WO2011131816A1 - Synthesis of oxoisoaporphine derivatives and the uses thereof as antimalarial agents - Google Patents

Synthesis of oxoisoaporphine derivatives and the uses thereof as antimalarial agents Download PDF

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WO2011131816A1
WO2011131816A1 PCT/ES2011/070279 ES2011070279W WO2011131816A1 WO 2011131816 A1 WO2011131816 A1 WO 2011131816A1 ES 2011070279 W ES2011070279 W ES 2011070279W WO 2011131816 A1 WO2011131816 A1 WO 2011131816A1
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substituted
unsubstituted
hydrogen
dibenzo
compounds
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PCT/ES2011/070279
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Spanish (es)
French (fr)
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Eduardo Sobarzo Sanchez
Eugenio Uriarte Villares
Mohamed Haddad
Joelle Quetin-Leclercq
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Universidade De Santiago De Compostela
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns certain compounds of the oxoisoaporphma type and their use as a medicament. These compounds and their derivatives are particularly useful in the prevention and treatment of malaria.
  • the invention also relates to pharmaceutical formulations containing these compounds and administered by oral ingestion.
  • naphthoquinones were found to have potent activity against P. falciparum in vitro, with IC 50 of InM, such as those derived from Atovaquone that selectively inhibit the mitochondrial electron transport system (cytochrome bci complex) [Fry, M .; Pudney, M. Biochem. Pharmacol 43, 1545 (1992)], as well as the collapse of the electro-potential through the mitochondrial membrane of the malaria parasite [Sri 3961 (1997)].
  • InM mitochondrial electron transport system
  • Menisporphine (14) Another way of obtaining the 7H-dibenzo [ ⁇ 3 ⁇ 4A] quinolin-7-one skeleton is through the reaction of anthraquinone 1-acetylenic derivatives with hydrazine.
  • anthraquinonyl acetylenes (15a-c) with NH 2 NH 2 generates the expected diazepines (16a-c) together with the oxoisoaporphins (17a-c) in variable yield [Shvartsberg, MS; Ivanchikova, ID; Vasilevsky, SF Tetrahedron Lett. 35, 2077 (1994)].
  • Oxoisoaporphins have a much more widespread history and dating back four decades. In this sense, said heterocycles formerly called 1-azabenzantrones have been synthesized by their varied applications as tinctures, among others.
  • tinctures consisting of oxoisoaporphine units are described in the synthesis of l-aza-2-hydroxybenzantrones (21), 3-bromo-2-methoxyazabenzantrone (22) and many more complex structures consisting of the union of two units of 1 - azabenzantrones by a sulfide bridge (23).
  • the compounds of the present invention showed a high degree of antimalarial effectiveness in vitro against the protozoan species present in a human, Plasmodium falciparum.
  • Such compounds, isomers of oxoaporphins that are widely distributed in nature as a natural oxidation of alkaloids called "aporphms” have been little studied around their pharmacological properties and, therefore, the present invention is the first example of Synthetic isoquinoline alkaloids of chemical structure 7H-dibenzo [ ⁇ 3 ⁇ 4A] quinolin-7-one or "oxoisoaporphine" whose efficiency as antimalarial compounds at low concentrations is demonstrated in the present invention.
  • the present invention is directed to the use of oxoaporphins such as 2,3-dihydro-oxoisoaporphine, oxoisoaporphine, 6-oxoisoaporphine, 2,3,8,9,10,11-hexahydro-oxoisoaporphine, 7-hydroxy-
  • oxoaporphins such as 2,3-dihydro-oxoisoaporphine, oxoisoaporphine, 6-oxoisoaporphine, 2,3,8,9,10,11-hexahydro-oxoisoaporphine, 7-hydroxy-
  • the oxoaporphine structures to which the present invention is preferably directed are: (I) 2,3-dihydro-7H-dibenzo [de, A] qumolin-7-one; (II) 7H-dibenzo [ ⁇ 3 ⁇ 4A] -quinolin-7- one; (III) 6H-dibenzo [ ⁇ 3 ⁇ 4A] quinolin-6-one; (IV) 2,3,8,9,10,1 l-hexahydro-7H- dibenzo [ ⁇ 3 ⁇ 4A] quinolin-7-one; (V) 7-hydroxy-1,2,3,1 lb-tetrahydro-7H-dibenzo [ ⁇ 3 ⁇ 4 h] quinine and (VI) 1,2,3, 7a, 8, 9, 10,11,1 la , 1 lb-decahydro-7H- dibenzo [ ⁇ 3 ⁇ 4A] quinolin-7-one and its pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxid
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, nitro, cyano, alkyl substituted or not substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and - NR a R b ;
  • R 10 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR a C (0) R b , - NR a C (0) OR b , -NR a C (0) NR a R b ;
  • R 11 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -S (0) m NR to R b , -C (0) NR to R b ;
  • R a and R b are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, R a and R b together form a substituted or unsubstituted heterocycle ring, 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and NR c , where R c is selected from hydrogen, substituted or unsubstituted alkyl, or -C (0) R b .
  • the present invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula I, II, III, IV, V or VI, as defined above, and a pharmaceutically acceptable carrier for use in the treatment of malaria.
  • the invention is also directed to the use of a compound of general formula
  • Alkyl refers to a linear or branched hydrocarbon chain that does not contain any instants, of 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, optionally substituted with one to three substituents selected from halogen, cyano, -OR b , -NR a S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected from 1 and 2, -NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , -NR to C (0) NR to R b , -CF 3 , -OCF 3 , cycloalkyl, cycloheteroalkyl, cyclo
  • Cycloalkyl refers to a cyclic hydrocarbon chain that does not contain any setting, from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms.
  • the cycloalkyl may be monocyclic, bicyclic or tricyclic and may include fused rings.
  • the cycloalkyl may be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, - NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , -NR to C (0) NR to R b , - CF 3 , -OCF 3 , alkyl, aryl and heteroaryl; where R a and R b are as previously defined.
  • Alkenyl refers to a linear or branched, cyclic or acyclic hydrocarbon chain, containing at least one setting, from 2 to 10 carbon atoms, preferably from 2 to 5 carbon atoms, optionally substituted with one to three substituents selected from halogen, cyano, -OR b , -NR a S (0) m R b where m is selected between 1 and
  • Cycloheteroalkyl refers to a cycloalkyl containing at least one heteroatom selected from oxygen, nitrogen or sulfur, for example: pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
  • the cycloheteroalkyl may be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , - NR to C (0) NR to R b , -CF 3 , -OCF 3 , alkyl, aryl and heteroaryl; where R a and R b are as previously defined.
  • Aryl refers to an aromatic hydrocarbon of 6 to 10 carbon atoms, for example: phenyl or naphthyl; optionally the aryl can be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , - C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , -NR to C (0) NR to R b , -CF 3 , -OCF 3 , alkyl, alkenyl, aryl and heteroaryl; where R a and R b are as
  • Heteroaryl refers to an aryl containing at least one heteroatom selected from oxygen, nitrogen or sulfur, for example: pyridyl, pyrazolyl, triazolyl, pyrimidyl, isoxazolyl, indolyl and thiazolyl; optionally the heteroaryl may be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected from 1 to 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , - NR to C (0) NR to R b
  • the invention is directed to the use of the compounds of formula I, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
  • R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, - OR b and -NR a R b ;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted alkenyl or unsubstituted, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ;
  • R a and R b are as defined above.
  • the compounds of formula I are preferably selected from those in which
  • R 1 and R 2 are hydrogen and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, and -OR b ;
  • R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
  • R 3 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 4 and R 5 are independently selected from hydrogen, methyl or hydroxyl.
  • the invention is directed to the use of the compounds of formula II, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, nitro, substituted or unsubstituted alkyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted aryl or -OR b ; where R b is as defined above.
  • the compounds of formula II are preferably selected from those in which R 1 and R 2 are selected from hydrogen or halogen, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each one of them independently selected from hydrogen, halogen, nitro, and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
  • the invention is directed to the use of the compounds of formula III, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 4 is hydroxyl or methoxy.
  • the invention is directed to the use of the compounds of formula IV, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
  • R, R, R, R, R and R are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR a R b ;
  • R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ; where R a and R b are as defined above.
  • the compounds of formula IV are preferably selected from those in which R 1 , R 2 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 3 , R 4 , R 5 are each selected from independently between hydrogen or -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl. More preferably R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 4 is hydrogen, hydroxyl or methoxy.
  • the invention is directed to the use of the compounds of formula 5, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
  • R, R, R, R, R and R are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR a R b ;
  • R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted aryl or unsubstituted, -OR b and -NR a R b ;
  • R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , - C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , - NR a C (0) NR a R b ; where R a and R b are as defined above.
  • the compounds of formula V are preferably selected from those in which R 1 , R 2 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen, and R 3 , R 4 , R 5 are preferably selected between hydrogen and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen and R 4 and R 5 are hydrogen, hydroxyl or methoxy.
  • the invention is directed to the use of the compounds of formula VI, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
  • R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR to R b ;
  • R, R, R, R, R, R, R, R, R, R are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted cycloheteroalkyl or unsubstituted, substituted or unsubstituted aryl, -OR b and -NR a R b ;
  • R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , - C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , or - NR a C (0) NR a R b ; where R a and R b are as defined above.
  • R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -S (0) m NR to R b , or -C (0) NR to R b ;
  • the compounds of formula VI are preferably selected from those in which R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen and R 3 , R 4 , R 5 , are each preferably selected from hydrogen, or -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
  • the compounds of formula I, II, III, IV, V, and VI are preferably selected from the compounds in the following list:
  • compositions of general formula (I), (II), (III), (IV), (V) and (VI) of the present invention with an available acid, for example an inorganic acid such as hydrochloric acid, or with an organic acid.
  • the compounds of general formula (I), (II), (III), (IV), (V) and (VI) used for the present invention may be contained in pharmaceutical forms suitable for administration by means of usual processes using substances auxiliaries such as liquid or solid materials.
  • compositions of the invention can be administered orally or parenterally (intramuscularly, subcutaneously or intravenously).
  • pharmaceutical compositions When pharmaceutical compositions are used by oral administration, they may appropriately have pharmaceutically acceptable formulations in the form of solutions, powders, tablets, tablets, capsules (including microcapsules), etc.
  • Suitable excipients for such formulations are pharmaceutically used liquids or fillers and diluents, solvents, lubricants, emulsifiers, condiments, coloring substances and / or pH regulators.
  • auxiliary substances which may be mentioned are magnesium carbonate or stearate, titanium dioxide, Opadry OYS 96-14, polyvinylpyrrolidone, croscarmellose sodium, lactose, mannitol and other sugars or alcohols derived from sugars, talc, lactoproteins, gelatins, starch, cellulose and their derivatives, vegetable and animal oils such as fish liver oil, sunflower, nut or sesame oils, polyethylene glycol and solvents such as, for example, distilled water and mono- or polyhydric alcohols such as glycerol.
  • compositions of the present invention are injectable compositions
  • pharmaceutically acceptable and acceptable formulations include sterilized water, isotonic saline solutions or buffers.
  • injectable compositions of the present invention may be sterilized powder compositions or lyophilized powder compositions that can be used by simple dissolution in sterilized water.
  • Pharmaceutically injectable compositions of the present invention may contain sugars (glucose, mannitol and dextran, etc.), polyhydric alcohols (glycerol, etc.) and inorganic salts (sodium, magnesium salts, etc.).
  • compositions of the present invention When the pharmaceutical compositions of the present invention are administered by intravenous injection or infusion, they may contain nutrients such as glucose, vitamins, amino acids and lipids.
  • compositions which are important and novel representations of the invention due to the presence of the antimalarial compounds examined as such.
  • Types of pharmaceutical compositions that can be used and included but not limited to are tablets, chewable tablets, capsules and other types contained in this invention.
  • a pharmaceutical container or container is described as containing one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such containers may be written various concepts such as instructions for use or a note in the manner prescribed by a government agency that regulates its manufacture, use or sale of pharmaceutical products, which also reflects the approval by the manufacturing agency , use or sale for humans or veterinary administration.
  • a suspension of 6% of human erythrocytes was prepared in the culture medium consisting of RMPI 1640 (GIBCO Laboratories, Grand Island, NY) diluted in sterilized water with 25 mL of HEPES (N-2-hydroxyethylpiperazin acid -N'-2- ethanesulfonic; Calbiochem, La Jolla, Calif.), 32 mM NaHC0 3 (GIBCO), and 10% fetal bovine serum inactivated (40 min at 56 ° C and then clarified by centrifugation) the human plasma of type A +.
  • HEPES N-2-hydroxyethylpiperazin acid -N'-2- ethanesulfonic
  • Calbiochem La Jolla, Calif.
  • 32 mM NaHC0 3 GGIBCO
  • 10% fetal bovine serum inactivated 40 min at 56 ° C and then clarified by centrifugation
  • the samples from the common cultures were mostly diluted in the culture medium that contained enough uninfected human erythrocytes (A +) to yield a final 1.5% hematocrit and 0.25 to 0.5% parasitemia in order to add microtiter plates.
  • the antiplasmodic activity of the compounds was estimated in vitro against Plasmodium falciparum chloroquine-resistant (FCBl) using the incorporation of [3H] -hypoxanthine (Amersham-France).
  • Erythrocytes were infected with P. falciparum suspended in complete culture medium in a 1.5% hematocrit. The suspension was distributed in 96-well microplates (200 ⁇ per well). The compounds were tested in triplicate in cultures with 1% parasitemia, especially in the ring stage. For each analysis, a parasite culture was incubated with the compound for 48 h in 5% C0 2 in 95% hygrometry and frozen until incorporation of [3H] -hypoxanthin. IC50 values were determined graphically at one percent of the inhibition against concentration curve.
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 4 represents a methoxy and R 5 represents a hydroxyl; it is 5-methoxy-6-hydroxy-2,3-dihydro-7H-dibenzo [ ⁇ ie, A] quinolin-7-one, hereinafter referred to as OXO 3.
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 4 represents a methoxy and R 5 represents a hydroxyl; it is 5-methoxy-6-hydroxy-7H-dibenzo [de, A] quinolin-7-one, hereinafter referred to as OXO 6;
  • R 4 represents a hydroxyl, it is the compound 5-hydroxy-7H-dibenzo [ ⁇ 3 ⁇ 4A] quinolin-7-one, hereinafter called OXO 7;
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 3 represents a bromine and R 4 represents a methoxy; it is 4-bromo-5-methoxy-7H-dibenzo [ ⁇ 3 ⁇ 4A] quinolin-7-one, hereinafter referred to as OXO 16;
  • EU a) in which if: - R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen and R 4 represents a methoxy, it is 5-methoxy-6H-dibenzo [ ⁇ 3 ⁇ 4A] quinolin-6-one, hereinafter called OXO 8.
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 is hydrogen, R 5 represents a methoxy and R 6 represents a hydroxyl; it is 5-methoxy-6-hydroxy-1,2,3, 7a, 8, 9, 10,11,1 la, l lb-decahydro-7H-dibenzo [ ⁇ ie, A] quinolin-7-one, called hereinafter OXO 10.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen and R 5 represents a methoxy; it is 5-methoxy-7-hydroxy-l, 2,3, 1 lb-tetrahydro-7H-dibenzo [ ⁇ 3 ⁇ 4A] quinoline, hereinafter referred to as OXO 11; Y
  • COMPOUND (IC 50 ) COMPOSITE (CI 50 )
  • IC 50 values were defined as the concentration of compound necessary to inhibit the growth of a cell or a certain biological process in 50% of the positive control.
  • the drug called chloroquine is used as a positive control in antimalarial activity assays.
  • the compounds of this invention have an antimalarial activity that could be applied in the early stages of infection at the liver level. This is the passage of the parasite to the liver and the subsequent infection of the liver cells by the sporozoites of P. falciparum.
  • the present invention provides possible pharmaceutical formulations for the preparation of a medicament, based on the compounds presented herein, for the treatment and prevention of malaria.
  • the doses in which the compound could be administered vary within a wide range, adjusting to the requirements of each particular case.
