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WO2022002898A1 - Dérivés de 6h-indolo(2,3-b)quinoxaline utiles en thérapie, en particulier dans une infection virale - Google Patents

Dérivés de 6h-indolo(2,3-b)quinoxaline utiles en thérapie, en particulier dans une infection virale Download PDF

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Publication number
WO2022002898A1
WO2022002898A1 PCT/EP2021/067787 EP2021067787W WO2022002898A1 WO 2022002898 A1 WO2022002898 A1 WO 2022002898A1 EP 2021067787 W EP2021067787 W EP 2021067787W WO 2022002898 A1 WO2022002898 A1 WO 2022002898A1
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Prior art keywords
compound
virus
pharmaceutically acceptable
acceptable salt
indolo
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English (en)
Inventor
Jan Bergman
Ngarita KINGI
Eva O'KEEFFE
Mohammed Homman
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Vironova Medical AB
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Vironova Medical AB
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    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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

Definitions

  • the present invention relates to certain 6H-indolo(2,3-b)quinoxaline derivatives for use in therapy, in particular in the treatment of a virus infection, e.g. herpes virus infection.
  • a virus infection e.g. herpes virus infection.
  • WO 96/19996 teaches a multi-step process comprising an initial step of nitration in 9-position to obtain the corresponding 9-nitro compound as a synthetic intermediate, the hydrogenation of which leads to the corresponding 9-amino compound, which subsequently is submitted to a diazotization, followed by treatment with a Cu-based catalyst to give the desired 9-hydroxy compound.
  • WO 96/19996 does not suggest that the 9-nitro compound or the 9-amino compound could have any therapeutic activity.
  • Herpesviridae is a large family of DNA viruses that cause infections in animals, including humans. The members of this family are also known as herpesviruses. According to the International Committee on the Taxonomy of Viruses (ICTV) the Herpesviridae family contains three subfamilies, viz. Alphaherpesvirinae, Betaherpesvirinae, and the Gammaherpesvirinae s u bf am i I i es .
  • the Alphaherpesvirinae subfamily consists of 42 species, 41 of which are classified into five genera, including the Simplexvirus and Varicellovirus genera, that infect humans and other mammals.
  • the human alphaherpesvirus 1 (HHV-1) and human alphaherpesvirus 2 (HHV-2) also referred to as herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2)
  • HSV-1 and HSV-2 infections range from benign self-limiting orofacial and genital infections to potentially life-threatening conditions such as encephalitis and generalized neonatal infections.
  • Orofacial HSV infections are primarily caused by HSV- 1, which becomes latent after a primary infection, e.g. in childhood. After reactivation a recurrent orofacial HSV infection develops, more commonly known as a cold sore. About half of the patients experience early symptoms, e.g. pain, burning or itching at the site of the subsequent lesions. The condition is generally rapidly self-limiting and the healing time of a typical episode is about 10 days from the initial symptoms. Viral replication in the lip is initiated early and maximum virus load is attained 24 hours after the onset of the reactivation. The virus concentration is then dramatically reduced and typically virus cannot be isolated 70-80 hours after the onset.
  • Genital HSV infections are most often caused by HSV-2 and following the primary infection the virus will latently infect sensory or autonomic ganglions. Reactivation will produce the local recurrent lesions on or near the genitals that are characteristic of the herpes infection.
  • HSV infections may also cause eye infection, herpes keratitis, the symptoms of which include pain in the eyes, redness, rash, blurred vision, tearing, discharge and sensitivity to light, and which - if left untreated - can even lead to blindness.
  • the Varicellovirus genus includes the human alphaherpesvirus 3, also referred to as varicella-zoster virus.
  • a primary infection with varicella-zoster virus (VZV) causes chicken- pox.
  • VZV becomes latent following the primary infection and can be activated as herpes zoster later in life. Zoster usually results in skin rash and intensive acute pain. In 30% of the patients, the pain can be prolonged and continue for weeks or months after the rash has disappeared, or may even be permanent.
  • HSV may, in addition to mucous or cutaneous manifestations, also cause keratitis in the eyes.
  • the Betaherpesvirinae subfamily contains, in particular the Cytomegalovirus genus, and the Roseolovirus genus.
  • the Cytomegalovirus genus includes e.g. human betaherpesvirus 5, also referred to as human cytomegalovirus (HCMV), causing latent infections that often go unnoticed in healthy people, but that can be life-threatening for the immunocompromised, such as HIV-infected persons, organ transplant recipients, or newborn infants.
  • HCMV human cytomegalovirus
  • HCMV infections can cause polyneuritis, myelitis, and heterophile- negative mononucleosis syndrome, as well as carditis and hepatitis.
  • HCMV may also cause viral birth defects in congenitally infected babies, and congenital HCMV infections may result in deafness and mental retardation.
  • HCMV can cause severe disseminated disease characterized by chorioretinitis, pneumonia, esophagitis, colitis, myelitis, meningitis, encephalitis, leukopenia, lymphocytosis, and hepatitis.
