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EP3976190A1 - Nouveaux composés endoperoxyde, leur procédé d'obtention et leurs utilisations pour le contrôle de la perkinsiose chez les bivalves - Google Patents

Nouveaux composés endoperoxyde, leur procédé d'obtention et leurs utilisations pour le contrôle de la perkinsiose chez les bivalves

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Publication number
EP3976190A1
EP3976190A1 EP19742475.7A EP19742475A EP3976190A1 EP 3976190 A1 EP3976190 A1 EP 3976190A1 EP 19742475 A EP19742475 A EP 19742475A EP 3976190 A1 EP3976190 A1 EP 3976190A1
Authority
EP
European Patent Office
Prior art keywords
compounds
tetraoxane
formula
spiro
bivalves
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19742475.7A
Other languages
German (de)
English (en)
Inventor
Maria CRISTIANO
Lília CABRAL
Ricardo Leite
José LEAL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ccmar Centro De Ciencias Do Mar Universidade Do Algarve
Instituto Gulbenkian de Ciência
Original Assignee
Ccmar Centro De Ciencias Do Mar Universidade Do Algarve
Instituto Gulbenkian de Ciência
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ccmar Centro De Ciencias Do Mar Universidade Do Algarve, Instituto Gulbenkian de Ciência filed Critical Ccmar Centro De Ciencias Do Mar Universidade Do Algarve
Publication of EP3976190A1 publication Critical patent/EP3976190A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • C07D323/04—Six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to new endoperoxide compounds and compositions, and to a process for producing them for prophylaxis and control of perkinsiosis in bivalves.
  • Endoperoxide compounds with biological activity against Perkinsus olseni herein described include 13 trioxolanes and 9 tetraoxanes .
  • Protozoan parasites of the genus Perkinsus are known to infect several species of marine molluscs worldwide, like oysters, abalones, clams, scallops, pearl oysters, cockles or mussels.
  • the present invention also describes the synthesis of these compounds, in particular of new endoperoxide compounds of the tetraoxane family.
  • compositions comprising endoperoxide compounds are useful for prophylaxis and control of perkinsiosis in bivalves.
  • the present invention also relates to a method of controlling perkinsiosis in bivalves.
  • the present invention is in the domain of aquaculture, medicine, pharmaceuticals and biochemistry. BACKGROUND OF THE INVENTION
  • Aquaculture is one of the most fast-growing food production industries, with an average annual growth rate of 5.8% between 2001 and 2016 (FAO, 2018) and a predicted growth of over 50% until 2030, supplying over 60% of marine and freshwater organisms for direct human consumption.
  • FAO Federal Organic Agriculture
  • Parasite-borne infections caused by obligate or opportunistic organisms may affect finfish and shellfish aquaculture, representing a key constraint to the production and economic viability of aquaculture facilities worldwide.
  • perkinsiosis In shellfish aquaculture, perkinsiosis is one of the most feared diseases. It is caused by protozoan parasites of the genus Perkinsus, which are known to infect several species of marine molluscs worldwide, like oysters, abalones, clams, scallops, pearl oysters, cockles or mussels.
  • compositions that are effective against the diseases caused by P. olseni in bivalve aquaculture, which affect its production impacting the producers with severe annual costs.
  • the present invention proposes the development of compositions based on peroxide compounds and implementation of a suitable therapeutic strategy for the prophylaxis and control of Perkinsosis in bivalves that is able to reduce the prevalence of P. olseni and thus mortality and morbidity in bivalves.
  • the present invention relates to new endoperoxide compounds, in particular to tetraoxane compounds and endoperoxide compositions, to a process for producing them, and to a method for prophylaxis and control of perkinsiosis in bivalves.
  • the present invention relates to novel tetraoxane compounds of formula I according to claim 1.
  • the present invention relates to pharmaceutical compositions comprising tetraoxane compounds according to claim 3.
  • compositions are very effective in reduction of morbidity and mortality of bivalves infected by P. olseni.
  • the present invention relates to pharmaceutical compositions comprising one or more of said compounds for treatment of diseases having P. olseni as etiological agent according to claim 6.