  • the different pharmaceutical compositions of the invention can be administered orally according to the different pharmaceutical formulations described in Tables 2 and 3:
  • Table 2 Pharmaceutical formulation and weight of the active ingredient plus the excipients of a tablet.
  • Table 3 Pharmaceutical formulation and weight of the active ingredient plus the excipients of a capsule.
  • OXOISOAPORFINS The following examples illustrate the invention of compounds with antimalarial activity, and should be considered for a better understanding thereof without involving a limitation:
  • NMR- 13 C (OXO 16) ⁇ (CDC1 3 , ppm): 56, 1 1 (0-5-CH 3 ), 1 10.98 (C-4), 1 18.96 (C-3), 1 19.64 ( C- 6), 122.07 (C-3b), 125.39 (Cl l), 127.65 (C-8), 130.47 (C-9), 131, 10 (C-6a), 131 , 76 (C-3a), 134.30 (C-10), 136.35 (C-7a / Cl la), 146.01 (C-2), 147.27 (Cl lb), 161, 71 ( C-5), 182.51 (C-7).

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Abstract

The present invention relates to certain compounds of the 2,3-dihydro-oxoisoaporphine, oxoisoaporphine, 6-oxoisoaporphine, 2,3,8,9,10,11-hexahydro-oxoisoaporphine, 7-hydroxy-,2,3,11b-tetrahydro-isoaporphine and 1,2,3,7a,8,9,10,11,11a,11b-decahydro-oxoisoaporphine type and to the derivatives thereof for use as a drug. These compounds and the derivatives thereof are particularly effective in preventing and treating malaria in vitro caused by the Protozoan species, Plasmodium falciparum, present in humans. The invention also relates to orally-administered pharmaceutical formulations containing said compounds, having established that 5-methoxy-6-oxoisoaporphine is highly active and selective in combating malaria. Said prevention appears to be effective in the first phases of infection in the liver.

Description

SÍNTESIS DE DERIVADOS DE OXOISOAPORFINAS Y SUS USOS  SYNTHESIS OF DERIVATIVES OF OXOISOAPORFINAS AND ITS USES
COMO AGENTES ANTIMALÁRICOS AS ANTIMALARIAN AGENTS
Sector de la técnica Technical sector
La presente invención concierne a ciertos compuestos del tipo oxoisoaporfma y su uso como un medicamento. Estos compuestos y sus derivados son particularmente útiles en la prevención y tratamiento contra la malaria. La invención también se refiere a las formulaciones farmacéuticas conteniendo estos compuestos y administrados por ingestión oral.  The present invention concerns certain compounds of the oxoisoaporphma type and their use as a medicament. These compounds and their derivatives are particularly useful in the prevention and treatment of malaria. The invention also relates to pharmaceutical formulations containing these compounds and administered by oral ingestion.
Estado de la técnica  State of the art
La Malaria es una enfermedad muy antigua originada probablemente en Africa y que acompaño a la migración humana a orillas del Mediterráneo, India y el sur-este asiático. Se cree inclusive que en la historia de la humanidad esta enfermedad nunca estuvo ausente, aún en la prehistoria. Más recientemente en la historia, en las zonas pantanosas de los alrededores de la ciudad de Roma, el nombre de la enfermedad surgió casi de forma espontánea (mal-aria; o "mal aire"), o también conocida como fiebre romana. Tal es la mortalidad de esta enfermedad que es la responsable de la muerte de la mitad de las personas que alguna vez la tuvieron [Riscoe, M.; Kelly, J. X.; Winter, R. Curr. Med. Chem. 12, 2539 (2005)]. Globalmente, cada 40 segundos un niño muere de malaria, resultando en una pérdida de más de 2000 vidas por día [Sachs, J. and Maloney, P. "The economic and social burden of malaria". A 1 ature London 415, 680 (2002)]. En este sentido, La Organización Mundial de la Salud (OMS) estima que hay entre 300-500 millones de casos de malaria anualmente, causando directamente 1 millón de muertes [World Health Organization, March 2002. Roll Back Malaria Infosheet 1 of l l .WHO: Geneva]. Actualmente la enfermedad se extiende por grandes áreas de Africa, America Central y Sudamérica, las islas del Caribe como Haití y República Dominicana, India, Europa del este y el Pacífico sur. Malaria is a very old disease probably originated in Africa and that accompanied human migration on the shores of the Mediterranean, India and South-East Asia. It is even believed that in the history of mankind this disease was never absent, even in prehistory. More recently in history, in the swampy areas around the city of Rome, the name of the disease arose almost spontaneously (mal-Aryan; or "bad air"), or also known as Roman fever. Such is the mortality of this disease that is responsible for the death of half of the people who once had it [Riscoe, M .; Kelly, JX; Winter, R. Curr. Med. Chem. 12, 2539 (2005)]. Globally, every 40 seconds a child dies of malaria, resulting in a loss of more than 2000 lives per day [Sachs, J. and Maloney, P. "The economic and social burden of malaria". A 1 ature London 415, 680 (2002)]. In this regard, the World Health Organization (WHO) estimates that there are between 300-500 million cases of malaria annually, directly causing 1 million deaths [World Health Organization, March 2002. Roll Back Malaria Infosheet 1 of ll .WHO : Geneva]. Currently the disease spreads over large areas of Africa, Central and South America, the Caribbean islands such as Haiti and the Dominican Republic, India, Eastern Europe and the South Pacific.
El tratamiento de la malaria se está volviendo más complicada a causa de la emergente resistencia a las drogas existentes por parte de la especie protozoaria presente en humanos, Plasmodium falciparum, transmitida por el mosquito vector de la malaria, el Anopheles gambiae. Además, en el continente africano, donde la malaria alberga el 90% de la mortalidad, dicho transmisor está ampliamente extendido en esta parte del mundo, por lo que es muy difícil su control. Más allá de su repercusión mediática, la malaria significa un impacto económico en países endémicos, costando en Africa $12 billones de dólares en pérdida del producto interno bruto (PIB) cada año y consumiendo casi el 40% de todo el gasto en salud pública. Así, esta enfermedad genera casi 500 millones de episodios clínicos y demandando 1.5 millones de vidas, mayormente niños jóvenes y mujeres embarazadas [Snow, R. W.; Guerra, C. A.; Noor, A. M.; Myint, H. Y.; Hay, S. I. Nature 434, 214 (2005)]. The treatment of malaria is becoming more complicated because of the emerging resistance to existing drugs by the protozoan species present in humans, Plasmodium falciparum, transmitted by the malaria vector mosquito, the Anopheles gambiae. In addition, in the African continent, where malaria is home to 90% of mortality, this transmitter is widely spread in this part of the world, making it very difficult to control. Beyond its media impact, malaria means an economic impact in endemic countries, costing in Africa $ 12 billion in loss of gross domestic product (GDP) each year and consuming almost 40% of all public health spending. Thus, this disease generates almost 500 million clinical episodes and demanding 1.5 million lives, mostly young children and pregnant women [Snow, RW; Guerra, CA; Noor, AM; Myint, HY; There, SI Nature 434, 214 (2005)].
Mientras el mundo espera el desarrollo de una vacuna para el control de la malaria, millones de vidas están aún dependiendo de agentes quimioterapéuticos o una terapia combinada para contrarrestar dicha resistencia química a los fármacos por parte del protozoo. While the world awaits the development of a vaccine for malaria control, millions of lives are still depending on chemotherapeutic agents or a combination therapy to counteract such chemical resistance to drugs by the protozoan.
Esto se traduce en Africa en una resistencia del P. falciparum a la droga antimalárica más barata y ampliamente usada como es la cloroquina, una quino lina que incluyendo a sus análogos [Krogstad, D. J. PCT patent WO9640138A1 (1996)], han sido capaces de prevenir y tratar la enfermedad plasmoidal a través de la identificación el mecanismo de acción de este fármaco sobre el ciclo de vida de la especie protozoaria [Petri Jr, W. A. Trends in Pharmacological Sciences, 24(5), 210 (2003); Kwiek, J. J.; Haystead, T. A. J.; Rudolph, J. Biochemistry 43, 4538 (2004)].  This translates into Africa in a resistance of P. falciparum to the cheapest and widely used antimalarial drug such as chloroquine, a quinine quinoa that including its analogues [Krogstad, DJ PCT patent WO9640138A1 (1996)], have been able to prevent and treat plasmoidal disease by identifying the mechanism of action of this drug on the life cycle of the protozoan species [Petri Jr, WA Trends in Pharmacological Sciences, 24 (5), 210 (2003); Kwiek, J. J .; Haystead, T. A. J .; Rudolph, J. Biochemistry 43, 4538 (2004)].
Aunque existen en la actualidad terapias basadas en la artemisina, un producto de la medicina tradicional china y derivada de la planta Artemisia annua (Asteraceae) utilizado sobre todo para tratar la malaria no complicada [O'Dowd, H.; Ploypradith, P.; Xie, S.; Shapiro, T.; Posner, G. Tetrahedron 55, 3625 (1999); Cheng, F.; Shen, J.; Luo, X.; Zhu, W.; Jiande, G.; Ji, R.; Jiang, H.; Chen, K. Bioorg. Med. Chem. 10, 2883 (2002); Posner, G.; Ploypradith, P.; Parker, M.; O Dowd, H.; Woo, S.-H.; Northrop, J.; Krasavin, M.; Dolan, P.; Kensler, T.; Xie, S.; Shapiro, T. J. Med. Chem. 42, 4275 (1999)], éste acelera la aparición de resistencias a ese producto en los parásitos causantes de la enfermedad. Sin embargo, cuando este producto se utiliza correctamente en combinación con otros antimaláricos sintéticos (lo que se conoce como Tratamientos Combinados de Artemisina, TCA), la eficacia de ese compuesto en la curación del paludismo no complicado alcanza casi el 95% y el parásito difícilmente se vuelve resistente al fármaco.  Although there are currently artemisin-based therapies, a product of traditional Chinese medicine and derived from the Artemisia annua plant (Asteraceae) used primarily to treat uncomplicated malaria [O'Dowd, H .; Ploypradith, P .; Xie, S .; Shapiro, T .; Posner, G. Tetrahedron 55, 3625 (1999); Cheng, F .; Shen, J .; Luo, X .; Zhu, W .; Jiande, G .; Ji, R .; Jiang, H .; Chen, K. Bioorg. Med. Chem. 10, 2883 (2002); Posner, G .; Ploypradith, P .; Parker, M .; Or Dowd, H .; Woo, S.-H .; Northrop, J .; Krasavin, M .; Dolan, P .; Kensler, T .; Xie, S .; Shapiro, T. J. Med. Chem. 42, 4275 (1999)], this accelerates the appearance of resistance to that product in the parasites causing the disease. However, when this product is used correctly in combination with other synthetic antimalarials (what is known as Combined Artemisin Treatments, TCA), the efficacy of that compound in the healing of uncomplicated malaria reaches almost 95% and the parasite hardly It becomes resistant to the drug.
Figure imgf000003_0001
Figure imgf000003_0001
Cloroquina Artemisina No obstante, la búsqueda de fármacos selectivos en el tratamiento y prevención de la malaria son recurrentes desde hace bastantes años atrás. En este sentido, la búsqueda de heterociclos con propiedades antimaláricas han sido objeto de estudios que se han extendido, por ejemplo, a derivados de acridina [Goldberg, A. A.; Kelly, W.; Silas Turner, H. G. B. patent N° 601768A (1945); Goldberg, A. A.; Besly, D. M. G. B. patent N° 704238A (1950)] y de pirimidinas [Schmaizi, K. J.; Sharma, S. Ch.; Christopherson, R. I. E. P. patent 0260057A2 (1988)]. Sin embargo, investigaciones realizadas durante la Segunda Guerra Mundial en el ámbito de los compuestos con actividad antimalárica, han reportado la síntesis de derivados de naftoquinonas [Fieser, L. F.; Richardson, A. P. J. Am. Chem. Soc. 70, 3156 (1948); Fieser, L. F.; Fieser, M. J. Am. Chem. Soc. 70, 3215 (1948); Fieser, L. F. J. Am. Chem. Soc. 70, 3232 (1948); Fieser, L. F.; Berligner, E.; Bondhus, F. j.; Chang, F. C; Dauben, W. G.; Ettlinger, M. G.; Fawaz, G.; Fields, M.; Fieser, M.; Heildelberger, C; Heymann, H.; Seligman, A. M.; Vaughan, W. R.; Wilson, A. G.; Wilson, E.; Wu, M. I.; Leffler, M.; Hamilin, K. E.; Hathaway, R. j.; Matson, E. j.; Moore, E. E.; Moore, M. B.; Rápala, R. T.; Zaugg, H. E. J. Am. Chem. Soc. 70, 3151 (1948); Fieser, L. F.; Schirmer, j. P.; Archer, S.; Lorentz, R. R.; Pfaffenbach, P. I. J. Med. Chem. 10, 513 (1967)], cuya considerable atención durante los programas de quimioterapia contra la malaria en los años 40, hicieron posible la síntesis de un exitoso compuesto de tratamiento como es la lapinona. Dicho compuesto dio paso a potenciales naftoquinonas antimaláricas derivadas de 2-acilhidracino-l,4-naftoquinonas aunque con muy pobre actividad frente a infecciones del protozoo en ratón [Dudley, K. H.; Wayne Miller, H. J. Med. Chem. 13(3), 535 (1970)]. Chloroquine Artemisin However, the search for selective drugs in the treatment and prevention of malaria have been recurring for many years. In this sense, the search for heterocycles with antimalarial properties have been the subject of studies that have extended, for example, to acridine derivatives [Goldberg, AA; Kelly, W .; Silas Turner, HGB patent No. 601768A (1945); Goldberg, AA; Besly, DMGB patent No. 704238A (1950)] and pyrimidines [Schmaizi, KJ; Sharma, S. Ch .; Christopherson, RIEP patent 0260057A2 (1988)]. However, research conducted during the Second World War in the field of compounds with antimalarial activity, have reported the synthesis of naphthoquinone derivatives [Fieser, LF; Richardson, APJ Am. Chem. Soc. 70, 3156 (1948); Fieser, LF; Fieser, MJ Am. Chem. Soc. 70, 3215 (1948); Fieser, LFJ Am. Chem. Soc. 70, 3232 (1948); Fieser, LF; Berligner, E .; Bondhus, F. j .; Chang, F. C; Dauben, WG; Ettlinger, MG; Fawaz, G .; Fields, M .; Fieser, M .; Heildelberger, C; Heymann, H .; Seligman, AM; Vaughan, WR; Wilson, AG; Wilson, E .; Wu, MI; Leffler, M .; Hamilin, KE; Hathaway, R. j .; Matson, E. j .; Moore, EE; Moore, MB; Scratch it, RT; Zaugg, HEJ Am. Chem. Soc. 70, 3151 (1948); Fieser, LF; Schirmer, j. P .; Archer, S .; Lorentz, RR; Pfaffenbach, PIJ Med. Chem. 10, 513 (1967)], whose considerable attention during malaria chemotherapy programs in the 1940s, made possible the synthesis of a successful treatment compound such as lapinone. Said compound gave way to potential antimalarial naphthoquinones derived from 2-acylhydrazino-l, 4-naphthoquinones although with very poor activity against protozoan infections in mice [Dudley, KH; Wayne Miller, HJ Med. Chem. 13 (3), 535 (1970)].
Más aún, algunas naftoquinonas fueron encontradas a tener una potente actividad contra el P. falciparum in vitro, con IC50 de InM, como los derivados de la Atovaquona que inhiben selectivamente el sistema transportador de electrones mitocondrial (complejo citocromo bci) [Fry, M.; Pudney, M. Biochem. Pharmacol. 43, 1545 (1992)], así como el colapso del electro-potencial a través de la membrana mitocondrial del parásito de la malaria [Sri 3961 (1997)]. Moreover, some naphthoquinones were found to have potent activity against P. falciparum in vitro, with IC 50 of InM, such as those derived from Atovaquone that selectively inhibit the mitochondrial electron transport system (cytochrome bci complex) [Fry, M .; Pudney, M. Biochem. Pharmacol 43, 1545 (1992)], as well as the collapse of the electro-potential through the mitochondrial membrane of the malaria parasite [Sri 3961 (1997)].