  • HCMV infection can cause severe retinitis, which can lead to blindness if not treated.
  • the Roseolovirus genus includes the human betaherpesvirus 6A (HHV-6A) and the human betaherpesvirus 6B (HHV-6B) (collectively denominated as HHV-6), as well as the human betaherpesvirus 7 (HHV-7).
  • HHV-6A human betaherpesvirus 6A
  • HHV-6B human betaherpesvirus 6B
  • HHV-7 human betaherpesvirus 7
  • HHV-6 infection in children often results in fever, diarrhea, sometimes with a rash. More rarely, the infection can also cause febrile seizures, encephalitis or intractable seizures.
  • HHV-6 In common with all other herpesviruses HHV-6 establishes life-long latency and can become reactivated later in life. Reactivation can occur in the brain, lungs, heart, kidney and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients and in some cases, can cause cognitive dysfunction, permanent disability and death. Except in acute or initial infections, the viral DNA can typically be found only by biopsy, as it does not circulate in peripheral blood.
  • HHV-6 may play a role in a subset of patients with chronic conditions.
  • HHV-6A has recently been found in the uterus of women suffering from infertility, in the thyroid tissue of patients with Hashimoto’s thyroiditis and has been suggested as a trigger for a subset of MS and chronic fatigue syndrome cases.
  • Findings of HHV-6B DNA in the brain biopsies of refractory epilepsy patients suggest the virus may play a role in at least some of these cases.
  • HHV-6 has also been tied to febrile seizures and status epilepticus. Both HHV-6 and HHV7 can cause exanthema subitum.
  • HHV-7 can contribute to the development of drug-induced hypersensitivity syndrome, encephalopathy, hemiconvulsion-hemiplegia-epilepsy syndrome, hepatitis infection, postinfectious myeloradiculoneuropathy, pityriasis rosea, as well as to reactivation of HHV-4, leading to "mononucleosis-like illness". Additionally, HHV-7 infection can cause complications in a variety of transplant types.
  • the Gammaherpesvirinae subfamily includes in particular the Epstein Barr virus (EBV) and Human gammaherpesvirus 8, or HHV-8, (also referred to as the Kaposi's sarcoma- associated herpesvirus (KSHV)).
  • EBV Epstein Barr virus
  • KSHV Kaposi's sarcoma- associated herpesvirus
  • EBV may cause infectious mononucleosis, but is also associated with various non-malignant, premalignant, and malignant lymphoproliferative diseases such as Burkitt lymphoma, hemophagocytic lymphohistiocytosis, and Hodgkin's lymphoma; non-lymphoid malignancies such as gastric cancer and nasopharyngeal carcinoma; and conditions associated with human immunodeficiency virus such as hairy leukoplakia and central nervous system lymphomas.
  • various non-malignant, premalignant, and malignant lymphoproliferative diseases such as Burkitt lymphoma, hemophagocytic lymphohistiocytosis, and Hodgkin's lymphoma
  • non-lymphoid malignancies such as gastric cancer and nasopharyngeal carcinoma
  • human immunodeficiency virus such as hairy leukoplakia and central nervous system lymphomas.
  • the virus is also associated with the childhood disorders of Alice in Wonderland syndrome and acute cerebellar ataxia and, based on some evidence, higher risks of developing certain autoimmune diseases, especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, and multiple sclerosis.
  • HHV-8 is a human cancer virus that causes Kaposi's sarcoma, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. There is no known cure for KSHV associated tumorigenesis.
  • herpesviridae virus types known to infect humans viz. herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, also known as HHV1 and HHV2), varicella- zoster virus (VZV, also known as HHV-3), Epstein-Barr virus (EBV or HHV-4), human cytomegalovirus (HCMV or HHV-5), human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (KSHV, also known as HHV-8), at least five, viz.
  • HSV-1 and HSV-2 also known as HHV1 and HHV2
  • VZV varicella- zoster virus
  • EBV or HHV-4 Epstein-Barr virus
  • HCMV or HHV-5 human herpesvirus 6A and 6B
  • HHV-6A and HHV-6B human
  • HSV-1, HSV-2, VZV, EBV and HCMV are extremely widespread among humans. More than 90% of adults have been infected with at least one of these, and a latent form of the virus remains in almost all humans who have been infected. There clearly remains a need for further, effective antiviral agents, preferably with reduced side effects, such as toxicity effects.
  • An object of the present invention is to provide compounds having a favourable therapeutic window, in terms of high antiviral activity compared to toxic side effects.
  • a first aspect is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;
  • Ri is selected from NO2, NH2, CN, and NH 3 + ; for use in therapy.
  • a further aspect is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined herein above, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • Ri is a moiety selected from OH, NO 2 , NH 2 , CN, CF 3 , NH 3 + , CH 3 O, and CF 3 O, for use in the treatment of a virus infection.
  • a further aspect is a compound of formula (I) as defined herein above, or pharmaceutically acceptable salt thereof, for use in the treatment of virus infection, wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with a further therapeutic agent.