  • Said compounds present IC50 values in a range from 8.1 to 268.3 mM.
  • compound LC131 was shown to be more active, with IC50 value of 38.6 mM.
  • compounds LC137 and LC139 demonstrated an IC50 value of 11.7 and 8.1 mM respectively.
  • some of these compounds demonstrated activity, in vitro and in vivo, against Plasmodium spp. that cause malaria in humans and their safety profiles were scrutinized, both for human treatment and environmental (aquatic habitats, conferring more safety to their use in new applications .
  • the present invention also relates to a process for producing a peroxide compound in only two synthetic steps according to claim 7.
  • the present invention relates to a method of controlling pathologies caused by P. olseni in bivalves by administrating a composition comprising at least a trioxolane and/or tetraoxane compound according to claim 8.
  • This method enables to increase shellfish aquaculture of marine molluscs such as oysters, abalones, clams, scallops, pearl oysters, cockles or mussels by reduction of morbidity and mortality of said bivalves infected by Perkinsus spp . It also can be useful to control parasitic infection of bivalves transferred between different areas and even countries.
  • Figure 1 presents the synthetic routes to the trioxolanes LC28, LC32 , LC50 , LC67 , LC68, LC92, LC93, LC135 and LC136.
  • Figure 2 presents the synthetic routes to the trioxolanes LC94, LC95 , LC129, LC130, LC131 and LC132.
  • Figure 3 presents the synthetic routes to tetraoxanes LC137, LC138, LC139 , LC140, LC157 and LC163.
  • Figure 4 presents the synthetic routes to the tetraoxanes LC146, LC153, LC159, LC165, LC179.
  • Figure 5 depicts the strategy used for desoxygenation of derivatives of artemisinin.
  • Figure 6 presents the synthetic routes to the 7-nitro-l , 2 , 3- benzoxadiazole (NBD) -tagged peroxides.
  • the present invention relates to new endoperoxide compounds, in particular to tetraoxane compounds and endoperoxide compositions, to a process for producing them, and to a method for prophylaxis and control of perkinsiosis in bivalves.
  • P. olseni and all the other Perkinsus species are phylogenetically close to Dinoflagellates but also to the genus Plasmodium and Toxoplasma, with organelles like plastids in common in the three genera.
  • organelles like plastids in common in the three genera.
  • Several metabolic pathways are also conserved, like the shikimate, the methylerythritol phosphate (MEP) pathway and the folate metabolism.
  • Tetraoxane or acetone peroxide define a family of compounds having a six-membered saturated heterocycle ring with two carbon atoms and four oxygen atoms. It is commonly produced by the reaction of acetone and hydrogen peroxide to yield a mixture of linear monomer and cyclic dimer, trimer, and tetramer forms.
  • Table 1 presents the novel tetraoxane compounds of general formula I, and their identification, namely their chemical formulae, IUPAC names and chemical representation.
  • R is :
  • Endoperoxide compounds according to the present invention are compounds that include besides the tetraoxane compounds of the previous section, other known tetraoxane and trioxolane compounds, which present bioactivity against P. olseni, in particular against perkinsiosis in bivalves.
  • Trioxolanes or diperoxides define a family of compounds having a five-membered saturated heterocycle ring with two carbon atoms and three oxygen atoms.
  • the endoperoxide compounds, according to the present invention are shown in Table 2, along with their identification, namely their chemical formulae, IUPAC names and chemical representation .
  • the screening for candidate drugs is done by exposing a known amount of Perkinsus olseni cells to a predefined range of concentrations of the compound to be tested. This method is based on a commercial assay to determine cell viability. After 72 hours of exposure the cells are tested for viability and statistical analysis is performed to determine IC50 and determined the potential of the candidate inhibitor.
  • Table 3 presents bioactivity values of some peroxide compounds on Perkinsus olseni.
  • endoperoxide compounds as described in the previous sections can be delivered directly to the bivalve population in powder formulations, in microcapsules, dissolved in DMSO, where the final dilution of DMSO should be below 0.05% v/v to avoid host toxicity, or in other acceptable formulations.