Figure imgf000004_0001
Figure imgf000004_0001
Lapinona; R = (CH2)8C-(OH)(«-C5H9)2 R' = alquilo o (CH2)ncicloalquilo
Figure imgf000005_0001
Lapinone; R = (CH 2 ) 8 C- (OH) («- C 5 H 9 ) 2 R '= alkyl or (CH 2 ) n cycloalkyl
Figure imgf000005_0001
Atovaquona  Atovaquone
No obstante, el mayor éxito reportado en el tratamiento de esta enfermedad radica en la síntesis de derivados de quinonas y antraquinonas, compuestos altamente extendidos en múltiples fuentes de origen natural y con una alta potencialidad debido a sus bajos costes de extracción de fuentes vegetales y/o animales, y su accesible obtención por métodos sintéticos.  However, the greatest success reported in the treatment of this disease lies in the synthesis of derivatives of quinones and anthraquinones, highly extended compounds in multiple sources of natural origin and with a high potential due to their low extraction costs from plant sources and / or animals, and their accessible obtaining by synthetic methods.
En este sentido, la actividad antimalarica de ciertas quinonas e hidroquinonas derivadas de la pentaquina, una 6-metoxi-8-aminoquinolina, había sido relacionada por su transformación en el interior del organismo huésped en su análogo de oxidación [Drake, N. L.; Pratt, Y. T. J. Am. Chem. Soc. 73, 544 (1951)]. Del mismo modo, la primera serie de antraquinonas que fueron testeadas como agentes antipalúdicos, estaban los bien conocidos antibióticos denominados ciclinas como la tetraciclina, doxiciclina, minociclina, oxitetraciclina, entre otros varios derivados [Clyde, D. F.; Miller, R. M.; Dupont, H. L.; Hornick, R. B. J. Trop. Med. Hyg. 74, 238 (1971); Willerson, D. Jr.; Rieckmann, K. H.; Carson, P. E.; Frischer, H. Am. J. Trop. Med. Hyg. 21, 857 (1972); Colwell, E. j.; Hickman, R. L.; Intraprasert, R.; Tirabutana, C. Am. J. Trop. Med. Hyg. 21, 144 (1972); Kaddu, J. B.; Warhurst, D. C. Trans. Roy. Soc. Trop. Med. Hyg. 67, 17 In this sense, the antimalarial activity of certain quinones and hydroquinones derived from pentaquine, a 6-methoxy-8-aminoquinoline, had been related by its transformation inside the host organism into its oxidation analog [Drake, N. L .; Pratt, Y. T. J. Am. Chem. Soc. 73, 544 (1951)]. Similarly, the first series of anthraquinones that were tested as antimalarial agents were the well-known antibiotics called cyclines such as tetracycline, doxycycline, minocycline, oxytetracycline, among several other derivatives [Clyde, D. F .; Miller, R. M .; Dupont, H. L .; Hornick, R. B. J. Trop. Med. Hyg. 74, 238 (1971); Willerson, D. Jr .; Rieckmann, K. H .; Carson, P. E .; Frischer, H. Am. J. Trop. Med. Hyg. 21, 857 (1972); Colwell, E. j .; Hickman, R. L .; Intraprasert, R .; Tirabutana, C. Am. J. Trop. Med. Hyg. 21, 144 (1972); Kaddu, J. B .; Warhurst, D.C. Trans. Roy Soc. Trop. Med. Hyg. 67, 17
(1973) ; Kaddu, J. B.; Warhurst, D. C; Peters, W. Ann. Trop. Med. Parasitol. 68, 41(1973); Kaddu, J. B .; Warhurst, D. C; Peters, W. Ann. Trop Med. Parasitol. 68, 41
(1974) ; Brogden, R. N.; Speight, T. M.; Avery, G. S. Drugs, 9, 251 (1975)]. Este tipo de estructuras fueron la base para potenciar la actividad contra el protozoo de la malaria por medio de complejos de metales-tetraciclinas (M = Mn, Fe, Co, Ni, Cu, Zn, y Cd) [Obaleye, J. A.; Adeyemi, O. G.; Balogun, E. A. Inter. J. Chem. 11, 101 (2001)] y pirazol-tetraciclina [Angustí, A.; Hou, S. T.; Jiang, X. S.; Komatsu, H.; Konishi, Y.; Kubo, T.; Lertvorachon, j.; Román, G. PCTInt. Appi, pp. 95 (2005)]. OH O OH O O tetraciclina; Rj = H, R2 = Me, R3 = OH, R4 = H (1974); Brogden, RN; Speight, TM; Avery, GS Drugs, 9, 251 (1975)]. These types of structures were the basis for enhancing the activity against malaria protozoa through metal-tetracycline complexes (M = Mn, Fe, Co, Ni, Cu, Zn, and Cd) [Obaleye, JA; Adeyemi, OG; Balogun, EA Inter. J. Chem. 11, 101 (2001)] and pyrazole-tetracycline [Angustí, A .; Hou, ST; Jiang, XS; Komatsu, H .; Konishi, Y .; Kubo, T .; Lertvorachon, j .; Román, G. PCTInt. Appi, pp. 95 (2005)]. OH O OH OO tetracycline; R j = H, R 2 = Me, R 3 = OH, R 4 = H
doxiciclina; Rl = H, R2 = Me, R3 = H, R4 = OH doxycycline; R l = H, R 2 = Me, R 3 = H, R 4 = OH
minociclina; R, = NMe2, R2 = H, R3 = H, R4 = H minocycline; R, = NMe 2 , R 2 = H, R 3 = H, R 4 = H
oxitetraciclina; R, = H, R2 = Me, R3 = OH, R4 = OH oxytetracycline; R, = H, R 2 = Me, R 3 = OH, R 4 = OH
Por otra parte, existen recientes reportes de antraquinonas oxigenadas naturales y sintéticas, entre los cuales se destaca el derivado 1,8-pentaetilenglicol, una antraquinona- éter-corona con una interesante actividad antimalárica en diferentes etapas del ciclo de vida del parásito [El Heiga, L. A.; Katzhendler, J.; Gean, K. F.; Bachrach, U. Biochem. Pharmacol. 39, 1620 (1990)], y una serie de hidroxi- y polihidroxiantraquinonas como el rufigallol con un IC50 de 10.5 ng/mL [Winter, R. W.; Cornell, K. A.; Johnson, L. L.; Isabelle, L. M.; Hinrichs, D. J.; Riscoe, M. K. Bioorg. Med. Chem. Lett. 5, 1927 (1995); Mahajan, S. S.; Kamath, V. R.; Ghatpande, S. S. Parasitology 131, 459 (2005)]. En recientes investigaciones llevadas a cabo en plantas medicinales tradicionales de Africa, algunos constituyentes activos contra la malaria han sido identificados como dímeros de antraquinonas, tales como la Joziknifolonas A y B [Abebe Wube, A.; Bucar, F.; Asres, K.; Gibbons, S.; Rattray, L.; Croft, S. L. Phytother. Res. 19, 472 (2005); Bringmann, G.; Mutanyatta-Comar, J.; Maksimenka, K.; Wanjohi, J. M.; Heydenreich, M.; Brun, R.; Müller, W. E. G.; Peter, M. G.; Midiwo, J. O.; Yenesew, A. Chem. Eur. J. 14, 1420 (2008)]. On the other hand, there are recent reports of natural and synthetic oxygenated anthraquinones, among which the 1,8-pentaethylene glycol derivative, an anthraquinone ether-crown with an interesting antimalarial activity at different stages of the parasite's life cycle [El Heiga , THE; Katzhendler, J .; Gean, KF; Bachrach, U. Biochem. Pharmacol 39, 1620 (1990)], and a series of hydroxy- and polyhydroxyanthraquinones such as rufigallol with an IC 50 of 10.5 ng / mL [Winter, RW; Cornell, KA; Johnson, LL; Isabelle, LM; Hinrichs, DJ; Riscoe, MK Bioorg. Med. Chem. Lett. 5, 1927 (1995); Mahajan, SS; Kamath, VR; Ghatpande, SS Parasitology 131, 459 (2005)]. In recent research conducted in traditional medicinal plants in Africa, some active constituents against malaria have been identified as anthraquinone dimers, such as Joziknifolonas A and B [Abebe Wube, A .; Bucar, F .; Asres, K .; Gibbons, S .; Rattray, L .; Croft, SL Phytother. Res. 19, 472 (2005); Bringmann, G .; Mutanyatta-Comar, J .; Maksimenka, K .; Wanjohi, JM; Heydenreich, M .; Brun, R .; Müller, WEG; Peter, MG; Midiwo, JO; Yenesew, A. Chem. Eur. J. 14, 1420 (2008)].
Figure imgf000006_0001
Figure imgf000006_0001
antraquinona-l,8-pentaetilenglicol Rufigallol anthraquinone-l, 8-pentaethylene glycol Rufigallol
Figure imgf000007_0001
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0002
No obstante, cabe destacar que uno de los compuestos más abundantes en la naturaleza y con variadas actividades farmacológicas, entre las cuales se destaca la actividad antimalárica, son los alcaloides isoquinolínicos. Así, por ejemplo, se ha descrito la síntesis y su aplicación medicinal en éste campo de algunos derivados de la (-)- roemrefidina, una aporfina extraída de una vid en Bolivia, que ha demostrado además no ser citotóxica frente a líneas celulares [Muñoz, V.; Sauvain, M; Mollinedo, P.; Callapa, J.; Rojas, I.; Giménez, A.; Valentín, A.; Mallie, M. Planta Med. 65(5), 448 (1999); Saxena, S.; Pant, N.; Jain, D. C; Bhakuni, R. S. Current Science 85(9), 1314 (2003)]. La investigación de otras aporfinas extraídas de tubérculos del Stephania erecta Craib (Menispermaceae) tales como la (-)-asimilobina, (-)-anonaína y la cassyticina han mostrado interesantes actividades antimaláricas frente a controles de cloroquina y artemisina [Likhitwitayawuid, K.; Angerhofer, C. K.; Chai, H.; Pezzuto, J. M.; Cordell, G. A. J. Nat. Prod. 56(9), 1468 (1993)]. También dentro de este grupo se han aislado algunos alcaloides bis-deshidroaporfmas provenientes de plantas medicinales de Tailandia. Sin embargo, estos compuestos han exhibido una moderada actividad antimalárica con valores de IC50 entre 4.1 y 5.4 ug/mL [Kanokmedhakul, S.; Kanokmedhakul, K., Yodbuddee, D.; Phonkerd, N. J. Nat. Prod. 66, 616 (2003)]. Menos comunes pero también con moderadas propiedades antimaláricas son los alcaloides fenólicos aporfina-bencilisoquinolina aislados de una hierba perenne indígena proveniente de China [Lin, L.-Z.; Hu, S.-F.; Chu, M.; Chan, T.-M.; Chai, H.; Angerhofer, C. K.; Pezzuto, J. M.; Cordell, G. A. Phytochemistry 50, 829 (1999)]. Recientemente, se ha patentado la síntesis y el uso farmacológico de alcaloides derivados de la morfina, y que presentan actividades antimaláricas importantes que pueden dar pistas sobre la resistencia del protozoo frente a fármacos de origen natural [Frappier, F.; Frappier, M.-P.; Frappier, J.; Mazier, D.; Carraz, M.; Franetich, J.-F.; Jossang, A.; Joyeau, R.; Rasoanaivo, P. USpatent 0038390 (2008)]. However, it should be noted that one of the most abundant compounds in nature and with varied pharmacological activities, among which antimalarial activity is highlighted, are the isoquinoline alkaloids. Thus, for example, it has been described the synthesis and its medicinal application in this field of some derivatives of (-) - roemrefidine, an aporphine extracted from a vine in Bolivia, which has also proved not to be cytotoxic against cell lines [Muñoz , V .; Sauvain, M; Mollinedo, P .; Callapa, J .; Rojas, I .; Giménez, A .; Valentine, A .; Mallie, M. Planta Med. 65 (5), 448 (1999); Saxena, S .; Pant, N .; Jain, D. C; Bhakuni, RS Current Science 85 (9), 1314 (2003)]. The investigation of other aporphins extracted from tubercles of Stephania erecta Craib (Menispermaceae) such as (-) - assylobin, (-) - anonaine and cassyticin have shown interesting antimalarial activities against chloroquine and artemisin controls [Likhitwitayawuid, K .; Angerhofer, CK; Chai, H .; Pezzuto, JM; Cordell, GAJ Nat. Prod. 56 (9), 1468 (1993)]. Also within this group some bis-dehydroaporphic alkaloids from medicinal plants in Thailand have been isolated. However, these compounds have exhibited moderate antimalarial activity with IC 50 values between 4.1 and 5.4 ug / mL [Kanokmedhakul, S .; Kanokmedhakul, K., Yodbuddee, D .; Phonkerd, NJ Nat. Prod. 66, 616 (2003)]. Less common but also with moderate antimalarial properties are the aporphine-benzylisoquinoline phenolic alkaloids isolated from an indigenous perennial herb from China [Lin, L.-Z .; Hu, S.-F .; Chu, M .; Chan, T.-M .; Chai, H .; Angerhofer, CK; Pezzuto, JM; Cordell, GA Phytochemistry 50, 829 (1999)]. Recently, the synthesis and pharmacological use of morphine-derived alkaloids has been patented, and that present important antimalarial activities that can give clues about protozoan resistance against drugs of natural origin [Frappier, F .; Frappier, M.-P .; Frappier, J .; Mazier, D .; Carraz, M .; Franetich, J.-F .; Jossang, A .; Joyeau, R .; Rasoanaivo, P. USpatent 0038390 (2008)].
Dado que los alcaloides isoquinolínicos presentes en la naturaleza como las aporfinas han sido, en muy pocos casos, estudiadas farmacológicamente contra la malaria, sus análogos oxidados denominados "oxoaporfinas " , isómeros referentes a los presentados en esta invención, han sido escasamente estudiados debido a su menor presencia en las plantas de recolección. No obstante, las plantas provenientes de la familia Annonaceae han demostrado contener constituyentes químicos importantes, incluyendo alcaloides, terpenoides entre otros, con interesantes actividades medicinales. Así, plantas colectadas en Tailandia de la Pseuduvaria setosa (King) J. Sinclair (Annonaceae) con una importante presencia de oxoaporfinas tales como oxoestefanina y liriodenina, mostraron tener actividad antimalárica, teniendo esta última un IC50 de 2.8 ug/mL comparado con la dihidroartemisina usada como control positivo [Wirasathien, L.; Boonarkart, Ch.; Pengsuparp, Th.; Suttisri, R. Pharmaceutical Biology 44(4), 274 (2006)]. Since isoquinolinic alkaloids present in nature such as aporphins have been, in very few cases, pharmacologically studied against malaria, their oxidized analogues called "oxoaporphins", isomers referring to those presented in this invention, have been poorly studied due to their Less presence in the collection plants. However, plants from the Annonaceae family have been shown to contain important chemical constituents, including alkaloids, terpenoids, among others, with interesting medicinal activities. Thus, plants collected in Thailand from Pseuduvaria setosa (King) J. Sinclair (Annonaceae) with an important presence of oxoaporphins such as oxoestefanina and liriodenina, showed to have antimalarial activity, the latter having an IC 50 of 2.8 ug / mL compared to the dihydroartemisin used as a positive control [Wirasathien, L .; Boonarkart, Ch .; Pengsuparp, Th .; Suttisri, R. Pharmaceutical Biology 44 (4), 274 (2006)].