  • a further aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2;
  • Ri is selected from OH, N0 2 , NH 2 , CN, CF 3 , NH 3 + , CH 3 0, and CF 3 0; in the manufacture of a medicament for the treatment of a virus infection.
  • a further aspect is a method for the treatment of a virus infection in a mammal by administering, to a mammal in need of such treatment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; and
  • Ri is selected from OH, N0 2 , NH 2 , CN, CF 3 , NH 3 + , CH 3 0, and CF 3 0. Further aspects and embodiments thereof are as described herein below.
  • CH 3 O (or methoxy) refers to a moiety of formula which moiety may also be represented as
  • NO 2 (or nitro) refers to a moiety of formula
  • NH 2 (or amino) refers to a moiety of formula
  • CN (or cyano) refers to a moiety of formula NoC — !
  • CF 3 (or trifluoromethyl) refers to a moiety of formula
  • NH 3 + refers to a moiety of formula
  • CF 3 O refers to a moiety of formula "Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • excipient refers to a pharmaceutically acceptable chemical, such as known to those of ordinary skill in the art of pharmacy to aid in the administration of the medicinal agent. It is a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients include binders, surfactants, diluents, disintegrants, antiadherents, and lubricants.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, etc.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) whether detectable or undetectable.
  • the term can also mean prolonging survival as compared to expected survival without the treatment.
  • mammal refers to a human or any mammalian animal, e.g. a primate, a farm animal, a pet animal, a laboratory animal, etc. Examples of such animals are monkeys, cows, sheep, horses, pigs, goats, dogs, cats, rabbits, mice, rats etc. Preferably, the mammal is a human.
  • n is an integer 1 or 2.
  • n is 2, i.e. the dimethylamino moiety is linked to the polycyclic ring system by propylene chain: -(CH2)3-.
  • n is 1, i.e. the compound of formula (I) is a compound of formula (la) wherein Ri is as defined herein.
  • the moiety Ri may be selected from OH, N0 2 , NH 2 , CN, CF 3 , NH 3 + , CH 3 0, and CF 3 0.
  • Ri is selected from OH, N0 2 , NH 2 , CN, CF 3 , NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CN, CF 3 , NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , CN, CF 3 , NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CF 3 , NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CN, NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CN, CF 3 , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CN, CF 3 , and NH 3 + .
  • Ri is selected from N0 2 , CF 3 , NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , NH 3 + , and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CN, and CF 3 0.
  • Ri is selected from N0 2 , NH 2 , CN, and NH 3 + .
  • Ri is selected from N0 2 , NH 2 , CN, and CF 3 .
  • Ri is selected from N0 2 , CN, CF 3 , and CF 3 0.
  • Ri is selected from NO 2 , CN, Nh , and CF 3 O.
  • Ri is selected from NO 2 , CN, CF 3 , and NH 3 + .
  • Ri is selected from NO 2 , NH 2 , CF 3 , and NH 3 + .
  • Ri is selected from NO 2 , NH 2 , CF 3 , and CF 3 O.
  • Ri is selected from NO 2 , NH 3 + , and CF 3 O.
  • Ri is selected from NO 2 , CF 3 , and CF 3 O. n some embodiments, Ri is selected from NO 2 , NH 2 , and CF 3 O. n some embodiments, Ri is selected from NO 2 , NH 2 , and NH 3 + . n some embodiments, Ri is selected from NO 2 , NH 2 , and CN. n some embodiments, Ri is selected from NO 2 , CN, and CF 3 . n some embodiments, Ri is selected from NO 2 , CF 3 , and NH 3 + . n some embodiments, Ri is selected from NO 2 , CN, and CF 3 O.
  • Ri is selected from NO 2 , NH 2 , and CF 3 . n some embodiments, Ri is selected from NO 2 , CN, and NH 3 + . n some embodiments, Ri is selected from NO 2 , NH 2 , and CN. n some embodiments, Ri is selected from NC> 2 and CF 3 O. n some embodiments, Ri is selected from NC> 2 and NH 3 + . n some embodiments, Ri is selected from NC> 2 and CF 3 . n some embodiments, Ri is selected from NC> 2 and CN. n some embodiments, Ri is selected from NC> 2 and NH 2 .
  • Ri is selected from OH, NO 2 , CN, CF 3 , NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CF 3 , NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CN, NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CN, CF 3 , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CN, CF 3 , and NH 3 + .
  • Ri is selected from OH, NO 2 , CF 3 , NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CN, and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CN, and NH 3 + . n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CN, and CF 3 .
  • Ri is selected from OH, NO 2 , CN, CF 3 , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , CN, NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , CN, CF 3 , and NH 3 + . n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CF 3 , and NH 3 + . n some embodiments, Ri is selected from OH, NO 2 , NH 2 , CF 3 , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 3 + , and CF 3 O.