  • Endoperoxide compositions comprising compounds or mixtures of compounds herein described can be prepared according to the known methods in the art with addition of one or more pharmaceutically acceptable vehicles, carriers, co-adjuvants or alike.
  • Suitable pharmaceutically acceptable vehicles that can be used in the compositions of the invention are: acetone, acetonitrile, butanone, dimethyl formamide, DMSO, ethanol, glycerol, isopropanol, methanol, polyethylene glycol (PEG- 400), propylene glycol, and solketal, and carriers include albumin (BSA) and cyclodextrin ( 2-hydroxypropyl-beta- cyclodextrin, or HPBCD, or similar.
  • compositions according to the invention can be presented in the form of a powder, dissolved powder in a solvent or carrier, or in oil form.
  • compositions may comprise compounds or mixtures of compounds herein described in a concentration of 8 mM to 700 mM, preferably of 10 mM to 500 mM, more preferably of 12 mM to 250 mM, even more preferably of 15 mM to 100 mM, or more advantageously of 20 mM to 50 mM.
  • Novel tetraoxane compounds of formula I according to the present invention can be easily synthesized from relatively cheap starting materials.
  • 1 , 2 , 4 , 5-tetraoxanes are achiral, and are known to be stable, compared to their 1,2,4- trioxolane counterparts .
  • the various tetraoxanes are synthesized using a one pot methodology. Ciclohexanone and derivatives are treated with hydrogen peroxide and formic acid to form the respective dihidroperoxides . Adamantanone is subsequently added, to produce tetraoxanes. Further chemical modifications of the substituents on the cyclohexyl ring can then be carried out, to increase chemical diversity or adjust pharmacologic properties .
  • tetraoxane compounds of formula I are produced by a process comprising the following steps:
  • Ciclohexanone and derivatives are treated with hydrogen peroxide and formic acid to form the respective dihidroperoxides; and (b) Adamantanone is subsequently added, to produce tetraoxanes;
  • endoperoxide compounds can be obtained by known processes. Namely, 1 , 2 , 4 , 5-tetraoxanes , 1 , 2 , 4-trioxolanes and artemisinin derivatives are synthesized by adapting procedures described in the literature (Marti et al . , 2011; Araujo et al., 2013; Lobo et al . , 2018; Fugi et al . , 2010) .
  • Trioxolanes LC50, LC28, LC23 and LC67 are obtained as described by Griesbaum coozonolysis (Griesbaum et al . , 1997; Griesbaum et al . , 1997) by reactions between freshly prepared 2- adamantanyl-O-methyl oxime (LC29) and the appropriate 4- substituted cyclohexanones. Reduction of trioxolane ester LC67 results in the corresponding trioxolane alcohol LC93, and hydrazinolysis of the alcohol produced the trioxolane phtalimide LC94. Reaction of LC93 with hydrazine hydrate leads to the trioxolane amine LC95.
  • This compound is then coupled to 3-chloro-l , 2-benzisothiazole 1,1-dioxide to produce the saccharyl-trioxolane conjugate LC130.
  • the trioxolane carboxylic acid LC68 is prepared by hydrolysis of the trioxolane ester LC67.
  • Trioxolane amide LC92 is accessed from LC68 and butylamine, through a peptide-like coupling methodology using EDC, HOBt and N-methylmorpholine .
  • Compounds LC135 and LC136 are obtained from LC50, under reductive amination conditions.
  • tetraoxanes are synthesized using a one pot methodology. Ciclohexanone and derivatives are treated with hydrogen peroxide and formic acid to form the respective dihidroperoxides . Adamantanone is subsequently added, to produce tetraoxanes LC137 and LC139. Tetraoxanes LC138 and LC140 are obtained using a similar methodology, but in this case the synthesis begins by formation of adamantanyl dihidroperoxide . Compounds LC163 and LC157 are obtained by reductive amination, with excellent yield.
  • the fluorescent peroxide probes are prepared using 4- chloro-7-nitro-l , 2 , 3-benzoxadiazole (NBD-C1) as tagging compound. This fluorophore is coupled to trioxolane LC95 and to tetraoxane LC165 to form trioxolane-NBD LC201 and tetraoxane-NBD LC200.