Figure imgf000008_0001
Figure imgf000008_0001
(-)-asimilobina; Rj = Me, R2 = R (-) - assylobin; R j = Me, R 2 = R
R = R' =R" = R" = H, OMe  R = R '= R "= R" = H, OMe
(-)-anonaína; Rj = R2 = -CH2-, R (-) - anonaine; R j = R 2 = -CH 2 -, R
Bis-deshidroaporfina  Bis-dehydroaporphine
cassyticina; Rj = R2 = -CH2-, R3 cassyticin; R j = R 2 = -CH 2 -, R 3
R5 = OMe R 5 = OMe
Derivados de morfina Morphine derivatives
Figure imgf000009_0001
Figure imgf000009_0001
Derivados de morfina  Morphine derivatives
Figure imgf000009_0002
Figure imgf000009_0002
oxoestefanina; R = OMe  oxoestefanina; R = OMe
liriodenina; R— H Aunque existen en la naturaleza una gran variedad de alcaloides aporfínicos, los más abundantes y mejor estudiados hasta la fecha son las aporfmas (ΊΗ- dibenzo[<ie,g]quinolinas) [Para mayor información sobre aporfmas, ver: Shamma, M.; Slusarchyk, W. A. Chem. Rev. 64, 59 (1964); Manske, R. H. F., en "The Alkaloids", Vol. 4, p. 119. Academic Press, New York (1964); Shamma, M. en "The Alkaloids", Vol. 9, p. 1. Academic Press, New York (1954)] y sus análogos oxidados, las oxoaporfmas (7H- dibenzo[<¾g]quinolin-7-ona) [Para ejemplos de oxoaporfmas ver; Ribas, I.; Sueiras, J., Castedo, L. Tetrahedron Lett. 3093 (1971); Phan, B. H.; Seguin, E.; Tillequin, F., Koch, M. Phytochemistry 35, 1363 (1994)]. Sin embargo, existe un pequeño grupo de alcaloides isoquinolínicos que ha sido poco investigado y cuya principal fuente natural procede de las enredaderas del Menispermum dauricum DC. (Menispermaceae) recolectados en Kyoto, Japón y posteriormente en China. Así, variados informes del aislamiento de nuevos alcaloides isoquinolínicos de color amarillo han sido publicados y que, según convincentes estudios espectrales y de síntesis, poseen un esqueleto de 7H- dibenzo[<ie,A]quinolin-7-ona sin precedentes en la naturaleza. Debido a su semejanza estructural con las oxoaporfmas, 7H-dibenzo[<¾g]quinolin-7-ona, dichos compuestos fueron denominados "oxoisoaporfmas". Estos novedosos heterociclos nitrogenados que están presentes en los rizomas de estas plantas, ampliamente usados en la medicina popular china son: menisporfina (1), dauriporfina (2), bianfugecina (3), bianfugedina (4), dauriporfinolina (5), 2,3-dihidro-menisporfina (6) y la 6-O-desmetilmenisporfma (7) [véase Kunitomo, J.; Satoh, M. Chem. Pharm. Bull. 30, 2659 (1982); Takani, M.; Takasu, Y.; Takahashi, K. Chem. Pharm. Bull. 31, 3091 (1983); Kunitomo, J.; Satoh, M.; Shingu, T. Tetrahedron 39, 3261 (1983); Hu, S.-M.; Xu, S.-X.; Yao, X.-S.; Cui, C.-B.; Tezuka, T.; Kikuchi, K. Chem. Pharm. Bull. 41, 1866 (1993); Kunitomo, J., Kaede, S.; Satoh, M. Chem. Pharm. Bull. 33, 2778 (1985); Sugimoto, Y.; Babiker, H.A.A.; Inanaga, S.; Kato, M.; Isogai, A. Phytochemistry 52, 1431 (1999); Kunitomo, J.-L; Miyata, Y. Heterocycles 24, 437 (1986)]. liriodenine; R— H Although there is a wide variety of aporphic alkaloids in nature, the most abundant and best studied to date are aporfmas (ΊΗ- dibenzo [<ie, g] quinolines) [For more information on aporfmas, see: Shamma, M .; Slusarchyk, WA Chem. Rev. 64, 59 (1964); Manske, RHF, in "The Alkaloids", Vol. 4, p. 119. Academic Press, New York (1964); Shamma, M. in "The Alkaloids", Vol. 9, p. 1. Academic Press, New York (1954)] and its oxidized analogs, oxoaporphs (7H- dibenzo [<¾g] quinolin-7-one) [For examples of oxoaporphms see; Ribas, I .; Sueiras, J., Castedo, L. Tetrahedron Lett. 3093 (1971); Phan, BH; Seguin, E .; Tillequin, F., Koch, M. Phytochemistry 35, 1363 (1994)]. However, there is a small group of isoquinoline alkaloids that has been little investigated and whose main natural source comes from the vines of Menispermum dauricum DC. (Menispermaceae) collected in Kyoto, Japan and later in China. Thus, various reports of the isolation of new yellow isoquinoline alkaloids have been published and that, according to convincing spectral and synthetic studies, they have a 7H-dibenzo [<ie, A] quinolin-7-one skeleton unprecedented in nature . Due to their structural similarity with oxoaporphs, 7H-dibenzo [<¾g] quinolin-7-one, said compounds were called "oxoisoaporphs." These novel nitrogen heterocycles that They are present in the rhizomes of these plants, widely used in Chinese folk medicine are: menisporphine (1), dauriporphine (2), bianfugecin (3), bianfugedin (4), dauriporfinoline (5), 2,3-dihydro-menisporphine (6) and 6-O-desmethylmenisporfma (7) [see Kunitomo, J .; Satoh, M. Chem. Pharm. Bull. 30, 2659 (1982); Takani, M .; Takasu, Y .; Takahashi, K. Chem. Pharm. Bull. 31, 3091 (1983); Kunitomo, J .; Satoh, M .; Shingu, T. Tetrahedron 39, 3261 (1983); Hu, S.-M .; Xu, S.-X .; Yao, X.-S .; Cui, C.-B .; Tezuka, T .; Kikuchi, K. Chem. Pharm. Bull. 41, 1866 (1993); Kunitomo, J., Kaede, S .; Satoh, M. Chem. Pharm. Bull. 33, 2778 (1985); Sugimoto, Y .; Babiker, HAA; Inanaga, S .; Kato, M .; Isogai, A. Phytochemistry 52, 1431 (1999); Kunitomo, J.-L; Miyata, Y. Heterocycles 24, 437 (1986)].
Sin embargo, posteriores trabajos reportaron el aislamiento de la 2,3-dihidro-dauriporfma (8) y de cuatro oxoisoaporfmas unidas en C-6 a grupos amino (9-12), siendo estas finalmente denominadas en su conjunto "daurioxoisoaporfmas" [Yu, B.-W; Meng, L.-H; Chen, J.-Y; Zhou, T.-X; Cheng, K.-F; Ding, J.; Qin, G.-W. J. Nat. Prod. 64 (7), 968 (2001)] a la que se agrega la lakshminina (13), de una nueva fuente natural, la Sciadotenia toxifera [Killmer, L.; Vogt, F. G.; Freyer, A. j.; Menachery, M. D.; Adelman, C. M. J. Nat. Prod. 66, 115, (2003)], perteneciente también a la familia de las Menispermáceas.  However, later work reported the isolation of 2,3-dihydro-dauriporphma (8) and four oxoisoaporphs linked in C-6 to amino groups (9-12), being finally referred to as "daurioxoisoaporphms" [Yu , B.-W; Meng, L.-H; Chen, J.-Y; Zhou, T.-X; Cheng, K.-F; Ding, J .; Qin, G.-W. J. Nat. Prod. 64 (7), 968 (2001)] to which lakshminin (13) is added, from a new natural source, Sciadotenia toxifera [Killmer, L .; Vogt, F. G .; Freyer, A. j .; Menachery, M. D .; Adelman, C. M. J. Nat. Prod. 66, 115, (2003)], also belonging to the Menispermáceas family.
(6); R4 = H (6); R 4 = H
(8); R4 = OMe (8); R 4 = OMe
9 = OMe = OMe
Figure imgf000010_0001
9 = OMe = OMe
Figure imgf000010_0001
Existen variados antecedentes que ilustran ampliamente la obtención de la estructura base de las oxoisoaporfmas. Como se mencionó anteriormente, el aislamiento de algunas oxoisoaporfinas de plantas del Menispermum dauricum DC, estuvo acompañado de la confirmación de sus respectivas estructuras a través de la síntesis de algunos de ellos. De esta forma, el grupo de Kunitomo publicó la síntesis total de la menisporfma a través de una serie de pasos, generando el producto deseado más un isómero con la formación de un esqueleto 4,5,7, 9-tetrametoxi-6H-dibenzo[<ie,A]quinolin-6-ona (14), como se muestra en el siguiente esquema: There is a varied background that illustrates widely the obtaining of the base structure of oxoisoaporphs. As mentioned earlier, the isolation of some Oxoisoaporphins of plants of Menispermum dauricum DC, was accompanied by the confirmation of their respective structures through the synthesis of some of them. In this way, the Kunitomo group published the total synthesis of the menisporphma through a series of steps, generating the desired product plus an isomer with the formation of a skeleton 4,5,7,9-tetramethoxy-6H-dibenzo [ <ie, A] quinolin-6-one (14), as shown in the following scheme:
Figure imgf000011_0001
Figure imgf000011_0001
menisporfina (14) Otra vía de obtención del esqueleto 7H-dibenzo[<¾A]quinolin-7-ona es a través de la reacción de derivados de 1-acetilénicos de antraquinona con hidracina. Así, la reacción de antraquinonilacetilenos (15a-c) con NH2NH2 genera las diazepinas esperadas (16a-c) junto con las oxoisoaporfinas (17a-c) en variable rendimiento [Shvartsberg, M. S.; Ivanchikova, I. D.; Vasilevsky, S. F. Tetrahedron Lett. 35, 2077 (1994)]. Variaciones del mismo proceso han introducido sustituyentes voluminosos en la posición 2 de la 1-etinil- 9,10-antraquinona, los cuales previenen la formación del heterociclo de siete miembros y favorecen la formación de la oxoisoaporfma, como se muestra en el siguiente esquema: Menisporphine (14) Another way of obtaining the 7H-dibenzo [<¾A] quinolin-7-one skeleton is through the reaction of anthraquinone 1-acetylenic derivatives with hydrazine. Thus, the reaction of anthraquinonyl acetylenes (15a-c) with NH 2 NH 2 generates the expected diazepines (16a-c) together with the oxoisoaporphins (17a-c) in variable yield [Shvartsberg, MS; Ivanchikova, ID; Vasilevsky, SF Tetrahedron Lett. 35, 2077 (1994)]. Variations of the same process have introduced bulky substituents at position 2 of 1-ethynyl-9,10-anthraquinone, which prevent the formation of the seven-membered heterocycle and favor the formation of oxoisoaporphma, as shown in the following scheme:
Figure imgf000011_0002
Figure imgf000011_0002
Otros procedimientos para generar derivados de oxoisoaporfinas con estructuras carbonadas rígidas han sido descritos pero con rendimientos pobres, involucrando la formación de espiras fusionados al esqueleto de la oxoisoaporfma por el uso de metales como el manganeso (III) [Bremner, J. B.; Jaturonrusmee, W.; Engelhardt, L. M.; White, A. H. Tetrahedron Lett. 30 (24), 3213 (1989); Bremner, J. B.; Jaturonrusmee, W. Aust. J. Chem. 43, 1461 (1990)]. Other procedures for generating oxoisoaporphine derivatives with rigid carbon structures have been described but with poor yields, involving formation of spirals fused to the skeleton of oxoisoaporphma by the use of metals such as manganese (III) [Bremner, JB; Jaturonrusmee, W .; Engelhardt, LM; White, AH Tetrahedron Lett. 30 (24), 3213 (1989); Bremner, JB; Jaturonrusmee, W. Aust. J. Chem. 43, 1461 (1990)].
Hace más de tres decadas, se informó de un estudio de ciclación entre β-feniletilaminas con ácido ftalaldehídico (AF) [Wheeler, D. D.; Young, D. C; Erley, D. S. J. Org. Chem. 22, 547 (1957)], cuyas ftalidas generadas (18a-c) fueron tratadas sin purificación ulterior con ácido polifosfórico (APF) para dar, en moderados rendimientos, dos 2,3-dihidro- oxoisoaporfmas (19d) y (19e). Sin embargo, cuando la amina fue la 3,4-metilendioxi- fenilisopropilamina o MDA se obtuvo la 2-metil-5,6-metilendioxi-2,3-dihidro- oxoisoaporfina (19f) como único producto final [Walker, G. N.; Kempton, R. J. J. Org. Chem. 36 (10), 1413 (1971)]. No obstante, 18a generó con buen rendimiento y bajo las mismas condiciones de trabajo 5,6,8, 12b-tetrahidro-8-isoindolo[i,2-a]isoquinolona (20), como se muestra en el siguiente esquema:  More than three decades ago, a cyclization study between β-phenylethylamines with phthalaldehyde acid (AF) was reported [Wheeler, D. D .; Young, D. C; Erley, D. S. J. Org. Chem. 22, 547 (1957)], whose phthalates generated (18a-c) were treated without further purification with polyphosphoric acid (APF) to give, in moderate yields, two 2,3-dihydro-oxoisoaporphs (19d) and (19e ). However, when the amine was 3,4-methylenedioxyphenylisopropylamine or MDA, 2-methyl-5,6-methylenedioxy-2,3-dihydroxoisoaporphine (19f) was obtained as the only end product [Walker, G. N .; Kempton, R. J. J. Org. Chem. 36 (10), 1413 (1971)]. However, 18a generated with good performance and under the same working conditions 5,6,8, 12b-tetrahydro-8-isoindolo [i, 2-a] isoquinolone (20), as shown in the following scheme:
Figure imgf000012_0001
Figure imgf000012_0001
10  10
Las oxoisoaporfinas poseen una historia mucho más extendida y que data de cuatro décadas atrás. En este sentido, dichos heterociclos denominados antiguamente 1-azabenzantronas han sido sintetizados por sus variadas aplicaciones como tinturas, entre otras. Oxoisoaporphins have a much more widespread history and dating back four decades. In this sense, said heterocycles formerly called 1-azabenzantrones have been synthesized by their varied applications as tinctures, among others.
Así, muchos de estos compuestos fueron sintetizados como prototipos de fotoconductores o semi-conductores orgánicos [Para mayor información sobre síntesis, propiedades como colorantes y ácido-base, ver: a) Pieri, G.; María Carlini, F.; Paffoni, C; Boffa, G. U. S. Patent W4,031,096 (1977). b) Boffa, G.; Crotti, A.; Pieri, G.; Mangini, A.; Tundo, A. U. S. Patent W 3,678,053 (1972). c) Ribaldone, G.; Borsotti, G.; Gonzati, F. U. S. Patent N° 3,960,866 (1976). d) Ribaldone, G. U. S. Patent W 3,943,136 (1976). e) Iwashima, S.; Ueda, T.; Honda, H.; Tsujika, T.; Ohno, M.; Aoki, J.; Kan, T. J. Chem. Soc. Perkin Trans. 1 2177 (1984). f) King, j.; Ramage, G.R. J. Chem. Soc. 936 (1954). g) Wick, A.K. Helv. Chim. Acta 49 (6), 1748 (1966). h) idem. 49 (6) 1755 (1966). i) Boffa, G.; Chiusoli U. S. Patent W 3,912,739 (1975)]. Thus, many of these compounds were synthesized as prototypes of organic photoconductors or semi-conductors [For more information on synthesis, properties such as dyes and acid-base, see: a) Pieri, G .; María Carlini, F .; Paffoni, C; Boffa, GUS Patent W4,031,096 (1977). b) Boffa, G .; Crotti, A .; Pieri, G .; Mangini, A .; Tundo, AUS Patent W 3,678,053 (1972). c) Ribaldone, G .; Borsotti, G .; Gonzati, FUS Patent No. 3,960,866 (1976). d) Ribaldone, GUS Patent W 3,943,136 (1976). e) Iwashima, S .; Ueda, T .; Honda, H .; Tsujika, T .; Ohno, M .; Aoki, J .; Kan, TJ Chem. Soc. Perkin Trans. 1 2177 (1984). f) King, j .; Ramage, GRJ Chem. Soc. 936 (1954). g) Wick, AK Helv. Chim. Minutes 49 (6), 1748 (1966). h) idem. 49 (6) 1755 (1966). i) Boffa, G .; Chiusoli US Patent W 3,912,739 (1975)].