  • Ri is selected from OH, NO 2 , CF 3 , and CF 3 O. n some embodiments, Ri is selected from OH, NO 2 , NH 2 , and CF 3 O. n some embodiments, Ri is selected from OH, NO2, NH2, and NH 3 + . n some embodiments, Ri is selected from OH, NO2, NH2, and CN. n some embodiments, Ri is selected from OH, NO 2 , CN, and CF 3 . n some embodiments, Ri is selected from OH, NO 2 , CF 3 , and NH3 + . n some embodiments, Ri is selected from OH, NO2, CN, and CF3O.
  • Ri is selected from OH, NO 2 , NH 2 , and CF 3 .
  • Ri is selected from OH, NO2, CN, and NH 3 + .
  • Ri is selected from OH, NO2, NH2, and CN.
  • Ri is selected from OH, NC>2and CF3O.
  • Ri is selected from OH, NC>2and NH 3 + .
  • Ri is selected from OH, NC>2and CF 3 .
  • Ri is selected from OH, NC>2and CN.
  • Ri is selected from OH, N0 2 and NH2.
  • Ri is selected from OH and NO2. n some embodiments, Ri is selected from CH 3 0, N0 2 , NH 2 , CN, CF 3 , NH 3 + , and CF 3 0. n some embodiments, Ri is selected from CH 3 0, N0 2 , CN, CF 3 , NH 3 + , and CF 3 0. n some embodiments, Ri is selected from CH 3 0, N0 2 , NH 2 , CF 3 , NH 3 + , and CF 3 0. n some embodiments, Ri is selected from CH 3 0, N0 2 , NH 2 , CN, NH 3 + , and CF 3 0.
  • Ri is selected from CH 3 O, NO 2 , NH 2 , CN, CF 3 , and CF 3 O. n some embodiments, Ri is selected from CH 3 0, N0 2 , NH 2 , CN, CF 3 , and NH 3 + . n some embodiments, R1 is selected from CH3O, NO2, CF3, NH3 + , and CF3O. n some embodiments, Ri is selected from CH 3 0, N0 2 , NH 2 , NH 3 + , and CF 3 0. n some embodiments, Ri is selected from CH 3 O, NO 2 , NH 2 , CN, and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , NH 2 , CN, and NH 3 + .
  • Ri is selected from CH 3 O, NO 2 , NH 2 , CN, and CF 3 .
  • Ri is selected from CH 3 O, NO 2 , CN, CF 3 , and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , CN, NH 3 + , and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , CN, CF 3 , and NH 3 + .
  • Ri is selected from CH 3 0, N0 2 , NH 2 , CF 3 , and NH 3 + .
  • Ri is selected from CH 3 O, NO 2 , NH 2 , CF 3 , and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , NH 3 + , and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , CF 3 , and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , NH 2 , and CF 3 O.
  • Ri is selected from CH 3 O, NO 2 , NH 2 , and NH 3 + .
  • Ri is selected from CH 3 O, NO 2 , NH 2 , and CN. n some embodiments, Ri is selected from CH 3 O, NO 2 , CN, and CF 3 . n some embodiments, Ri is selected from CH 3 O, NO 2 , CF 3 , and NH 3 + . n some embodiments, Ri is selected from CH 3 O, NO 2 , CN, and CF 3 O. n some embodiments, Ri is selected from CH 3 O, NO 2 , NH 2 , and CF 3 . n some embodiments, Ri is selected from CH 3 O, NO 2 , CN, and NH 3 + .
  • Ri is selected from CH 3 O, NO 2 , NH 2 , and CN. n some embodiments, Ri is selected from CH 3 O, N0 2 and CF 3 O. n some embodiments, Ri is selected from CH 3 O, N0 2 and NH 3 + . n some embodiments, Ri is selected from CH 3 O, N0 2 and CF 3 . n some embodiments, Ri is selected from CH 3 O, N0 2 and CN. n some embodiments, Ri is selected from CH 3 O, N0 2 and NH 2 . n some embodiments, Ri is selected from OH, CH 3 O, NO 2 , CN, CF 3 , NH 3 + , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CF 3 , NH 3 + , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CN, NH 3 + , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CN, CF 3 , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CN, CF 3 , and NH 3 + .
  • Ri is selected from OH, CH 3 O, NO 2 , CF 3 , NH 3 + , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , NH 3 + , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CN, and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CN, and NH 3 + .
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CN, and CF 3 .
  • Ri is selected from OH, CH 3 O, NO 2 , CN, CF 3 , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , CN, NH 3 + , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , CN, CF 3 , and NH 3 + .
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CF 3 , and NH 3 + .
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , CF 3 , and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 3 + , and CF 3 O. n some embodiments, Ri is selected from OH, CH 3 O, NO 2 , CF 3 , and CF 3 O. n some embodiments, Ri is selected from OH, CH 3 O, NO 2 , NH 2 , and CF 3 O. n some embodiments, Ri is selected from OH, CH 3 O, NO 2 , NH 2 , and NH 3 + . n some embodiments, Ri is selected from OH, CH 3 O, NO 2 , NH 2 , and CN. n some embodiments, Ri is selected from OH, CH 3 O, NO 2 , CN, and CF 3 .