  • this application is directed to maternity bivalves but also collected in the natural habitat for purposes of repopulation and seeding with sizes between 2 to 10mm. This ensures a repopulation with bivalves free of Perkinsus spp . It is also possible to treat selected bivalves for breeding.
  • the expression "controlling" has the meaning of: treating, preventing or reducing the prevalence of Perkinsus spp . in bivalves.
  • compositions according to the present invention produced from powdered compounds dissolved in 0.05% DMSO are provided to the bivalve population to be controlled along with the conventional microalgae diet.
  • the exposure is performed in closed-circuit tanks for a period of 24h to 48h, preferably for a period of 48h hours with daily renewal of 10% of the water.
  • Example 7 General procedure for the preparation of Adamantane- 2-spiro-3 ' -8 ' -oxo-1 ' , 2 ' , 4 ' -trioxaspiro [ 4 , 5 ] decane LC50 and Adamantane-2-spiro-3 ' -8 ' -ethoxycarbony1-1 ' , 2 ' , 4 ' - trioxaspiro [ 4 , 5 ] decane LC67.
  • Trioxolanes were prepared by coupling O-methyl-2-adamantanone oxime, LC29 with a cyclohexanone derivative, through ozonolysis as described by Vennerstrom.
  • Ozone produced with an ozone generator Sander Labor- Ozonizator 301.7 (0.5 L/min O2, 140 V), was passed through a solution of dichloromethane at -78°C and flushed into a solution of O-methyl ketone oxime and a ketone, in pentane/dichloromethane (6:4) at 0°C. After completion, the solution was flushed with nitrogen for 5 min and concentrated under reduced pressure at room temperature to give a crude material that was purified by column chromatography.
  • Example 8 Preparation of Adamantane-2-spiro-3'-8'-oxo- l',2',4'-trioxaspiro[4,5] decane, LC50.
  • Example 9 Preparation of Adamantane-2-spiro-3 ' -8 ' - ethoxycarbony1-1 ' , 2 ' , 4'-trioxaspiro [4, 5] decane , LC67.
  • Example 10 Preparation of Adamantane-2-spiro-3 ' - 8 ' - hydroxymethyl-1 ' , 2 ' , 4'-trioxaspiro [4, 5] decane , LC93.
  • Example 13 Preparation of Adamantane-2-spiro-3 ' -8 ' - hydroxymethyl-1 ' , 2 ' , 4'-trioxaspiro [4, 5] decane-1 , 2- benzisothiazole-1 , 1-dioxide, LC129, as described by Lobo et al . [Lobo L, Cabral LIL, Sena MI, et al . 2018. New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum. Malaria Journal. 17:1-11. doi :10.1186/sl2936-018-2281-x].
  • Example 15 Preparation of Adamantane-2-spiro-3 ' -8 ' - hydroxymethyl-1 ' , 2 ' , 4'-trioxaspiro [4, 5] decane-1-phenyl-1H- tetrazole, LC132. To a solution of adamantane-2-spiro-3 ' -8 ' - hydroxymethyl-1 ' , 2 ' , 4'-trioxaspiro [4, 5] decane ,
  • Example 18 Preparation of Adamantane-2-spiro-3 ' - 8 ' [ ( aminotetrazole ) amino ] -1 ' , 2 ' , 4'-trioxaspiro [4, 5] decane , LC136. Prepared according to general procedure 2 to give LC136 as a white solid (80% yield); m.p.
  • LC138 adamantane-2-spiro-3 , -l , ,2 , ,4 , ,5' -tetraoxane-6 ' -spiro- l"-piperidine LC139 and Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 '-spiro-l"-cyclohexanone LC140.
  • Example 20 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' -spiro-1 " -cyclohexane , LC137 as described by Ghorai et al . [Ghorai P & Dussault PH. 2009. Broadly Applicable Synthesis of 1 , 2 , 4 , 5-Tetraoxanes . Org. Lett. 11, 213-216].
  • i/ T'o- 0 ' prepared according to the described in example 19 to give LC137 as a white solid (32% yield); m.p. 57-59°C.
  • Example 21 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' -spiro-l"-cyclohexane-4"-ethyl carboxylate, LC138.