Algunos ejemplos de tinturas constituidas por unidades de oxoisoaporfinas están descritos en la síntesis de l-aza-2-hidroxibenzantronas (21), 3-bromo-2-metoxiazabenzantrona (22) y estructuras muchos más complejas consistentes en la unión de dos unidades de 1- azabenzantronas por un puente sulfuro (23). Debido a la versatilidad en la formación de derivados sustituidos en la posición 3 (24) del esqueleto isoquinolínico, se han podido sintetizar una gran variedad de tinturas fluorescentes a granel de poliestireno, polimetacrilato de metilo o aceites minerales para diferentes usos en la industria, e hidrocarburos azapolicíclicos con propiedades fotoconductoras, pigmentos fluorescentes, ácido-base y electrónicas [véase Mikhailova, T. A.; Zaitsev, B. E.; Sheban, G. V.; Gorelik, M. V. Chem. Heterocycl. Compd. (Engl. Transí.) 17, 594 (1981); Carlini, F. M.; Paffoni, C; Boffa, G. Dyes Pigm. 3, 59 (1982); Zee-Cheng, R. K.-Y.; Podrebarac, E. G.; Menon, C. S.; Cheng, C. C. j. J. Med. Chem. 22, 501 (1979); Valkanas, G.; Hopff, H. J. Org. Chem., 27, 3680 (1962); Solodar, W. E.; Simón, M. S. J. Org. Chem. 27, 689 (1962); Krapcho, A. P.; Petry, M. E. J. Heterocycl. Chem. 26, 1509 (1989); Krapcho, A. P.; Shaw, K. J. J. Org. Chem. 48, 3341 (1983)].  Some examples of tinctures consisting of oxoisoaporphine units are described in the synthesis of l-aza-2-hydroxybenzantrones (21), 3-bromo-2-methoxyazabenzantrone (22) and many more complex structures consisting of the union of two units of 1 - azabenzantrones by a sulfide bridge (23). Due to the versatility in the formation of substituted derivatives at position 3 (24) of the isoquinoline skeleton, a wide variety of fluorescent dyes made of polystyrene, methyl polymethacrylate or mineral oils for different uses in the industry have been synthesized, and azapolyclic hydrocarbons with photoconductive, fluorescent, acid-base and electronic properties [see Mikhailova, TA; Zaitsev, B. E .; Sheban, G. V .; Gorelik, M. V. Chem. Heterocycl. Compd. (Engl. Transí.) 17, 594 (1981); Carlini, F. M .; Paffoni, C; Boffa, G. Reyes Pigm. 3, 59 (1982); Zee-Cheng, R. K.-Y .; Podrebarac, E. G .; Menon, C. S .; Cheng, C. C. j. J. Med. Chem. 22, 501 (1979); Valkanas, G .; Hopff, H. J. Org. Chem., 27, 3680 (1962); Solodar, W. E .; Simón, M. S. J. Org. Chem. 27, 689 (1962); Krapcho, A. P .; Petry, M. E. J. Heterocycl. Chem. 26, 1509 (1989); Krapcho, A. P .; Shaw, K. J. J. Org. Chem. 48, 3341 (1983)].
Figure imgf000013_0001
En el mismo contexto de buscar nuevos compuestos derivados de la misma estructura química, a finales de la década de los 80, derivados de 7H-dibenzo[<¾A]quinolin-7-ona fueron sintetizados por medio de una nueva ruta que involucraba variadas etapas a partir de N-feniletilftalimidas (25) [Fabre, J.-L; Farge, D.; James, C. U.S. Patent N° 4,128,650 (1978)], generando con ácido sulfúrico fumante 3,4-dihidro-oxoisoaporfina (3,4-dihidro- 1-azabenzantrona) (26), cuya versatilidad y buen rendimiento fue usado como un segundo procedimiento experimental para generar los derivados usados de la presente invención.
Figure imgf000013_0001
In the same context of looking for new compounds derived from the same chemical structure, at the end of the 80's, 7H-dibenzo [<¾A] quinolin-7-one derivatives were synthesized by means of a new route that involved various stages from N-phenylethylphthalimides (25) [Fabre, J.-L; Farge, D .; James, CUS Patent No. 4,128,650 (1978)], generating with smoking sulfuric acid 3,4-dihydro-oxoisoaporphine (3,4-dihydro-1-azabenzantrone) (26), whose versatility and good performance was used as a second procedure experimental to generate the derivatives used of the present invention.
Figure imgf000014_0001
Figure imgf000014_0001
(26)  (26)
A partir de estos antecedentes, se ha estudiado la síntesis y reactividad de estos heterociclos a través de la utilización de análogos de dihidro- y oxoisoaporfmas [Sobarzo- Sánchez, E., De la Fuente, J., Castedo, L. Magn. Reson. Chem. 43, 1080 (2005)] por medio de agentes oxidantes y la utilización de metales e hidrogenación catalítica, generando inesperadamente algunos análogos interesantes para la presente invención con la reducción parcial o total de los anillos aromáticos, pérdida de sustituyentes y una concomitante enolización del sistema quinolínico [Sobarzo-Sánchez, E, Cassels, B. K.; Castedo, L. Synlett. 11, 1647 (2003)]. Además, se ha podido comprobar la gran reactividad que tienen estos compuestos bajo un comportamiento electroquímico que nos entrega una valiosa información de la capacidad como posibles antioxidantes y anticancerígenos respecto a ciertas estructuras análogas como las imino-quinonas [véase Sobarzo-Sánchez, E., Olea-Azar, C, Alarcón, J., Opazo, L., Cassels, B. K. J. Chil. Chem. Soc, 48(2), 79 (2003); Sobarzo-Sánchez, E.; Castedo, L.; De la Fuente, J. R. Struct. Chem. 17, 483 (2006); Clark, G. R.; Robinson, K.; Denny, W. A.; Lee, Η. Η. Acta Crystallogr., Sect. B, 49, 342 (1993); Molinski, T. S. Chem. Rev. 93, 1825 (1993); Fukuzumi, S.; Itoh, S.; Komori, T.; Suenobu, T.; Ishida, A.; Fujitsuka, M.; Ito, O. J. Am. Chem. Soc. 122, 8435 (2000); Chen, W.; Koenigs, L. L.; Thompson, S. J.; Peter, R. M.; Rettie, A. E.; Trager, W. F.; Nelson, S. D. Chem. Res. Toxicol. 11, 295 (1998)].  From this background, the synthesis and reactivity of these heterocycles have been studied through the use of dihydro- and oxoisoaporphic analogs [Sobarzo-Sánchez, E., De la Fuente, J., Castedo, L. Magn. Reson Chem. 43, 1080 (2005)] by means of oxidizing agents and the use of metals and catalytic hydrogenation, unexpectedly generating some interesting analogues for the present invention with the partial or total reduction of aromatic rings, loss of substituents and a concomitant enolization of the quinolinic system [Sobarzo-Sánchez, E, Cassels, BK; Castedo, L. Synlett. 11, 1647 (2003)]. In addition, it has been possible to verify the great reactivity that these compounds have under an electrochemical behavior that gives us valuable information on the capacity as possible antioxidants and anticancer agents with respect to certain analogous structures such as imino-quinones [see Sobarzo-Sánchez, E., Olea-Azar, C, Alarcón, J., Opazo, L., Cassels, BKJ Chil. Chem. Soc, 48 (2), 79 (2003); Sobarzo-Sánchez, E .; Castedo, L .; De la Fuente, J. R. Struct. Chem. 17, 483 (2006); Clark, G. R .; Robinson, K .; Denny, W. A .; Lee, Η. Η Acta Crystallogr., Sect. B, 49, 342 (1993); Molinski, T. S. Chem. Rev. 93, 1825 (1993); Fukuzumi, S .; Itoh, S .; Komori, T .; Suenobu, T .; Ishida, A .; Fujitsuka, M .; Ito, O. J. Am. Chem. Soc. 122, 8435 (2000); Chen, W .; Koenigs, L. L .; Thompson, S. J .; Peter, R. M .; Rettie, A.E .; Trager, W. F .; Nelson, S. D. Chem. Res. Toxicol. 11, 295 (1998)].
La fotorreducción de estos derivados de dihidro- y oxoisoaporfmas han llevado a estudiar la posibilidad de utilizarlos como acumuladores de energía en sistemas supramoleculares debido a su capacidad de transferencia de electrones [véase De la Fuente, J. R., Jullian, C, Saitz, C, Sobarzo-Sánchez, E., Neira, V., González, C, López, R., Pessoa-Mahana,The photoreduction of these dihydro- and oxoisoaporphic derivatives have led to study the possibility of using them as energy accumulators in supramolecular systems due to its electron transfer capacity [see De la Fuente, JR, Jullian, C, Saitz, C, Sobarzo-Sánchez, E., Neira, V., González, C, López, R., Pessoa-Mahana,
H. Photochem. Photobiol. Sci. 3, 194 (2004); De la Fuente, J. R., Neira, V., Saitz, C, Jullian, C, Sobarzo-Sánchez, E. J. Phys. Chem. A 109, 5897 (2005); De la Fuente, J. R., Jullian, C, Saitz, C, Neira, V., Poblete, O., Sobarzo-Sánchez, E. J. Org. Chem. 70, 8712 (2005)], siendo posible la utilización de estos alcaloides como quimiosensores en la detección de especies cargadas a nivel biológico. H. Photochem. Photobiol Sci. 3, 194 (2004); De la Fuente, J. R., Neira, V., Saitz, C, Jullian, C, Sobarzo-Sánchez, E. J. Phys. Chem. A 109, 5897 (2005); De la Fuente, J. R., Jullian, C, Saitz, C, Neira, V., Poblete, O., Sobarzo-Sánchez, E. J. Org. Chem. 70, 8712 (2005)], the use of these alkaloids being possible as chemosensors in the detection of biological-charged species.
Descripción de la invención Description of the invention
Los compuestos de la presente invención mostraron un alto grado de efectividad antimalárica in vitro frente a la especie protozoaria presente un humanos, Plasmodium falciparum. Dichos compuestos, isómeros de las oxoaporfinas que están ampliamente distribuidas en la naturaleza como una oxidación natural de los alcaloides denominados "aporfmas", han sido poco estudiados en torno a sus propiedades farmacológicas y, por lo tanto, la presente invención es el primer ejemplo de alcaloides isoquinolínicos sintéticos de estructura química 7H-dibenzo[<¾A]quinolin-7-ona u "oxoisoaporfina" cuya eficiencia como compuestos antipalúdicos a concentraciones bajas se demuestra en la presente invención. The compounds of the present invention showed a high degree of antimalarial effectiveness in vitro against the protozoan species present in a human, Plasmodium falciparum. Such compounds, isomers of oxoaporphins that are widely distributed in nature as a natural oxidation of alkaloids called "aporphms", have been little studied around their pharmacological properties and, therefore, the present invention is the first example of Synthetic isoquinoline alkaloids of chemical structure 7H-dibenzo [<¾A] quinolin-7-one or "oxoisoaporphine" whose efficiency as antimalarial compounds at low concentrations is demonstrated in the present invention.
La presente invención se dirige al uso de oxoaporfinas como 2,3-dihidro-oxoisoaporfina, oxoisoaporfina, 6-oxoisoaporfina, 2,3,8,9,10,11-hexahidro-oxoisoaporfina, 7-hidroxi- The present invention is directed to the use of oxoaporphins such as 2,3-dihydro-oxoisoaporphine, oxoisoaporphine, 6-oxoisoaporphine, 2,3,8,9,10,11-hexahydro-oxoisoaporphine, 7-hydroxy-
I, 2,3,1 lb-tetrahidro-isoaporfina y 1,2,3, 7a,8,9, 10,11,1 la,l lb-decahidrooxoisoaporfina y sus derivados para preparar una composición farmacéutica útil en el tratamiento antimalárico, en particular contra la especie protozoaria presente en humanos, Plasmodium falciparum. I, 2,3,1 lb-tetrahydro-isoaporphine and 1,2,3, 7a, 8,9, 10,11,1 la, l lb-decahydrooxoisoaporphine and its derivatives to prepare a pharmaceutical composition useful in antimalarial treatment, in particular against the protozoan species present in humans, Plasmodium falciparum.
Las estructuras de oxoaporfinas a las que se dirige preferentemente la presente invención son: (I) 2,3-dihidro-7H-dibenzo[de,A]qumolin-7-ona; (II) 7H-dibenzo[<¾A]-quinolin-7- ona; (III) 6H-dibenzo[<¾A]quinolin-6-ona; (IV) 2,3,8,9,10,1 l-hexahidro-7H- dibenzo[<¾A]quinolin-7-ona; (V) 7-hidroxi- 1,2,3,1 lb-tetrahidro-7H- dibenzo[<¾ h] quino lina y (VI) 1,2,3, 7a,8, 9, 10,11,1 la,l lb-decahidro-7H- dibenzo[<¾A]quinolin-7-ona y sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos, The oxoaporphine structures to which the present invention is preferably directed are: (I) 2,3-dihydro-7H-dibenzo [de, A] qumolin-7-one; (II) 7H-dibenzo [<¾A] -quinolin-7- one; (III) 6H-dibenzo [<¾A] quinolin-6-one; (IV) 2,3,8,9,10,1 l-hexahydro-7H- dibenzo [<¾A] quinolin-7-one; (V) 7-hydroxy-1,2,3,1 lb-tetrahydro-7H-dibenzo [<¾ h] quinine and (VI) 1,2,3, 7a, 8, 9, 10,11,1 la , 1 lb-decahydro-7H- dibenzo [<¾A] quinolin-7-one and its pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides,
Figure imgf000016_0001
Figure imgf000016_0001
Figure imgf000016_0002
donde
Figure imgf000016_0002
where
- R1, R2, R3, R4, R5, R6, R7, R8, y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, nitro, ciano, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y - NRaRb; - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, nitro, cyano, alkyl substituted or not substituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and - NR a R b ;
- R10 se selecciona entre hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -NRaRb, -S(0)mNRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, - NRaC(0)ORb, -NRaC(0)NRaRb; - R 10 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR a C (0) R b , - NR a C (0) OR b , -NR a C (0) NR a R b ;
- R11 se selecciona entre hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -S(0)mNRaRb, -C(0)NRaRb; - R 11 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -S (0) m NR to R b , -C (0) NR to R b ;
Ra y Rb se seleccionan independientemente entre hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, heteroarilo sustituido o no sustituido, o, Ra y Rb conjuntamente forman un anillo de heterociclo sustituido o no sustituido, de 4 a 7 miembros conteniendo 0-2 heteroátomos adicionales independientemente seleccionados entre oxígeno, azufre y N-Rc, donde Rc se selecciona entre hidrógeno, alquilo sustituido o no sustituido, o -C(0)Rb. R a and R b are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, R a and R b together form a substituted or unsubstituted heterocycle ring, 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and NR c , where R c is selected from hydrogen, substituted or unsubstituted alkyl, or -C (0) R b .
En otro aspecto la presente invención también se dirige a una composición farmacéutica que comprende un compuesto de fórmula general I, II, III, IV, V ó VI, como se definieron anteriormente, y un vehículo farmacéuticamente aceptable para su uso en el tratamiento de malaria.  In another aspect the present invention is also directed to a pharmaceutical composition comprising a compound of general formula I, II, III, IV, V or VI, as defined above, and a pharmaceutically acceptable carrier for use in the treatment of malaria. .
En otro aspecto la invención también se dirige al uso de un compuesto de fórmula general In another aspect the invention is also directed to the use of a compound of general formula
1, II, III, IV, V ó VI, como se definieron anteriormente, para la preparación de un medicamento para administrar por vía oral en el tratamiento de malaria. 1, II, III, IV, V or VI, as defined above, for the preparation of a medicament for oral administration in the treatment of malaria.