  • Ri is selected from OH, CH 3 O, NO 2 , CF 3 , and NH 3 + .
  • Ri is selected from OH, CH 3 O, NO 2 , CN, and CF 3 O.
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , and CF 3 .
  • Ri is selected from OH, CH 3 O, NO 2 , CN, and NH 3 + .
  • Ri is selected from OH, CH 3 O, NO 2 , NH 2 , and CN.
  • Ri is selected from OH, CH 3 O, N02and CF 3 O.
  • Ri is selected from OH, CH 3 O, N02and NH 3 + .
  • Ri is selected from OH, CH 3 O, NC> 2 and CF 3 .
  • Ri is selected from OH, CH 3 O, N02and CN.
  • Ri is selected from OH, CH 3 O, N02and NH 2 .
  • Ri is selected from OH, CH 3 O, and NO 2 .
  • Ri is selected from OH and CH 3 O.
  • Ri is selected from CH 3 O and NH 2 .
  • Ri is selected from CH 3 O and NO 2 .
  • Ri is selected from OH and NO 2 . n some embodiments, Ri is selected from OH and NH 2 . n some embodiments, Ri is selected from OH and CN. n some embodiments, Ri is selected from OH and CF 3 . n some embodiments, Ri is selected from OH and CF 3 O. n some embodiments, Ri is selected from CH 3 O and NO 2 . n some embodiments, Ri is selected from CH 3 O and CF 3 O. n some embodiments, Ri is selected from CH 3 O and CN. n some embodiments, Ri is selected from CH 3 O and CF 3 . n some embodiments, Ri is selected from CF 3 O and CF 3 .
  • Ri is selected from NH 2 and NH 3 + . n some embodiments, Ri is selected from NH 2 and CN. n some embodiments, Ri is OH. n some embodiments, Ri is CH 3 O. n some embodiments, Ri is NH 2 . n some embodiments, Ri is NO 2 .
  • the compound of formula (I) may be represented by formula (lb) wherein n is 1 or 2.
  • n is 2. In some other embodiments, n is 1, i.e. the compound of formula (lb) is 2-(2,3-dimethyl-9-nitro-6H-indolo[2,3-b]quinoxalin-6- yl)-N,N-dimethylethanamine), represented by formula
  • a further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy, wherein n is 1 or 2, e.g. n is 1; and Ri is selected from NO2, NH2, CN, and Nh ; or from any of the subgroups thereof, as mentioned herein above, for example, from NO2, NH2, and CN; or from NO2, NH2, and Nh ; or from NO2 and NH2; or from NO2 and CN; or Ri is NO2; or Ri is NH2 or Nh ; or Ri is NH2; or Ri is CN.
  • a compound of formula (I) may be prepared by following the method as described herein, or e.g. by methods as generally described in WO 87/04436 and in WO 96/19996, e.g. in Examples 1, 3 and 4 of WO 96/19996, the contents of which are incorporated herein by reference.
  • a compound of wherein Ri is CN may be prepared, for example, by following the method described in Example 3, herein below, using the appropriate 6/-/-indolo[2,3-b]quinoxaline derivative as a starting material.
  • Ri 6/-/-indolo[2,3-b]quinoxaline derivative
  • the latter may be obtained as an acid addition salt of the former, e.g. by reacting the former with an appropriate acid, e.g. a hydrohalic acid, such as hydrochloric acid.
  • a pharmaceutically acceptable salt of the compound of formula (I) may be an acid addition salt or a base addition salt.
  • acids or bases are used which form suitable pharmaceutically acceptable salts.
  • acids are inorganic acids such as hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid; organic aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
  • hydrohalogen acids sulfuric acid, phosphoric acid, nitric acid
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases such as alkoxides, alkyl amides, alkyl and aryl amines, and the like.
  • bases useful in preparing salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
  • a pharmaceutical composition according to the invention may be for topical (local) or systemic administration, e.g. for enteral administration, such as rectal or oral administration, in particular oral administration, or for parenteral administration to a mammal (especially a human), and comprises a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof, as active ingredient, in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier.
  • the therapeutically effective amount of the active ingredient is as defined herein above and depends e.g. on the species of mammal, the body weight, the age, the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • enteral e.g.
  • the pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salt(s) thereof as the active component.
  • the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the formulation of the active compound may comprise an encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds of the invention also may be administered parenterally, e.g. by inhalation, injection or infusion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intracutaneous and subcutaneous injection or infusion.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable or infusible preparation, for example, as a sterile aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g. Tween 80), and suspending agents.
  • the sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • the pharmaceutical composition may be a solution in 1,3-butanediol.
  • acceptable vehicles and solvents include, but are not limited to, mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA.
  • Suitable stabilizing agents may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • suitable pharmaceutical formulations are as particles, aerosols, powders, mists or droplets, e.g. with an average size of about 10 pm in diameter or less.
  • compositions for inhalation may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the pharmaceutical compositions of the invention also may be administered topically, to the skin or to a mucous membrane.
  • the pharmaceutical composition may be e.g.
