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EP-4255391-B1 - LUMINOL FOR USE IN THE TREATMENT OF SEQUELAE OF A SARS-COV-2 INFECTION

EP4255391B1EP 4255391 B1EP4255391 B1EP 4255391B1EP-4255391-B1

Inventors

  • BRYSCH, WOLFGANG
  • KAISER, ASTRID
  • SCHULZ, PETRA
  • SCHUMANN, Sara
  • WEGERER, Jörg

Dates

Publication Date
20260506
Application Date
20211201

Claims (13)

  1. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the treatment of a sequela of a SARS-CoV-2 infection, wherein said sequela of a SARS-CoV-2 infection is selected from a group comprising chronic fatigue, dyspnea, cough, headache, joint pain, chest pain, muscle pain, muscle weakness, difficulties with thinking and concentration, memory problems, depression, anxiety, mood swings, sleep disorders, insomnia, intermittent fever, heart palpitations, inflammation of the heart muscle, lung function abnormalities, acute kidney injury, rash, hair loss and teeth loss.
  2. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to Claim 1, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.
  3. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use according to claim 2, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydrate polymorph forms I, II or III characterized by crystallography values determined by means of x-ray powder diagrams: d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and/or 2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3 for Form I, d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and/or 2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8 for Form II, and d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and/or 2-theta values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93 for Form III.
  4. Pharmaceutical composition for use in the treatment of a sequela of a SARS-CoV-2 infection, wherein said composition contains 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, a carrier and at least one pharmaceutically acceptable excipient and said sequela of a SARS-CoV-2 infection is selected from a group comprising chronic fatigue, dyspnea, cough, headache, joint pain, chest pain, muscle pain, muscle weakness, difficulties with thinking and concentration, memory problems, depression, anxiety, mood swings, sleep disorders, insomnia, intermittent fever, heart palpitations, inflammation of the heart muscle, lung function abnormalities, acute kidney injury, rash, hair loss and teeth loss.
  5. Combination of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts and at least one active agent selected from a group comprising steroidal and non-steroidal anti-inflammatory drugs, immunomodulators, immunosuppressive agents; anti-infective agents like antibiotics, antiretroviral agents, antiviral agents, antifungal agents and antiprotozoal agents, analgesics, anticoagulants, antiplatelet drugs, bronchodilators, pulmonary vasodilators, mucolytic agents, pulmonary surfactants, antioxidants, ENaC-activating agents, HMG-CoA reductase inhibitors, calcium antagonists or AT 1 receptor antagonists for use in the treatment of a sequela of a SARS-CoV-2 infection, wherein said steroidal and non-steroidal anti-inflammatory drugs are selected from a group comprising corticosteroids, glucocorticoids, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, deltasone, triamcinolone, tixocortol pivalate, mometasone, amcinonide, budesonide, desonide, fluociconide, fluocinolone, halcinonide, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate, acetylsalicylic acid, salicylic acid and salicylates, acetaminophen (paracetamol), salsalate, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celexoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixin, licofelone, H-harpagide, flunixin, tiaprofenic acid, said immunomodulators are selected from a group comprising thalidomide, lenalidomide, pomalidomide and apremilast, said immunosuppressive agents are selected from a group comprising cytostatic drugs such as alkylating agents (such as cyclophosphamide), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide, protein synthesis inhibitors and certain antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin and mithramycin, intercalating agents such as mitoxantrone; antibodies such as muromonab-CD3, rituximab, ustekinumab, alemtuzumab, natalizumab, basiliximab, tocilizumab and daclizumab; drugs acting on immunophilins such as ciclosporin, tacrolimus and sirolimus, non-classified immunosuppressive agents such as beta-interferon and gamma-interferon, opioids, TNF binding proteins such as infliximab, etanercept and adalimumab; curcumin, catechins, mycophenolic acid, fingolimod, myriocin and fumaric acid dimethyl esters, said anti-infective agents like antibiotics, antiretroviral agents, antiviral agents, antifungal agents and antiprotozoal agents are selected from a group comprising imipenem, meropenem, ertapenem, cephalosporins, aztreonam, penicillins such as penicillin G and penicillin V, piperacillin, mezlocillin, ampicillin, amoxicillin, flucloxacillin, methicillin, oxacillin, clavulanic acid, sulbactam, tazobactam, sultamicillin, fosfomycin, teicoplanin, vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, chloramphenicol, fusidic acid, cethromycin, narbomycin, telithromycin, clindamycin, lincomycin, daptomycin, dalfopristin, quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocumarine, sulfadiazine, sulfadoxin, sulfamethoxazole, sulfasalazine, pyrimethamine, trimethoprim, rifampicin, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine, zalcitabine, entecavir, adefovir, elvucitabine, fosalvudine(-tidoxil), fozivudintidoxil, lagiciclovir, alamifovir, clevudine, pradefovir, telbivudine, efavirenz, etravirine, nevirapine, rilpivirine, delavirdine, emivirine, lersivirine, raltegravir, elvitegravir, dolutegravir, MK-2048, saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir, brecanavir, mozenavir, tipranavir, enfuvirtide, maraviroc, ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, vicriviroc, amantadine, rimantadine, pleconaril, idoxuridine, aciclovir, brivudine, famciclovir, penciclovir, sorivudin, valaciclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirin, taribavirin, filibuvir, nesbuvir, tegobuvir, fosdevirin, favipiravir, avifavir, merimepodib, asunaprevir, balapiravir, boceprivir, ciluprevir, danoprevir, daclatasvir, narlaprevir, telaprevir, simeprevir, vanipevir, rupintrivir, remdesivir, fomivirsen, amenamevir, alisporivir, bevirimat, letermovir, laninamavir, oseltamivir, peramivir, zanamivir, abafungin, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, amorolfine, butenafine, nafitifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, balsam