Descripción detallada de la invención Detailed description of the invention
"Alquilo" se refiere a una cadena hidrocarbonada lineal o ramificada que no contiene ninguna instauración, de 1 a 10 átomos de carbono, preferiblemente de 1 a 4 átomos de carbono, opcionalmente sustituidos con uno a tres sustituyentes seleccionados entre halógeno, ciano, -ORb, -NRaS(0)mRb donde m se selecciona entre 1 y 2, -SRb, -S(O) mRb, -S(0)mNRaRb donde m se selecciona entre 1 y 2, -NRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -NRaC(0)NRaRb, -CF3, -OCF3, cicloalquilo, cicloheteroalquilo, arilo y heteroarilo; donde Ra y Rb son como se definieron previamente. "Cicloalquilo" se refiere a una cadena hidrocarbonada cíclica que no contiene ninguna instauración, de 3 a 10 átomos de carbono, preferiblemente de 5 a 6 átomos de carbono. El cicloalquilo puede ser monocíclico, bicíclico o tricíclico y puede incluir anillos fusionados. Opcionalmente el cicloalquilo puede estar sustituido con uno a tres sustituyentes seleccionados entre halógeno, ciano, -ORb, -NRaS(0)mRb donde m se selecciona entre 1 y 2, -SRb, -S(O) mRb, -S(0)mNRaRb donde m se selecciona entre 1 y 2, - NRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -NRaC(0)NRaRb, - CF3, -OCF3, alquilo, arilo y heteroarilo; donde Ra y Rb son como se definieron previamente. "Alkyl" refers to a linear or branched hydrocarbon chain that does not contain any instants, of 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, optionally substituted with one to three substituents selected from halogen, cyano, -OR b , -NR a S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected from 1 and 2, -NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , -NR to C (0) NR to R b , -CF 3 , -OCF 3 , cycloalkyl, cycloheteroalkyl, aryl and heteroaryl; where R a and R b are as previously defined. "Cycloalkyl" refers to a cyclic hydrocarbon chain that does not contain any setting, from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms. The cycloalkyl may be monocyclic, bicyclic or tricyclic and may include fused rings. Optionally the cycloalkyl may be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, - NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , -NR to C (0) NR to R b , - CF 3 , -OCF 3 , alkyl, aryl and heteroaryl; where R a and R b are as previously defined.
"Alquenilo" se refiere a una cadena hidrocarbonada lineal o ramificada, cíclica o acíclica, que contiene al menos una instauración, de 2 a 10 átomos de carbono, preferiblemente de 2 a 5 átomos de carbono, opcionalmente sustituidos con uno a tres sustituyentes seleccionados entre halógeno, ciano, -ORb, -NRaS(0)mRb donde m se selecciona entre 1 y"Alkenyl" refers to a linear or branched, cyclic or acyclic hydrocarbon chain, containing at least one setting, from 2 to 10 carbon atoms, preferably from 2 to 5 carbon atoms, optionally substituted with one to three substituents selected from halogen, cyano, -OR b , -NR a S (0) m R b where m is selected between 1 and
2, -SRb, -S(O) mRb, -S(0)mNRaRb donde m se selecciona entre 1 y 2, -NRaRb, -C(0)Rb, - C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -NRaC(0)NRaRb, -CF3, -OCF3, alquilo, cicloalquilo, cicloheteroalquilo, arilo y heteroarilo; donde Ra y Rb son como se definieron previamente. 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , - C0 2 R b , -C (0) NR to R b , -NR to C (0) R b , -NR to C (0) OR b , -NR to C (0) NR to R b , -CF 3 , -OCF 3 , alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl; where R a and R b are as previously defined.
"Cicloheteroalquilo" se refiere a un cicloalquilo que contiene al menos un heteroátomo seleccionado entre oxígeno, nitrógeno o azufre, por ejemplo: pirrolidinilo, morfolinilo, piperazinilo y piperidinilo. Opcionalmente el cicloheteroalquilo puede estar sustituido con uno a tres sustituyentes seleccionados entre halógeno, ciano, -ORb, -NRaS(0)mRb donde m se selecciona entre 1 y 2, -SRb, -S(O) mRb, -S(0)mNRaRb donde m se selecciona entre 1 y 2, -NRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, - NRaC(0)NRaRb, -CF3, -OCF3, alquilo, arilo y heteroarilo; donde Ra y Rb son como se definieron previamente . "Cycloheteroalkyl" refers to a cycloalkyl containing at least one heteroatom selected from oxygen, nitrogen or sulfur, for example: pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl. Optionally the cycloheteroalkyl may be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , - NR to C (0) NR to R b , -CF 3 , -OCF 3 , alkyl, aryl and heteroaryl; where R a and R b are as previously defined.
"Arilo" se refiere a un hidrocarburo aromático de 6 a 10 átomos de carbono, por ejemplo: fenilo o naftilo; opcionalmente el arilo puede estar sustituido con uno a tres sustituyentes seleccionados entre halógeno, ciano, -ORb, -NRaS(0)mRb donde m se selecciona entre 1 y 2, -SRb, -S(O) mRb, -S(0)mNRaRb donde m se selecciona entre 1 y 2, -NRaRb, -C(0)Rb, - C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -NRaC(0)NRaRb, -CF3, -OCF3, alquilo, alquenilo, arilo y heteroarilo; donde Ra y Rb son como se definieron previamente. "Heteroarilo" se refiere a un arilo que contiene al menos un heteroátomo seleccionado entre oxígeno, nitrógeno o azufre, por ejemplo: piridilo, pirazolilo, triazolilo, pirimidilo, isoxazolilo, indolilo y tiazolilo; opcionalmente el heteroarilo puede estar sustituido con uno a tres sustituyentes seleccionados entre halógeno, ciano, -ORb, -NRaS(0)mRb donde m se selecciona entre 1 y 2, -SRb, -S(O) mRb, -S(0)mNRaRb donde m se selecciona entre 1 y 2, -NRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, - NRaC(0)NRaRb, -CF3, -OCF3, alquilo, alquenilo, arilo y heteroarilo; donde Ra y Rb son como se definieron previamente. "Aryl" refers to an aromatic hydrocarbon of 6 to 10 carbon atoms, for example: phenyl or naphthyl; optionally the aryl can be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected between 1 and 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , - C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , -NR to C (0) NR to R b , -CF 3 , -OCF 3 , alkyl, alkenyl, aryl and heteroaryl; where R a and R b are as previously defined. "Heteroaryl" refers to an aryl containing at least one heteroatom selected from oxygen, nitrogen or sulfur, for example: pyridyl, pyrazolyl, triazolyl, pyrimidyl, isoxazolyl, indolyl and thiazolyl; optionally the heteroaryl may be substituted with one to three substituents selected from halogen, cyano, -OR b , -NR to S (0) m R b where m is selected from 1 to 2, -SR b , -S (O) m R b , -S (0) m NR a R b where m is selected between 1 and 2, -NR a R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR to C (0) R b , -NR to C (0) OR b , - NR to C (0) NR to R b , -CF 3 , -OCF 3 , alkyl, alkenyl, aryl and heteroaryl; where R a and R b are as previously defined.
De acuerdo a un aspecto particular, la invención se dirige al uso de los compuestos de fórmula I, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos para preparar una composición farmacéutica útil en el tratamiento antimalárico seleccionados preferentemente entre aquellos en donde
Figure imgf000019_0001
According to a particular aspect, the invention is directed to the use of the compounds of formula I, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
Figure imgf000019_0001
- R1 y R2 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, - ORb y -NRaRb; - R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, - OR b and -NR a R b ;
- R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted alkenyl or unsubstituted, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ;
donde Ra y Rb son como se definieron anteriormente. where R a and R b are as defined above.
Más particularmente, los compuestos de fórmula I se seleccionan preferentemente entre aquellos en donde  More particularly, the compounds of formula I are preferably selected from those in which
R1 y R2 son hidrógeno y R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, y -ORb; R 1 and R 2 are hydrogen and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, and -OR b ;
donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. En un modo más preferible donde R3, R6, R7, R8 y R9 son hidrógeno y R4 y R5 se seleccionan independientemente entre hidrógeno, metilo o hidroxilo. where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl. In a more preferable mode where R 3 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 4 and R 5 are independently selected from hydrogen, methyl or hydroxyl.
De acuerdo a un aspecto particular, la invención se dirige al uso de los compuestos de fórmula II, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos para preparar una composición farmacéutica útil en el tratamiento antimalárico seleccionados preferentemente entre aquellos en donde
Figure imgf000020_0001
According to a particular aspect, the invention is directed to the use of the compounds of formula II, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
Figure imgf000020_0001
- R1, R2, R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, nitro, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, arilo sustituido o no sustituido o -ORb; donde Rb es como se definió anteriormente. - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, nitro, substituted or unsubstituted alkyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted aryl or -OR b ; where R b is as defined above.
Más particularmente, los compuestos de fórmula II se seleccionan preferentemente entre aquellos en donde R1 y R2 se seleccionan entre hidrógeno o halógeno, y R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, nitro, y -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. More particularly, the compounds of formula II are preferably selected from those in which R 1 and R 2 are selected from hydrogen or halogen, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each one of them independently selected from hydrogen, halogen, nitro, and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
De acuerdo a un aspecto particular, la invención se dirige al uso de los compuestos de fórmula III, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos para preparar una composición farmacéutica útil en el tratamiento antimalárico seleccionados preferentemente entre aquellos en donde According to a particular aspect, the invention is directed to the use of the compounds of formula III, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
R3 R2 R 3 R 2
(III) R1, R2, R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, y -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. (III) R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
Más preferiblemente R1, R2, R3, R5, R6, R7, R8 y R9 son hidrógeno y R4 es hidroxilo o metoxilo. More preferably R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 4 is hydroxyl or methoxy.
De acuerdo a un aspecto particular, la invención se dirige al uso de los compuestos de fórmula IV, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos para preparar una composición farmacéutica útil en el tratamiento antimalárico seleccionados preferentemente entre aquellos en donde According to a particular aspect, the invention is directed to the use of the compounds of formula IV, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
Figure imgf000021_0001
Figure imgf000021_0001
1 2 6 7 8 9  1 2 6 7 8 9
- R , R , R , R , R y R son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -ORb y -NRaRb; - R, R, R, R, R and R are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR a R b ;
- R3, R4, R5 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; donde Ra y Rb son como se definieron anteriormente. - R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ; where R a and R b are as defined above.
Más particularmente, los compuestos de fórmula IV se seleccionan preferentemente entre aquellos en donde R1, R2, R6, R7, R8 y R9 son hidrógeno y R3, R4, R5 son cada uno de ellos seleccionados de forma independiente entre hidrógeno o -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. Más preferiblemente R1, R2, R3, R5, R6, R7, R8 y R9 son hidrógeno y R4 es hidrógeno, hidroxilo o metoxilo. De acuerdo a un aspecto particular, la invención se dirige al uso de los compuestos de fórmula 5, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos para preparar una composición farmacéutica útil en el tratamiento antimalárico seleccionados preferentemente entre aquellos en donde More particularly, the compounds of formula IV are preferably selected from those in which R 1 , R 2 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 3 , R 4 , R 5 are each selected from independently between hydrogen or -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl. More preferably R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 4 is hydrogen, hydroxyl or methoxy. According to a particular aspect, the invention is directed to the use of the compounds of formula 5, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
Figure imgf000022_0001
Figure imgf000022_0001
1 2 6 7 8 9  1 2 6 7 8 9
- R , R , R , R , R y R son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -ORb y -NRaRb; - R, R, R, R, R and R are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR a R b ;
- R3, R4, R5 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted aryl or unsubstituted, -OR b and -NR a R b ;
- R10 es hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -NRaRb, -S(0)mNRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, - NRaC(0)NRaRb; donde Ra y Rb son como se definieron anteriormente. - R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , - C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , - NR a C (0) NR a R b ; where R a and R b are as defined above.
Más particularmente, los compuestos de fórmula V se seleccionan preferentemente entre aquellos en donde R1, R2, R6, R7, R8, R9 y R10 son hidrógeno, y R3, R4, R5 se seleccionan preferentemente entre hidrógeno y -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. More particularly, the compounds of formula V are preferably selected from those in which R 1 , R 2 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen, and R 3 , R 4 , R 5 are preferably selected between hydrogen and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
Más preferiblemente R1, R2, R3, R6, R7, R8, R9 y R10 son hidrógeno y R4 y R5 son hidrógeno, hidroxilo o metoxilo. More preferably R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen and R 4 and R 5 are hydrogen, hydroxyl or methoxy.
De acuerdo a un aspecto particular, la invención se dirige al uso de los compuestos de fórmula VI, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, estereoisómeros y N-óxidos para preparar una composición farmacéutica útil en el tratamiento antimalárico seleccionados preferentemente entre aquellos en donde
Figure imgf000023_0001
According to a particular aspect, the invention is directed to the use of the compounds of formula VI, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides to prepare a pharmaceutical composition useful in the antimalarial treatment preferably selected from those where
Figure imgf000023_0001
donde where
- R1 y R2 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, -ORb y -NRaRb; - R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR to R b ;
- R , R , R , R , R , R , R son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R, R, R, R, R, R, R are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted cycloheteroalkyl or unsubstituted, substituted or unsubstituted aryl, -OR b and -NR a R b ;
- R10 es hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -NRaRb, -S(0)mNRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, o - NRaC(0)NRaRb; donde Ra y Rb son como se definieron anteriormente. - R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , - C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , or - NR a C (0) NR a R b ; where R a and R b are as defined above.
- R11 es hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -S(0)mNRaRb, o -C(0)NRaRb; - R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -S (0) m NR to R b , or -C (0) NR to R b ;
Más particularmente, los compuestos de fórmula VI se seleccionan preferentemente entre aquellos en donde R1, R2, R5, R6, R7, R8, R9, R10 y R11 son hidrógeno y R3, R4, R5, son cada uno de ellos seleccionados preferentemente entre hidrógeno, o -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. More particularly, the compounds of formula VI are preferably selected from those in which R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen and R 3 , R 4 , R 5 , are each preferably selected from hydrogen, or -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
De acuerdo a un aspecto más particular, los compuestos de fórmula I, II, III, IV, V, y VI se seleccionan preferentemente entre los compuestos de la siguiente lista: According to a more particular aspect, the compounds of formula I, II, III, IV, V, and VI are preferably selected from the compounds in the following list:
1. 2,3-dihidro-7H-dibenzo[de,A]quinolin-7-ona  1. 2,3-dihydro-7H-dibenzo [de, A] quinolin-7-one
2. 5 -metoxi-2,3 -dihidro-7H-dibenzo [de, /z]quinolin-7-ona  2. 5 -methoxy-2,3-dihydro-7H-dibenzo [de, / z] quinolin-7-one
3. 5-metoxi-6-hidroxi-2,3-dihidro-7H-dibenzo[(ie,A]quinolin-7-ona  3. 5-Methoxy-6-hydroxy-2,3-dihydro-7H-dibenzo [(ie, A] quinolin-7-one
4. 7H-dibenzo [de, h] quino lin-7-ona  4. 7H-dibenzo [de, h] quino lin-7-one
5. 5 -metoxi-7H-dibenzo [de, h] quino lin-7-ona 6. 5 -metoxi-6-hidroxi-7H-dibenzo [de, /z]quinolin-7-ona 5. 5 -methoxy-7H-dibenzo [de, h] quino lin-7-one 6. 5 -methoxy-6-hydroxy-7H-dibenzo [de, / z] quinolin-7-one
7. 5 -hidroxi-7H-dibenzo [de, /z]quinolin-7-ona  7. 5-Hydroxy-7H-dibenzo [de, / z] quinolin-7-one
8. 3 -bromo-7H-dibenzo [de, /z]quinolin-7-ona  8. 3-Bromo-7H-dibenzo [de, / z] quinolin-7-one
9. 3-bromo-5-metoxi-7H-dibenzo[ e,A]qumolin-7-ona  9. 3-Bromo-5-methoxy-7H-dibenzo [e, A] qumolin-7-one
10. 4-bromo-5-metoxi-7H-dibenzo[(ie,A]quinolin-7-ona  10. 4-Bromo-5-methoxy-7H-dibenzo [(ie, A] quinolin-7-one
11. 9-nitro-7H-dibenzo[ e,A]qumolin-7-ona  11. 9-nitro-7H-dibenzo [e, A] qumolin-7-one
12. 4-nitro-5 -metoxi-7H-dibenzo [de, /z]quinolin-7-ona  12. 4-nitro-5-methoxy-7H-dibenzo [de, / z] quinolin-7-one
13. 5 -metoxi-6H-dibenzo [de, h] quino lin-6-ona  13. 5 -methoxy-6H-dibenzo [de, h] quino lin-6-one
14. 5-metoxi-2,3,8,9,10,l l-hexahidro-7H-dibenzo[(ie,A]quinolin-7-ona  14. 5-methoxy-2,3,8,9,10, l-hexahydro-7H-dibenzo [(ie, A] quinolin-7-one
15. 2,3,8,9,10,1 l-hexahidro-7H-dibenzo[<ie,A]quinolin-7-ona  15. 2,3,8,9,10,1 l-Hexahydro-7H-dibenzo [<ie, A] quinolin-7-one
16. 5-metoxi-6-hidroxi-l,2,3, 7a,8,9, 10,11,1 la,l lb-decahidro-7H- dibenzo [de, h] quino lin-7-ona  16. 5-methoxy-6-hydroxy-l, 2,3, 7a, 8,9, 10,11,1 la, l lb-decahydro-7H- dibenzo [de, h] quino lin-7-one
17. 5 -metoxi-7-hidroxi- 1,2,3,11 b-tetrahidro-7H-dibenzo [de, /z]quinolina  17. 5 -methoxy-7-hydroxy- 1,2,3,11 b-tetrahydro-7H-dibenzo [de, / z] quinoline
18. 7 -hidroxi- 1,2,3,1 lb-tetrahidro-7H-dibenzo[de,A]quinolina  18. 7-Hydroxy- 1,2,3,1 lb-tetrahydro-7H-dibenzo [de, A] quinoline
SALES FARMACÉUTICAMENTE ACEPTABLES PHARMACEUTICALLY ACCEPTABLE SALTS
Las sales farmacéuticamente aceptables pueden ser obtenidas de procedimientos estándares conocidos, por ejemplo, a través de la mezcla de los compuestos de fórmula general (I), (II), (III), (IV), (V) y (VI) de la presente invención con un ácido disponible, por ejemplo un ácido inorgánico como ácido clorhídrico, o con un ácido orgánico.  Pharmaceutically acceptable salts may be obtained from known standard procedures, for example, by mixing the compounds of general formula (I), (II), (III), (IV), (V) and (VI) of the present invention with an available acid, for example an inorganic acid such as hydrochloric acid, or with an organic acid.