  • the composition may be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
  • Suitable pharmaceutical excipients e.g. carriers, and methods of preparing pharmaceutical dosage forms are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in art of drug formulation.
  • the pharmaceutical compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90% of a compound of formula (I), together with at least one pharmaceutically acceptable excipient.
  • the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Suitable daily dosages typically ranges from 1 to 1000 mg, e.g. 1-500 mg daily, or 1-50 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and the indication towards which the administration is directed, etc.
  • Compounds of the invention may be administered as pharmaceutical formulations including those suitable for enteral or parenteral administration.
  • the preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • the compounds of the present invention may also be used or administered in combination with one or more additional therapeutically active agents, e.g. drugs useful in the treatment of a viral disorder.
  • the components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • (B) another therapeutic agent e.g. one that is useful in the treatment of a virus infection; whereby (A) and (B) is formulated in admixture with a pharmaceutically acceptable excipient.
  • Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent, and a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier; and/or
  • a pharmaceutical formulation including a compound of the invention, as defined herein, in admixture with a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent in admixture with a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • a pharmaceutically acceptable excipient e.g. an adjuvant, diluent or carrier
  • the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional therapeutically active ingredient, e.g. selected from antiviral agents, antibiotics, anaesthetic agents, analgesic agents, antiphlogistic agents and anti-inflammatory agents.
  • the additional therapeutically active ingredient comprises or is an antiviral agent.
  • the antiviral agents suitable for the purposes of the present invention are topically acceptable antiviral compounds, which in addition to being specific inhibitors of herpes virus multiplication also are active after topical administration and in addition are pharmaceutically acceptable for topical administration. This means that the toxicity of the antivirals must be sufficiently low to allow for a continuous contact with the human body and in particular with the skin and mucous membranes.
  • antiviral agents are substances within the group comprising compounds acting on viral DNA polymerase, such as nucleoside analogues after phosphorylation to their triphosphate forms; phosphonoformic and phosphonoacetic acids and their analogues; and other antiviral compounds having a different mechanism of action.
  • antiviral agents which can be used in the combination of the invention can be mentioned acyclovir (ACV), ACV-phosphonate, brivudine (bromovinyldeoxyuridine, BVDU), carbocyclic BVDU, buciclovir, CDG (carbocyclic 2'- deoxyguanosine), cidofovir (HPMPC, GS504), cyclic HPMPC, desciclovir, edoxudine, famciclovir, ganciclovir (GCV), GCV-phosphonate, genivir (DIP-253), H2G (9-[4-hydroxy-2- (hydroxy-methyl)butyl]-guanine), HPMPA, lobucavir (bishydroxymethylcyclobutylguanine, BHCG), netivudine (zonavir, B W882C87), penciclovir, PMEA (9-(2-phosphonylmethoxy- ethyl)aden
  • Preferred antiviral agents are those with specific antiviral activity such as herpes specific nucleoside analogues which are preferentially phosphorylated in virus-infected cells and have very low or non-existent incorporation into cellular DNA as well as other compounds with specific antiviral activity.
  • Acyclovir for instance, has a selectivity ratio for the inhibitory activity against HSV-1 in vitro of about 2000.
  • brivudine cidofovir
  • desciclovir desciclovir
  • famciclovir ganciclovir
  • HOE 961 lobucavir
  • netivudine penciclovir
  • PMEA sorivudine
  • valacyclovir 2242
  • BPFA BPFA
  • PFA PAA
  • a suitable antiphlogistic agent i.e. an agent capable of reducing inflammation, pain and/or fever, e.g. may be a non-steroidal anti-inflammatory drug (NSAID), such as diclofenac (lUPAC name 2-(2,6-dichloranilino) phenylacetic acid), or ibuprofen, (lUPAC name (RS)-2- (4-(2-methylpropyl)phenyl)propanoic acid), or a pharmaceutically acceptable salt thereof, e.g. a sodium, potassium or diethylamine salt thereof.
  • NSAID non-steroidal anti-inflammatory drug
  • a suitable anaesthetic agent e.g. may be lidocaine (lUPAC name 2-(diethylamino)-N-(2,6- dimethylphenyl)acetamide).
  • a suitable antiinflammatory agent e.g. may be adenosine (lUPAC name: (2R,3R,4S,5R)-2-(6- amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol.
  • the antiinflammatory agent also may be selected from antiinflammatory glucocorticoids.
  • a suitable glucocorticoid can be either naturally occurring or synthetic and can be selected from any of the Group l-ID glucocorticoids, according to a classification system for topical glucocorticoids used in the Nordic countries, corresponding to less potent, low or moderately potent glucocorticoids.
  • glucocorticosteroids examples include alclometasone, amicinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasone, clocortolone, cloprednol, cortison, desonide, desoximethasone, dexamethasone, diflorosane, diflucortolone, difluprednate, fludrocortisone, fludroxycortid, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluprednidene, fluticasone, halcinonide, halobetasol, halometasone, hydrocortisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednicarbate, prednisone, pre
  • Some preferred glucocorticoids are hydrocortisone, alclometasone, desonide, fluprednidene, flumethasone, hydrocortisone butyrate, clobetasone, triamcinolone acetonide, betamethasone, budesonide, desoximethasone, diflorosane, fluocinolone, fluocortolone, fluticasone, methylprednisolone aceponate, mometasone and rofleponide; in particular hydrocortisone, budesonide and fluticasone.