  • Example 22 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' -spiro-l"-piperidine, LC139. Prepared according to the described in example 19 to give LC139 as a yellow solid (51% yield); m.p. 65-67 0 C . !
  • Example 23 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' -spiro-l"-cyclohexanone, LC140, as described by Marti et al . [Marti F, Chadwick J, Amewu RK, et al . 2011. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. Med. Chem. Commun. 2, 661-665. doi: 10.1039/clmd00102g] Prepared according to the described in example 19 to give LC140 as a white solid (51% yield) .
  • Example 24 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' -spiro-l"-cyclohexane-4"-hydroxymethyl , LC146.
  • Example 25 Preparation of Adamantane-2-spiro-3 , -l',2',4',5'- tetraoxane-6 ' -spiro-1 "-cyclohexane-4"-aminomethy1 , LC165. solution of adamantane-2-spiro-3 ' - 1 ' , 2 ' , 4 ' , 5 ' -tetraoxane-6 ' -spiro-1
  • CDCI3 18.63, 26,65, 28.94, 33.40, 33.93, 36.44, 41.53, 46.76, 108.16, 110.13 ppm; MS (El), m/z 310.36[M + H] + .
  • Example 26 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' spiro-l"-cyclohexane-4"-carboxylic acid, LC153. To a solution of adamantane-2-spiro-3 ' -
  • Example 27 General Procedure for the preparation of adamantane-2-spiro-3 ' -1' , 2' , ' , b' -tetraoxane-6 ' spiro-1"- cyclohexane-4"- [ ( ( tert-butyl-4-aminobutyl ) carbamate) amino] LC157 and Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' -tetraoxane- 6 ' spiro-l"-cyclohexane-4"- [( aminotetrazole ) amino ] LC163.
  • Example 28 Preparation of Adamantane-2-spiro-3 ' -1 ' , 2 ' , 4 ' , 5 ' - tetraoxane-6 ' spiro-l"-cyclohexane-4"- [ ( ( tert-butyl-4- aminobutyl ) carbamate ) amino ] , LC157.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés et compositions d'endoperoxyde, et un procédé pour leur production pour la prophylaxie et le contrôle de la perkinsiose chez les bivalves. Les composés d'endoperoxyde présentant une activité biologique contre la Perkinsus olseni comprennent 13 trioxolanes et 9 tétraoxanes. Les parasites protozoaires du genre Perkinsus sont connus pour infecter plusieurs espèces de mollusques marins dans le monde, comme les huîtres, les ormeaux, les myes, les pétoncles, les huîtres perlières, les coques ou les moules. La présente invention concerne également la synthèse de ces composés, en particulier de nouveaux composés d'endoperoxydes de la famille des tétraoxane. Les compositions comprenant des composés d'endoperoxyde sont utiles pour la prophylaxie et le contrôle de la perkinsiose chez les bivalves. Par conséquent, la présente invention concerne également un procédé de contrôle de la perkinsiose chez les bivalves. La présente invention se rapporte au domaine de l'aquaculture, de la médecine, de produits pharmaceutiques et de la biochimie.
EP19742475.7A 2019-05-31 2019-05-31 Nouveaux composés endoperoxyde, leur procédé d'obtention et leurs utilisations pour le contrôle de la perkinsiose chez les bivalves Withdrawn EP3976190A1 (fr)

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PCT/IB2019/054545 WO2020240266A1 (fr) 2019-05-31 2019-05-31 Nouveaux composés endoperoxyde, leur procédé d'obtention et leurs utilisations pour le contrôle de la perkinsiose chez les bivalves

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EP3976190A1 true EP3976190A1 (fr) 2022-04-06

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US20250064840A1 (en) * 2021-12-16 2025-02-27 Faculdade De Farmácia Da Universidade De Lisboa Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof

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US6906205B2 (en) * 2002-06-21 2005-06-14 Medicines For Malaria Venture Mmv Spiro and dispiro 1,2,4-trioxolane antimalarials
GB0619333D0 (en) 2006-09-30 2006-11-08 Univ Liverpool Dispiro tetraoxane compounds

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