PREPARACIONES FARMACÉUTICAS PHARMACEUTICAL PREPARATIONS
Los compuestos de fórmula general (I), (II), (III), (IV), (V) y (VI) usados para la presente invención pueden estar contenidos en formas farmacéuticas adecuadas para la administración por medio de procesos usuales usando sustancias auxiliares tales como materiales líquidos o sólidos.  The compounds of general formula (I), (II), (III), (IV), (V) and (VI) used for the present invention may be contained in pharmaceutical forms suitable for administration by means of usual processes using substances auxiliaries such as liquid or solid materials.
Las composiciones farmacéuticas de la invención pueden ser administradas por vía oral o parenteral (intramuscular, subcutánea o intravenosa). Cuando las composiciones farmacéuticas son usadas por administración oral, ellas pueden tener apropiadamente formulaciones aceptables farmacéuticamente en la forma de soluciones, polvos, tabletas, comprimidos, cápsulas (incluyendo microcápsulas), etc. Excipientes convenientes para tales formulaciones son los líquidos farmacéuticamente usados o sólidos de relleno y diluyentes, solventes, lubricantes, emulsionantes, condimentos, sustancias colorantes y/o reguladoras del pH. Sustancias auxiliares frecuentemente usadas que pueden ser mencionadas son carbonato o estearato de magnesio, dióxido de titanio, Opadry OYS 96-14, polivinilpirrolidona, croscarmellosa de sodio, lactosa, manitol y otros azúcares o alcoholes derivados de azúcares, talco, lactoproteinas, gelatinas, almidón, celulosa y sus derivados, aceites vegetales y animales tales como aceite de hígados de pescado, girasol, aceites de nuez o sésamo, polietilen glicol y solventes tales como, por ejemplo, agua destilada y alcoholes mono- o polihídricos tales como el glicerol. The pharmaceutical compositions of the invention can be administered orally or parenterally (intramuscularly, subcutaneously or intravenously). When pharmaceutical compositions are used by oral administration, they may appropriately have pharmaceutically acceptable formulations in the form of solutions, powders, tablets, tablets, capsules (including microcapsules), etc. Suitable excipients for such formulations are pharmaceutically used liquids or fillers and diluents, solvents, lubricants, emulsifiers, condiments, coloring substances and / or pH regulators. Frequently used auxiliary substances which may be mentioned are magnesium carbonate or stearate, titanium dioxide, Opadry OYS 96-14, polyvinylpyrrolidone, croscarmellose sodium, lactose, mannitol and other sugars or alcohols derived from sugars, talc, lactoproteins, gelatins, starch, cellulose and their derivatives, vegetable and animal oils such as fish liver oil, sunflower, nut or sesame oils, polyethylene glycol and solvents such as, for example, distilled water and mono- or polyhydric alcohols such as glycerol.
Cuando las composiciones farmacéuticas de la presente invención son composiciones inyectables, formulaciones aceptables y disponibles farmacéuticamente incluyen agua esterilizada, soluciones salinas isotónicas o tampones. Alternativamente, composiciones inyectables de la presente invención pueden ser composiciones de polvo esterilizadas o composiciones de polvo liofilizadas que puedan ser usadas por simple disolución en agua esterilizada. Composiciones farmacéuticamente inyectables de la presente invención pueden contener azúcares (glucosa, manitol y dextrán, etc), alcoholes polihídricos (glicerol, etc.) y sales inorgánicas (sales de sodio, magnesio, etc.).  When the pharmaceutical compositions of the present invention are injectable compositions, pharmaceutically acceptable and acceptable formulations include sterilized water, isotonic saline solutions or buffers. Alternatively, injectable compositions of the present invention may be sterilized powder compositions or lyophilized powder compositions that can be used by simple dissolution in sterilized water. Pharmaceutically injectable compositions of the present invention may contain sugars (glucose, mannitol and dextran, etc.), polyhydric alcohols (glycerol, etc.) and inorganic salts (sodium, magnesium salts, etc.).
Cuando las composiciones farmacéuticas de la presente invención son administradas por inyección intravenosa o infusión, estas pueden contener nutrientes tales como glucosa, vitaminas, aminoácidos y lípidos.  When the pharmaceutical compositions of the present invention are administered by intravenous injection or infusion, they may contain nutrients such as glucose, vitamins, amino acids and lipids.
Los compuestos de fórmula general (I), (II), (III), (IV), (V) y (VI) usados para la presente invención, pueden ser administrados como composiciones farmacéuticas, las cuales son importantes y novedosas representaciones de la invención debido a la presencia de los compuestos antipalúdicos examinados como tal. Tipos de composiciones farmacéuticas que pueden ser usadas e incluidas pero no limitadas son tabletas, tabletas masticables, cápsulas y otros tipos contenidas en esta invención. En la presentación de la invención, un envase o contendedor farmacéutico se describe conteniendo uno o más recipientes rellenos con uno o más de los ingredientes de una composición farmacéutica de la invención. Asociado con tales recipientes pueden ser escritos varios conceptos tales como instrucciones para su uso o una nota en la forma prescrita por una agencia de gobierno que regule su manufactura, uso o venta de los productos farmacéuticos, que además refleje la aprobación por la agencia de manufactura, uso o venta para humanos o administración veterinaria.  The compounds of general formula (I), (II), (III), (IV), (V) and (VI) used for the present invention can be administered as pharmaceutical compositions, which are important and novel representations of the invention due to the presence of the antimalarial compounds examined as such. Types of pharmaceutical compositions that can be used and included but not limited to are tablets, chewable tablets, capsules and other types contained in this invention. In the presentation of the invention, a pharmaceutical container or container is described as containing one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such containers may be written various concepts such as instructions for use or a note in the manner prescribed by a government agency that regulates its manufacture, use or sale of pharmaceutical products, which also reflects the approval by the manufacturing agency , use or sale for humans or veterinary administration.
MÉTODOS FARMACOLÓGICOSPHARMACOLOGICAL METHODS
DETERMINACIÓN DE LA ACTIVIDAD ANTIMALÁRICA Procedimiento de Cultivo DETERMINATION OF ANTIMALAR ACTIVITY Cultivation Procedure
Una suspensión de 6% de eritrocitos del tipo humano (A+) fue preparada en el medio de cultivo que consistió en RMPI 1640 (GIBCO Laboratories, Grand Island, N.Y.) diluido en agua esterilizada con 25 mL de HEPES (ácido N-2-hidroxietilpiperazin-N'-2- etanosulfónico; Calbiochem, La Jolla, Calif.), 32 mM NaHC03 (GIBCO), y 10% de suero bovino fetal hicieron inactivo (40 min a 56°C y después aclarado por centrifugación) el plasma humano del tipo A+. A suspension of 6% of human erythrocytes (A +) was prepared in the culture medium consisting of RMPI 1640 (GIBCO Laboratories, Grand Island, NY) diluted in sterilized water with 25 mL of HEPES (N-2-hydroxyethylpiperazin acid -N'-2- ethanesulfonic; Calbiochem, La Jolla, Calif.), 32 mM NaHC0 3 (GIBCO), and 10% fetal bovine serum inactivated (40 min at 56 ° C and then clarified by centrifugation) the human plasma of type A +.
Los cultivos comunes fueron mantenidos en 5.0 mL de suspensión de eritrocito al 6%> en los frascos de cultivo de 25 mL del tejido (Corning Glass Works, Corning, N.Y.). Los frascos fueron limpiados con un chorro de agua con una mezcla de gases conteniendo 5% 02, 5% C02 y 90% N2 (Air Products Corp., Allentown, Pa.), sellado e incubado a 37°C. Los mejores resultados fueron obtenidos en experimentos individuales cuando la cuota de crecimiento en los cultivos comunes era alta según lo indicado por una duplicación de la parasitemia cada 24 h. Esto fue logrado por los cambios diarios del medio de cultivo y por la dilución con los eritrocitos frescos cada 2 o 3 días para que menos del 2% de las células fueran infectadas en cualquier momento. Para cada experimento, las muestras de las cultivos comunes fueron mayormente diluidas en el medio de cultivo que contenía suficientes eritrocitos humanos (A+) no infectados para rendir un hematocrito final de 1.5% y la parasitemia de 0.25 a 0.5% con objeto de la adición a las placas de microtitulación. Common cultures were maintained in 5.0 mL of 6% erythrocyte suspension> in the 25 mL culture flasks of the tissue (Corning Glass Works, Corning, NY). The bottles were cleaned with a water jet with a mixture of gases containing 5% 0 2 , 5% C0 2 and 90% N 2 (Air Products Corp., Allentown, Pa.), Sealed and incubated at 37 ° C. The best results were obtained in individual experiments when the growth rate in common crops was high as indicated by a doubling of parasitemia every 24 h. This was achieved by daily changes in the culture medium and by dilution with fresh red blood cells every 2 or 3 days so that less than 2% of the cells were infected at any time. For each experiment, the samples from the common cultures were mostly diluted in the culture medium that contained enough uninfected human erythrocytes (A +) to yield a final 1.5% hematocrit and 0.25 to 0.5% parasitemia in order to add microtiter plates.
Medición de la Actividad Antimalárica y Fármacos Usados  Measurement of Antimalarial Activity and Drugs Used
La actividad antiplasmódica de los compuestos era estimada in vitro contra Plasmodium falciparum cloroquina-resistente (FCBl) usando la incorporación de la [3H]-hipoxantina (Amersham-Francia). Eritrocitos fueron infectados con P. falciparum suspendido en medio de cultivo completo en un hematócrito de 1.5%. La suspensión fue distribuida en microplacas de 96 pocilios (200 μΐ por pozo). Los compuestos fueron probados en triplicado en culturas con la 1% de parasitemia sobre todo en la etapa del anillo. Para cada análisis, un cultivo de parásito fue incubado con el compuesto por 48 h en 5% C02 en 95% de higrometría y congelada hasta la incorporación de la [3H]-hipoxantina. Los valores CI50 fueron determinados gráficamente en un por ciento de la inhibición contra curva de la concentración. The antiplasmodic activity of the compounds was estimated in vitro against Plasmodium falciparum chloroquine-resistant (FCBl) using the incorporation of [3H] -hypoxanthine (Amersham-France). Erythrocytes were infected with P. falciparum suspended in complete culture medium in a 1.5% hematocrit. The suspension was distributed in 96-well microplates (200 μΐ per well). The compounds were tested in triplicate in cultures with 1% parasitemia, especially in the ring stage. For each analysis, a parasite culture was incubated with the compound for 48 h in 5% C0 2 in 95% hygrometry and frozen until incorporation of [3H] -hypoxanthin. IC50 values were determined graphically at one percent of the inhibition against concentration curve.
EVALUACIÓN DE COMPUESTOS Los compuestos usados para la presente invención están basados en las sig fórmulas generales: EVALUATION OF COMPOUNDS The compounds used for the present invention are based on the following general formulas:
A 2,3-DIHIDRO-7H-DIBENZO[^A]QUINOLIN-7-ONA (2,3-DIHIDRO- OXOISOAPORFINA), Fórmula general (I):  A 2,3-DIHIDRO-7H-DIBENZO [^ A] QUINOLIN-7-ONA (2,3-DIHIDRO- OXOISOAPORFINE), General Formula (I):
Figure imgf000027_0001
Figure imgf000027_0001
En que:  In which:
a) en que si: - R1, R2, R3, R4, R5, R6, R7, R8 y R9 es hidrógeno, se trata de 2,3- dihidro-7H-dibenzo[de,A]quinolin-7-ona, llamado de aquí en adelante OXO 1; b) en que si: - R1, R2, R3, R5, R6, R7, R8 y R9 es hidrógeno y R4 representa un metoxilo, se trata de 5-metoxi-2,3-dihidro-7H-dibenzo[<ie,A]quinolin-7-ona, llamado de aquí en adelante OXO 2; y a) in that if: - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, it is 2,3-dihydro-7H-dibenzo [de , A] quinolin-7-one, hereinafter referred to as OXO 1; b) in that if: - R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen and R 4 represents a methoxy, it is 5-methoxy-2,3- dihydro-7H-dibenzo [<ie, A] quinolin-7-one, hereinafter referred to as OXO 2; Y
c) en que si:- R1, R2, R3, R6, R7, R8 y R9 es hidrógeno, R4 representa un metoxilo y R5 representa un hidroxilo; se trata de 5-metoxi-6-hidroxi-2,3-dihidro-7H- dibenzo[<ie,A]quinolin-7-ona, llamado de aquí en adelante OXO 3. c) where: - R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 4 represents a methoxy and R 5 represents a hydroxyl; it is 5-methoxy-6-hydroxy-2,3-dihydro-7H-dibenzo [<ie, A] quinolin-7-one, hereinafter referred to as OXO 3.