  • a suitable antibiotic e.g. may be selected from clindomycin, erythromycin, mupirocin, bacitracin, polymyxin and neomycin.
  • a further aspect is a process for the preparation of a pharmaceutical formulation, which process suitably comprises bringing into association a compound of the invention, as herein defined, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier.
  • a pharmaceutically acceptable excipient e.g. an adjuvant, diluent or carrier.
  • a further aspect is the use of a compound of formula (I) as defined herein, for the manufacture of a medicament for the treatment of a virus infection.
  • a further aspect is a method of treating a virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), as herein defined.
  • the compounds of the invention may be administered to a subject in need of treatment e.g. by use of a pharmaceutical formulation and administration route as generally outlined herein above, however it should be realized that precise treatment regime, e.g. dosage, will normally be determined by the treating physician.
  • references to the treatment of a particular virus infection take their normal meanings in the field of medicine.
  • the terms may refer to achieving a reduction in the severity of one or more clinical symptom associated with the infection.
  • references to patients will refer to a living subject being treated, including mammalian (e.g. human) patients.
  • the term effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient.
  • the effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).
  • a compound of formula (I) as defined herein can be used for the prophylaxis and/or treatment of a virus infection in a mammal, e.g. a human, e.g. a primary or recurrent virus infection.
  • Prophylactic treatment may be performed in patients having a regularly recurrent condition linked to the virus.
  • the virus infection treated herein is an infection by a virus belonging to the Herpesviridae family, e.g. to any one of the Alphaherpesvirinae, Betaherpesvirinae, and the Gammaherpesvirinae s u bf am i I i es .
  • the virus belongs to the Alphaherpesvirinae subfamily, e.g. it is a virus selected from the Simplexvirus and Varicellovirus genera.
  • the virus when virus belongs to the Alphaherpesvirinae subfamily, the virus more particularly belongs to the Simplexvirus genus.
  • the virus is a Herpes simplex virus (HSV).
  • the Herpes simplex virus is Herpes simplex virus 1 (HSV-1).
  • the Herpes simplex virus is Herpes simplex virus 2 (HSV-2).
  • the virus when virus belongs to the Alphaherpesvirinae subfamily, the virus belongs to the Varicellovirus genus. In some embodiments, the virus is human Alphaherpesvirus 3 (varicella-zoster virus).
  • the virus is one belonging to the Betaherpesvirinae subfamily, e.g. it is a virus selected from the Cytomegalovirus and Roseolovirus genera.
  • the virus when virus belongs to the Betaherpesvirinae subfamily, the virus more particularly belongs to the Cytomegalovirus genus, e.g. the virus is human cytomegalovirus (HCMV).
  • the virus when virus belongs to the Betaherpesvirinae subfamily, the virus belongs to the Roseolovirus genus, e.g. the virus is human betaherpesvirus 6 (HHV-6) or human betaherpesvirus 7 (HHV-7).
  • the virus is HHV-6.
  • the virus is HHV-7.
  • the virus is one belonging to the Gammaherpesvirinae subfamily. In some of these embodiments, the virus is Epstein Barr virus (EBV). In some other embodiments, the virus is Kaposi's sarcoma-associated herpesvirus (KSHV)).
  • EBV Epstein Barr virus
  • KSHV Kaposi's sarcoma-associated herpesvirus
  • the disorder treated according to the present invention may be any one of those known to be associated with (or caused by) infection by a virus as mentioned herein above, such as any of those mentioned under “Background of the invention” herein above, such as a cold sore, eye keratitis, a genital infection, herpes zoster, etc.
  • the patient may be an immunocompromised person, a person undergoing a transplantation, a person suffering from recurrent herpes infection (e.g. recurrent herpes labialis), a pregnant female, or any person infected by or suspected being infected by the virus, etc.
  • treatment may be used to prevent occurrence of one or more of the symptoms associated with the particular virus infection, or to reduce severity of one or more of the symptoms associated with the particular virus infection, or to shorten the time of an outbreak of such symptoms.
  • the infection is an HSV infection, such as herpes labialis.
  • the pharmaceutical composition is for topical application to the skin or mucosa of the infected patient, e.g. as an ointment, a gel, a solution etc.
  • TCID5 0 Tissue culture infectious dose where 50% of the cell containing wells are infected.
  • Vero cells ATCC CCL-81 were inoculated with serially diluted HSV-1, 10 1 - 10 8 in incomplete medium and incubated at 37 °C and 5 % CO2.
  • the compound according to the invention tested in this assay was 2-(2,3-dimethyl-9-nitro-6H-indolo[2,3-b]quinoxalin-6-yl)- N,N-dimethylethanamine hydrochloride salt (9-NO 2 -B220-HCI).