of Peru, metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetin, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cyclohunailembonate, quinine, mefloquine, pyrimethamine, artmether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumefantrine, sulfadoxine, meglumine antimoniate, benznidazole, sodium stibogluconate, fumagillin, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethrum, phenothrin, bio-allethrin, imidacloprid, moxidectin, nitenpyram, fipronil, pyriprol, selamectin, dimpylate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil and eucalyptus oil, said analgesics are selected from a group comprising NSAIDs; opioid analgesics such as morphine, fentanyl, methadone, oxycodon, carfentanyl, dihydroetorphine, ohmefentanyl, etorphine sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levomethadone, hydrocodone, pintramide, nalbuphine, tapentadol, pentazocin, dihydrocodeine, codeine, pethidine, tramadol, tilidine, meptazinol, naloxone, naltrexone, diprenorphine, loperamide, apomorphine; epibatidine; scopolamine; ziconitide; cannabinoids such as tetrahydrocannabinol, cannabidiol, marinol; flupirtine; ketamine and local anesthetics; said anticoagulants are selected from a group comprising heparins, coumarins such as phenprocoumon and warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, ximelagatran, hirudine, lepirudine, bivalirudine, citrate, EDTA, fondaparinux, argatroban and andotamixaban; said antiplatelet drugs are selected from a group comprising abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, eptifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine and tirofiban; said bronchodilators are selected from a group comprising short-acting beta-2 agonists such as salbutamol, albuterol, bitolterol, fenoterol, isoprenaline, levosalbutamol, levalbuterol, orciprenaline, pirbuterol, procaterol, ritodrine and terbutaline; long-acting beta-2 agonists such as arformoterol, bambuterol, clenbuterol, formoterol and salmeterol; ultra-long-acting beta-2 agonists such as abediterol, carmoterol, indacaterol, olodaterol and vilanterol and beta-2 agonists with unknown time of action such as isoxsuprine, mabuterol and zilpaterol; muscarinic anticholinergics such as ipratropium bromide, tiotropium bromide, oxitropium bromide, glycopyrronium bromide, aclidinium bromide, umeclidinium bromide, atropine, hyoscyamine, aclidinium bromide, 4-DAMP, darifenacin, DAU-5884, procyclidine, oxybutynin, tolterodine and zamifenacin; said pulmonary vasodilators are selected from a group comprising epinephrine, ephedrine, theophylline, TSG12, nitric oxide and prostacyclin analogues such as iloprost, epoprostenol and treprostinil; said mucolytic agents are selected from a group comprising N-acetylcysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine and dornase alfa; said pulmonary surfactants are selected from a group comprising Colfosceril palmitate, Pumactant, KL-4, Venticute and Lucinactant and animal-derived surfactants such as Beractant, Calfactant and Poractant alfa; said antioxidant is inhaled carbon monoxide; said ENaC-activating agents are selected from a group comprising AP301 and S3969; said HMG-CoA reductase inhibitors are selected from a group comprising atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; said calcium antagonists are selected from a group comprising verapamil, gallopamil, fendiline, nimodipine, nifedipine, nitrendipine, amlodipine, felodipine, lercanidipine, nicardipine, lacidipine, isradipine, nisoldipine, nivaldipine, manidipine, clevidipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, pranidipine, diltiazem, mibefradil, bepridil, flunarizine and fluspirilene; and said AT 1 receptor antagonists are selected from a group comprising losartan, valsartan, candesartan, telmisartan, irbesartan, olmesartan, eprosartan, fimasartan, azilsartan, milfasartan, pomisartan, pratosartan, ripisartan, tasosartan, saprosartan and EXP 3174, and said sequela of a SARS-CoV-2 infection is selected from a group comprising chronic fatigue, dyspnea, cough, headache, joint pain, chest pain, muscle pain, muscle weakness, difficulties with thinking and concentration, memory problems, depression, anxiety, mood swings, sleep disorders, insomnia, intermittent fever, heart palpitations, inflammation of the heart muscle, lung function abnormalities, acute kidney injury, rash, hair loss and teeth loss.
  6. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, wherein said substance, composition or combination is applied orally in the form of tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets, pills, powders, granulates, juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids, edible foams, mousses, oil-in-water emulsions or water-in-oil emulsions.
  7. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, in a formulation for inhalatory administration.
  8. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, for use in a formulation according to claim 7, wherein the inhalatory administration is carried out by means of a vibrating mesh nebulizer.
  9. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, wherein said substance, composition or combination is applied in form of liposomes, micelles, multilamellar vesicles or a cyclodextrin complex.
  10. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, in a formulation for sublingual tablets.
  11. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, wherein the administration of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, said composition according to the invention or a combination according to the invention is carried out by means of a throat spray, nose spray or nose drops.
  12. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, wherein said substance, composition or combination is formulated as a lyophilizate.
  13. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use as defined in any one of claims 1 to 3, a composition for use as defined in claim 4 or a combination for use as defined in claim 5, in the form of an intravenous injection, intraarterial injection or intraperitoneal injection.

