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide, for preparing a medicament for inhibiting the enzyme . human immunodeficiency virus integrese (HIV integrase).
2. Use according to claim 1, characterized in that the compound corresponds to the formula
Ns
CH,Z CHj wherein Rj is hydrogen or Br.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9402241A SE504289C2 (en) | 1994-06-23 | 1994-06-23 | Use of certain indolo-2,3b-quinoxalins for the preparation of a drug for inhibiting the enzyme HIV integrase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9500751A0 AP9500751A0 (en) | 1995-07-31 |
| AP604A true AP604A (en) | 1997-07-21 |
Family
ID=20394513
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1995/000751A AP604A (en) | 1994-06-23 | 1995-06-21 | Substituted indoloquinoxalines and their use as HIV integrase inhibiting compositions. |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5866575A (en) |
| EP (1) | EP0760662B1 (en) |
| AP (1) | AP604A (en) |
| AU (1) | AU2812195A (en) |
| DE (1) | DE69523450T2 (en) |
| ES (1) | ES2166400T3 (en) |
| IL (1) | IL114201A (en) |
| SE (1) | SE504289C2 (en) |
| WO (1) | WO1996000067A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE504289C2 (en) * | 1994-06-23 | 1996-12-23 | Leif J I Lundblad | Use of certain indolo-2,3b-quinoxalins for the preparation of a drug for inhibiting the enzyme HIV integrase |
| SE504862C2 (en) * | 1994-12-27 | 1997-05-20 | Leif J I Lundblad | Use of certain indolo- §2,3b-quinoxalines for the preparation of a drug for the protection of DNA in the initiation and / or promotional phase of carcinogenesis and for the prevention of oxidative stress in patients with diseases related to free radicals |
| US6465466B1 (en) | 1995-12-22 | 2002-10-15 | Leif J. I. Lundblad | Uses of indolo-2 [2,3b] -quinoxalines |
| SE9704723D0 (en) * | 1997-12-17 | 1997-12-17 | Leif J I Lundblad | ligands |
| SE516133C2 (en) * | 1999-02-25 | 2001-11-19 | Lundblad Leif J I | Use of certain substituted indoloquinoxalins for the preparation of an agent for the protection of tissues, organs and cells during transplantation |
| WO2021250204A1 (en) * | 2020-06-10 | 2021-12-16 | Cyxone Ab | Oral formulation comprising a crystalline form of rabeximod |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0238459A1 (en) * | 1986-01-21 | 1987-09-23 | Lundblad, Leif | Substituted indoloquinoxalines |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE504289C2 (en) * | 1994-06-23 | 1996-12-23 | Leif J I Lundblad | Use of certain indolo-2,3b-quinoxalins for the preparation of a drug for inhibiting the enzyme HIV integrase |
| SE504862C2 (en) * | 1994-12-27 | 1997-05-20 | Leif J I Lundblad | Use of certain indolo- §2,3b-quinoxalines for the preparation of a drug for the protection of DNA in the initiation and / or promotional phase of carcinogenesis and for the prevention of oxidative stress in patients with diseases related to free radicals |
-
1994
- 1994-06-23 SE SE9402241A patent/SE504289C2/en not_active IP Right Cessation
-
1995
- 1995-06-18 IL IL11420195A patent/IL114201A/en not_active IP Right Cessation
- 1995-06-19 US US08/765,263 patent/US5866575A/en not_active Expired - Fee Related
- 1995-06-19 AU AU28121/95A patent/AU2812195A/en not_active Abandoned
- 1995-06-19 EP EP95923639A patent/EP0760662B1/en not_active Expired - Lifetime
- 1995-06-19 DE DE69523450T patent/DE69523450T2/en not_active Expired - Fee Related
- 1995-06-19 ES ES95923639T patent/ES2166400T3/en not_active Expired - Lifetime
- 1995-06-19 WO PCT/SE1995/000747 patent/WO1996000067A1/en not_active Ceased
- 1995-06-21 AP APAP/P/1995/000751A patent/AP604A/en active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0238459A1 (en) * | 1986-01-21 | 1987-09-23 | Lundblad, Leif | Substituted indoloquinoxalines |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69523450D1 (en) | 2001-11-29 |
| IL114201A (en) | 2000-11-21 |
| US5866575A (en) | 1999-02-02 |
| SE504289C2 (en) | 1996-12-23 |
| SE9402241D0 (en) | 1994-06-23 |
| EP0760662B1 (en) | 2001-10-24 |
| SE9402241L (en) | 1995-12-24 |
| AU2812195A (en) | 1996-01-19 |
| AP9500751A0 (en) | 1995-07-31 |
| EP0760662A1 (en) | 1997-03-12 |
| DE69523450T2 (en) | 2002-05-16 |
| WO1996000067A1 (en) | 1996-01-04 |
| IL114201A0 (en) | 1995-10-31 |
| ES2166400T3 (en) | 2002-04-16 |
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