  • the prior art compound B220 was used as a test reference compound. The compounds were added 1 hour after inoculation. A positive control was included, where the Vero cells were inoculated with HSV-1 virus at the same dilutions as the test plates and received cell growth medium one-hour after inoculation.
  • the virus titer (Logio TCIDso/mL) was calculated on the titrations made and the virus inactivating effect of the antiviral drug on HSV-1 virus was calculated as the ratio of the virus titers in the absence and presence of the test compound.
  • the positive control had an HSV-1 titer of 7.25 logio TCID 50 per ml_, which was in line with the expected titer of 7.1 logio/ml_.
  • the antiviral effect of the four compounds 9-methoxy-B220, 9-NO 2 -B220, 9-OH-B220, and 9- NH 2 -B220 was evaluated on virus infected cells in a plaque assay.
  • the chemical name and structural formulas of the compounds are shown in Table 3.
  • the cells used in the assay were Vero cells (ATCC CCL-81).
  • the virus used in the assay was Herpes Simplex Type I (HSV-1) (ATCC VR-260D).
  • HSV-1 Herpes Simplex Type I
  • the media used in the assay are shown in Table 4. TABLE 4
  • HSV-1 was diluted in incomplete medium to 60-120 PFU/ml.
  • the medium on the Vero cells in the 6-well plates was removed under sterile conditions. The cells were washed 2 times with 2-3 ml of room tempered, sterile PBS with Ca 2+ and Mg 2+ . The final wash was removed from the Vero cells. Diluted HSV-1 (500 pL/well) was added to 5 wells of each 6-well plate with Vero cells. One of the HSV-1 inoculated wells was used as positive control. Incomplete medium was added to one well of each plate with Vero cells, as negative control. The plates were incubated for 1 hour at +37 ⁇ 1 °C, 5 ⁇ 1 % CO2 and a humidity of 90 ⁇ 5 % and were rocked every 15 minutes.
  • the tested compounds were first diluted to 1 mM using 100 % DMSO as diluent, and then further diluted in PBS with Ca 2+ and Mg 2+ to provide stock solutions containing the substances at 100 times the final concentration (2 mM, 1 pM, 0.2 pM and 0.04 pM).
  • the 1.8 % agarose solution (25 ml portions) was melted in a microwave oven and kept at 40 °C in a water bath. Portions of the complete medium (25 ml) were kept in the same water bath at 40 °C. The complete medium (25 ml) was added to the agarose solution (25 ml) and mixed well (agarose overlay). The agarose overlay was aliquoted in portions of 4.95 ml per 15 ml tube and kept in the water bath at 40 °C. After 1 hour of incubation the HSV-1 inoculum was removed from the Vero cells in the 6-well plates. The cells were washed twice with 2 - 3 ml of room tempered, sterile PBS with Ca 2+ and Mg 2+ . The final wash was removed from the Vero cells.
  • the 4.95 ml agarose overlay was spiked with 50 pl_ of the substance stock solution (100x), mixed well and 2 ml/well were carefully added to two wells for each substance concentration.
  • Agarose overlay with incomplete medium 50 mI_/4.95 ml agarose overlay
  • the agarose overlay was allowed to solidify before the plates were moved to an incubator (+37 ⁇ 1 °C, 5 ⁇ 1 % CO2 and a humidity of 90 ⁇ 5 %) and left for 2 days. At the end of the incubation, plaques were visualized by staining with neutral red.
  • the capacity of the substances to reduce HSV-1 infection was calculated by comparing the number of plaques that developed on the Vero cell cultures in the absence and presence of the substances.
  • the substances 9-NO 2 -B220 and 9-OH-B220 had the strongest inactivating effect on the HSV-1 virus. Only a couple of plaques were detected at 2 mM and at 1 mM there was about 50 % reduction in the number of plaques, compared to the positive control.
  • Substance 9-MeO-B220 also inactivated HSV-1 but to a lower extent, about 70 % reduction at 2 mM and a minor reduction at 1 mM.
  • Substances 9-NH 2 -B220 reduced the number of HSV-1 plaques by about 70 % at 2 mM, and about 50 % at a concentration of 1 mM.
  • Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph/Mass Selective Detector (MSD) (Single Quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed by two methods using either an ACE 3 C8 (3.0 x 50 mm) column with a gradient of acetonitrile in 0.1% aqueous TFA over 3 min and a flow of 1 mL/min, or an XBridge C18 (3.0 x 50 mm) column with a gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow of 1 mL/min. NMR spectra were recorded on a Bruker 400 MHz instrument at 25 °C.

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Abstract

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé en thérapie. L'invention concerne également une composition pharmaceutique comprenant un composé de formule (I). Le composé est utile dans le traitement d'une infection virale.
PCT/EP2021/067787 2020-06-29 2021-06-29 Dérivés de 6h-indolo(2,3-b)quinoxaline utiles en thérapie, en particulier dans une infection virale Ceased WO2022002898A1 (fr)

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