Description

The present application relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts in the treatment of a sequela of a SARS-CoV-2 infection. In particular, the invention relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for said purposes. Pharmaceutical compositions, combinations, advantageous formulation techniques and a method of treatment are disclosed. BACKGROUND OF THE INVENTION As a result of ecological, climatic and demographic changes, so-called 'emerging' viruses are increasingly being transmitted from their natural animal hosts to humans. Due to accelerated globalization, they bear the risk of triggering a pandemic. Emerging viruses may cause acute and often life-threatening diseases. Coronaviridae have become notorious for such transmissions. Examples are Severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), and most recently, the outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in Wuhan, China. A total of over 251.1 million SARS-CoV-2 cases with about 5.09 million casualties worldwide have been reported by the Johns Hopkins University Coronavirus Resource Center, as of November 10th, 2021. The incubation period of SARS-CoV-2 ranges between two days and two weeks, in some cases up to one month. The disease resulting from a SARS-CoV-2 infection is called COVID-19. Typical symptoms of COVID-19 are fever, cough, and shortness of breath. However, the infection can also cause severe pulmonary injury, leading to rapid onset of progressive malfunction of the lungs, especially with regard to the ability to take up oxygen. This is usually associated with the malfunction of other organs. This acute lung injury (ALI) condition is associated with extensive lung inflammation and accumulation of fluid in the alveoli. It is characterized by diffuse pulmonary microvascular injury resulting in increased permeability and, thus, non-cardiogenic pulmonary edema. In consequence, this leads to pathologically low oxygen levels in the lungs. Other common symptoms associated with COVID-19 patients in ICU care are pulmonary embolism, thrombosis, venous thromboembolism and brain ischemia. Coronaviruses are primarily spread through close contact, in particular through respiratory droplets from coughs and sneezes. In contrast to the SARS-CoV-1 and MERS-CoV, SARS-CoV-2 can be transmitted from human to human during the incubation period while the infected patient does not show yet any symptoms of disease. Moreover, SARS-CoV-2 can already replicate in the throat. In contrast, the receptors for SARS -CoV and MERS-CoV are located deep in the lungs. Thus, SARS-CoV-2 can be transmitted much easier from human to human in comparison to SARS-CoV-1 and MERS-CoV which strongly increases the infection rate. In general, coronaviruses (family Coronaviridae, group Coronaviruses) form a relatively diverse group of large, enveloped, positive strand RNA viruses, which can cause different types of diarrhea and respiratory diseases in humans and animals. They have a very narrow host range and replicate very poorly in cell culture. However, cell culture systems for SARS-CoV-2 could be successfully established. Sequencing of SARS-CoV-2 revealed an approx. 29.8 kbp genome consisting of 14 open reading frames. Moreover, the virus is phylogenetically closely related to the SARS-CoV-1 (89.1% nucleotide similarity) (cf. Wu et al. (2020) Nature 579: 265-269). Like other coronaviruses, SARS-CoV-2 enters the cell by endocytosis and membrane fusion. The viruses are released from the cell by the secretory pathway. The natural reservoir of the virus is unknown. To date, no specific therapeutic options for the treatment of SARS-CoV-2 infections, respectively COVID-19 are established. Some success could be achieved with the antiviral drugs remdesivir, avifavir and favipiravir. A nasal spray containing nanoantibodies against the SARS-CoV-2 spike protein is a promising development (AeroNabs). In severe stage COVID-19 patients the administration of the glucocorticoid dexamethasone showed to be effective. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt Form I could almost completely block the replication of SARS-CoV-2 in Vero B4 cell culture but does not mention a therapeutic use in the treatment of sequelae of a SARS-CoV-2 infection (Schumann et al. (2020) Int J Mol Sci 21: 8803). However, there is growing evidence that a considerable number of patients who have overcome a SARS-CoV-2 infection, i.e. who don't show any acute COVID-19 symptoms (anymore) and aren't infectious anymore, develop long-lasting disease-like effects that can seriously impair their life quality. Obviously, these long-lasting disease-like effects are the sequela(e) of the previous SARS-CoV-2 infection. Given the short time since their description, there is not much known about their etiology and there is n