B 7H-DIBENZO[^A]QUINOLIN-7-ONA (OXOISOAPORFINA), Fórmula general (II):  B 7H-DIBENZO [^ A] QUINOLIN-7-ONA (OXOISOAPORFINA), General Formula (II):
Figure imgf000027_0002
Figure imgf000027_0002
En que:  In which:
a) en que si: - R1, R2, R3, R4, R5, R6, R7, R8 y R9 es hidrógeno, se trata de 7H- dibenzo[<¾A]quinolin-7-ona, llamado de aquí en adelante OXO 4; b) en que si: - R1, R2, R3, R5, R6, R7, R8 y R9 es hidrógeno y R4 representa un metoxilo, se trata de 5-metoxi-7H-dibenzo[<¾A]quinolin-7-ona, llamado de aquí en adelante OXO 5; a) in which if: - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, it is 7H- dibenzo [<¾A] quinolin-7- ona, called hereafter OXO 4; b) where: - R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen and R 4 represents a methoxy, it is 5-methoxy-7H-dibenzo [ <¾A] quinolin-7-one, hereinafter referred to as OXO 5;
c) en que si:- R1, R2, R3, R6, R7, R8 y R9 es hidrógeno, R4 representa un metoxilo y R5 representa un hidroxilo; se trata de 5-metoxi-6-hidroxi-7H- dibenzo[de,A]quinolin-7-ona, llamado de aquí en adelante OXO 6; c) where: - R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 4 represents a methoxy and R 5 represents a hydroxyl; it is 5-methoxy-6-hydroxy-7H-dibenzo [de, A] quinolin-7-one, hereinafter referred to as OXO 6;
d) en que si: - R1, R2, R3, R5, R6, R7, R8 y R9 es hidrógeno, R4 representa un hidroxilo, se trata del compuesto 5-hidroxi-7H-dibenzo[<¾A]quinolin-7-ona, llamado de aquí en adelante OXO 7; d) where: - R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 4 represents a hydroxyl, it is the compound 5-hydroxy-7H-dibenzo [<¾A] quinolin-7-one, hereinafter called OXO 7;
e) en que si: - R1, R3, R4, R5, R6, R7, R8 y R9 es hidrógeno y R2 representa un bromo, se trata de 3-bromo-7H-dibenzo[<¾A]quinolin-7-ona, llamado de aquí en adelante OXO 14; e) in that if: - R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen and R 2 represents a bromine, it is 3-bromo-7H-dibenzo [ <¾A] quinolin-7-one, hereinafter referred to as OXO 14;
f) en que si; - R1, R3, R5, R6, R7, R8 y R9 es hidrógeno, R2 representa un bromo y R4 representa un metoxilo; se trata de 3-bromo-5-metoxi-7H-dibenzo[<¾A]quinolin- 7-ona, llamado de aquí en adelante OXO 15; f) yes; - R 1 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 2 represents a bromine and R 4 represents a methoxy; it is 3-bromo-5-methoxy-7H-dibenzo [<¾A] quinolin-7-one, hereinafter referred to as OXO 15;
g) en que si: - R1, R2, R5, R6, R7, R8 y R9 es hidrógeno, R3 representa un bromo y R4 representa un metoxilo; se trata de 4-bromo-5-metoxi-7H-dibenzo[<¾A]quinolin- 7-ona, llamado de aquí en adelante OXO 16; g) where: - R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 3 represents a bromine and R 4 represents a methoxy; it is 4-bromo-5-methoxy-7H-dibenzo [<¾A] quinolin-7-one, hereinafter referred to as OXO 16;
h) en que si: - R1, R2, R3, R4, R5, R6, R8 y R9 es hidrógeno y R7 es nitro; se trata de 9- nitro-7H-dibenzo[<¾A]quinolin-7-ona, llamado de aquí en adelante OXO 17; y i) en que si: - R1, R2, R5, R6, R7, R8 y R9 es hidrógeno, R3 representa un nitro y R4 representa un metoxilo; se trata de 4-nitro-5-metoxi-7H-dibenzo[ e,A]quinolin-7- ona, llamado de aquí en adelante OXO 18. h) where: - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 is hydrogen and R 7 is nitro; it is 9-nitro-7H-dibenzo [<¾A] quinolin-7-one, hereinafter referred to as OXO 17; and i) where: - R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen, R 3 represents a nitro and R 4 represents a methoxy; it is 4-nitro-5-methoxy-7H-dibenzo [e, A] quinolin-7- one, hereinafter referred to as OXO 18.
C 6H-DIBENZO[^A]QUINOLIN-6-ONA (6-OXOISOAPORFINA), Fórmula general (III):  C 6H-DIBENZO [^ A] QUINOLIN-6-ONA (6-OXOISOAPORFINA), General Formula (III):
Figure imgf000028_0001
Figure imgf000028_0001
ue: a) en que si: - R1, R2, R3, R5, R6, R7, R8 y R9 es hidrógeno y R4 representa un metoxilo, se trata de 5-metoxi-6H-dibenzo[<¾A]quinolin-6-ona, llamado de aquí en adelante OXO 8. EU: a) in which if: - R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen and R 4 represents a methoxy, it is 5-methoxy-6H-dibenzo [ <¾A] quinolin-6-one, hereinafter called OXO 8.
D 2,3,8,9,10,1 l-HEXAHIDRO-7H-DIBENZO[^A]QUINOLIN-7-ONA D 2,3,8,9,10,1 l-HEXAHYDRO-7H-DIBENZO [^ A] QUINOLIN-7-ONA
(2,3,8,9,10,11-HEX -OXOISOAPORFINA), Fórmula general (IV):  (2,3,8,9,10,11-HEX -OXOISOAPORFINE), General formula (IV):
Figure imgf000029_0001
Figure imgf000029_0001
En que:  In which:
a) en que si: - R1, R2, R3, R5, R6, R7, R8 y R9 es hidrógeno y R4 representa un metoxilo; se trata de 5-metoxi-2,3,8,9,10,l l-hexahidro-7H- dibenzo[<¾A]quinolin-7-ona, llamado de aquí en adelante OXO 12; y b) en que si: - R1, R2, R3, R4, R5, R6, R7, R8 y R9 es hidrógeno; se trata de 2,3,8,9,10,1 l-hexahidro-7H-dibenzo[<ie,A]quinolin-7-ona, llamado de aquí en adelante OXO 13; a) where: - R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen and R 4 represents a methoxy; it is 5-methoxy-2,3,8,9,10, l-hexahydro-7H-dibenzo [<¾A] quinolin-7-one, hereinafter referred to as OXO 12; and b) in which if: - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is hydrogen; it is 2,3,8,9,10,1 l-hexahydro-7H-dibenzo [<ie, A] quinolin-7-one, hereinafter referred to as OXO 13;
E l,2,3,7a,8,9,10,l 1,1 la,l lb-DECAHIDRO-7H-DIBENZO[^A]QUINOLIN-7- ONA (l,2,3,7a,8,9,10,ll,lla,llb-DECAHIDRO-OXOISOAPORFINA), E l, 2,3,7a, 8,9,10, l 1,1 la, l lb-DECAHIDRO-7H-DIBENZO [^ A] QUINOLIN-7- ONA (l, 2,3,7a, 8,9 , 10, ll, lla, llb-DECAHIDRO-OXOISOAPORFINA),
Fórmula general (V): General formula (V):
Figure imgf000029_0002
Figure imgf000029_0002
En que:  In which:
a) en que si: - R1, R2, R3, R4, R7, R8, R9 y R10 es hidrógeno, R5 representa un metoxilo y R6 representa un hidroxilo; se trata de 5-metoxi-6-hidroxi- 1,2,3, 7a,8, 9, 10,11,1 la,l lb-decahidro-7H-dibenzo[<ie,A]quinolin-7-ona, llamado de aquí en adelante OXO 10. a) where: - R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 is hydrogen, R 5 represents a methoxy and R 6 represents a hydroxyl; it is 5-methoxy-6-hydroxy-1,2,3, 7a, 8, 9, 10,11,1 la, l lb-decahydro-7H-dibenzo [<ie, A] quinolin-7-one, called hereinafter OXO 10.
7-HIDROXI-l ,2,3, 1 lb-TETRAHIDRO-7H-DIBENZO[^A]QUINOLINA  7-HYDROXI-l, 2,3, 1 lb-TETRAHIDRO-7H-DIBENZO [^ A] QUINOLINA
(7-HIDROXI-l,2,3,llb-TETRAHIDRO-ISOAPORFINA), Fórmula general (VI):  (7-HIDROXI-l, 2,3, llb-TETRAHIDRO-ISOAPORFINA), General formula (VI):
Figure imgf000030_0001
Figure imgf000030_0001
En que:  In which:
a) en que si: - R1, R2, R3, R4, R6, R7, R8, R9, R10 y R11 es hidrógeno y R5 representa un metoxilo; se trata de 5-metoxi-7-hidroxi-l,2,3,l lb-tetrahidro-7H- dibenzo[<¾A]quinolina, llamado de aquí en adelante OXO 11; y a) where: - R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen and R 5 represents a methoxy; it is 5-methoxy-7-hydroxy-l, 2,3, 1 lb-tetrahydro-7H-dibenzo [<¾A] quinoline, hereinafter referred to as OXO 11; Y
b) en que si: - R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 y R11 es hidrógeno; se trata de 7-hidroxi-l,2,3,l lb-tetrahidro-7H-dibenzo[(ie,A]quinolina, llamado de aquí en adelante OXO 9. b) where: - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen; it is 7-hydroxy-l, 2,3, 1 lb-tetrahydro-7H-dibenzo [(ie, A] quinoline, hereinafter referred to as OXO 9.
OBTENCIÓN DE LOS COMPUESTOS ENSAYADOS OBTAINING TESTED COMPOUNDS
Los compuestos denominados OXO 17, OXO 1 a OXO 8, y 0X0 10 a 0X0 14, que fueron ensayados en experimentos de monoamino oxidasa (MAO), y que han sido descritos en esta memoria, han sido sintetizados de acuerdo a las referencias bibliográficas mencionadas anteriormente [Fabre, J.-L; Farge, D.; James, C. U.S. Patent N° 4,128,650 (1978); Sobarzo-Sánchez, E, Cassels, B. K.; Castedo, L. Synlett. 11, 1647 (2003); Sobarzo-Sánchez, E., De la Fuente, J., Castedo, L. Magn. Reson. Chem. 43, 1080 (2005)]. Los derivados de oxoisoaporfinas denominados OXO 9, OXO 10, OXO 15 y OXO 16 fueron obtenidos de acuerdo al procedimiento experimental descrito y expuesto en la sección "Procedimiento experimental de nuevos análogos de oxoisoaporfinas'" . Compounds called OXO 17, OXO 1 to OXO 8, and 0X0 10 to 0X0 14, which were tested in monoamine oxidase (MAO) experiments, and which have been described herein, have been synthesized according to the bibliographic references mentioned previously [Fabre, J.-L; Farge, D .; James, CUS Patent No. 4,128,650 (1978); Sobarzo-Sánchez, E, Cassels, BK; Castedo, L. Synlett. 11, 1647 (2003); Sobarzo-Sánchez, E., De la Fuente, J., Castedo, L. Magn. Reson Chem. 43, 1080 (2005)]. Derivatives oxoisoaporfinas called OXO 9 OXO 10 OXO OXO 15 and 16 were obtained according to the experimental procedure described and set forth in the "Experimental procedure analogous to oxoisoaporfinas new '" section.
RESULTADOS FARMACOLÓGICOS Y FORMULACIÓN DEL COMPUESTO Los compuestos usados para la presente invención tienen una importante actividad antimalárica frente a la especie protozoaria presente en humanos, P. falciparum. Los valores de CI50 de los compuestos de fórmula general (I), (II), (III), (IV), (V) y (VI) detallados anteriormente son mostrados en la siguiente Tabla 1 : PHARMACOLOGICAL RESULTS AND COMPOSITE FORMULATION The compounds used for the present invention have an important antimalarial activity against the protozoan species present in humans, P. falciparum. The IC 50 values of the compounds of general formula (I), (II), (III), (IV), (V) and (VI) detailed above are shown in the following Table 1:
Tabla 1. Actividades antimaláricas medidos en CI50 (μΜ) de derivados de oxoisoaporfmas (incluyendo el control de referencia Cloroquina) sobre el Plasmodium falciparum. Table 1. Antimalarial activities measured in IC 50 (μΜ) of oxoisoaporphic derivatives (including the Chloroquine reference control) on Plasmodium falciparum.
Actividad antipalúdica Actividad antipalúdicaAntimalarial activity Antimalarial activity
COMPUESTO (CI50) COMPUESTO (CI50) COMPOUND (IC 50 ) COMPOSITE (CI 50 )
P. falciparum P. falciparum  P. falciparum P. falciparum
0X0 1 105.03 + 9.34 0X0 11 108.63 + 1.30 0X0 1 105.03 + 9.34 0X0 11 108.63 + 1.30
0X0 2 64.56 + 5.36 OXO 12 13.84 + 1.200X0 2 64.56 + 5.36 OXO 12 13.84 + 1.20
0X0 3 82.35 + 17.90 0X0 13 14.75 + 0.590X0 3 82.35 + 17.90 0X0 13 14.75 + 0.59
0X0 4 41.51 + 2.44 0X0 14 91.89 ± 11.390X0 4 41.51 + 2.44 0X0 14 91.89 ± 11.39
0X0 5 7.27 + 3.24 0X0 15 > 300 0X0 5 7.27 + 3.24 0X0 15> 300
0X0 6 55.90 + 7.65 0X0 16 > 300  0X0 6 55.90 + 7.65 0X0 16> 300
0X0 7 98.41 + 12.35 0X0 17 97.74 + 5.12 0X0 7 98.41 + 12.35 0X0 17 97.74 + 5.12
0X0 8 1.45 + 0.99 0X0 18 59.58 + 8.080X0 8 1.45 + 0.99 0X0 18 59.58 + 8.08
0X0 9 21.19 + 1.50 Cloroquina 0.097 0X0 9 21.19 + 1.50 Chloroquine 0.097
0X0 10 101.91 ± 2.55 * Los valores de CI50 fueron definidos como la concentración de compuesto necesaria para inhibir el crecimiento de una célula o un determinado proceso biológico en un 50% del control positivo. El fármaco llamado cloroquina es usado como control positivo en los ensayos de actividad antimalárica. 0X0 10 101.91 ± 2.55 * IC 50 values were defined as the concentration of compound necessary to inhibit the growth of a cell or a certain biological process in 50% of the positive control. The drug called chloroquine is used as a positive control in antimalarial activity assays.
Los compuestos de esta invención tienen una actividad antimalárica que podría ser aplicada en las primeras fases de infección a nivel hepático. Esto es el paso del parásito al hígado y la posterior infección de las células hepáticas por los esporozoítos del P. falciparum. En otro aspecto, la presente invención proporciona posibles formulaciones farmacéuticas para la preparación de un medicamento, basadas sobre los compuestos presentados aquí, para el tratamiento y prevención de la malaria. The compounds of this invention have an antimalarial activity that could be applied in the early stages of infection at the liver level. This is the passage of the parasite to the liver and the subsequent infection of the liver cells by the sporozoites of P. falciparum. In another aspect, the present invention provides possible pharmaceutical formulations for the preparation of a medicament, based on the compounds presented herein, for the treatment and prevention of malaria.
Las dosis en las cuales el compuesto podría ser administrado varían dentro de un amplio rango, ajustándose a los requerimientos de cada caso en particular. Las diferentes composiciones farmacéuticas de la invención pueden ser administradas por vía oral de acuerdo a las diferentes formulaciones farmacéuticas descritas en las Tablas 2 y 3 :  The doses in which the compound could be administered vary within a wide range, adjusting to the requirements of each particular case. The different pharmaceutical compositions of the invention can be administered orally according to the different pharmaceutical formulations described in Tables 2 and 3:
EJEMPLO A: Tableta  EXAMPLE A: Tablet
Tabla 2. Formulación farmacéutica y peso del ingrediente activo más los excipientes de una tableta. Table 2. Pharmaceutical formulation and weight of the active ingredient plus the excipients of a tablet.
Componente mg/Tableta Mg / tablet component
Ingrediente activo 150  Active ingredient 150
Celulosa microcristalina 100  100 microcrystalline cellulose
Almidón 100  100 starch
Croscarmellosa de sodio 75  Croscarmellose sodium 75
Estearato de magnesio 75  75 mg magnesium stearate
Peso de la Tableta 500 Tablet Weight 500
EJEMPLO B: Cápsula EXAMPLE B: Capsule
Tabla 3. Formulación farmacéutica y peso del ingrediente activo más los excipientes de una cápsula. Table 3. Pharmaceutical formulation and weight of the active ingredient plus the excipients of a capsule.
Componente mg/Cápsula Mg / capsule component
Ingrediente activo 80  Active ingredient 80
Almidón de maíz pre-gelatinizada 100  100 pre-gelatinized corn starch
Microcristales de celulosa 50  Cellulose microcrystals 50
Opadry OYS 96-14 20  Opadry OYS 96-14 20
Peso de la Cápsula 250 Capsule Weight 250
PROCEDIMIENTO EXPERIMENTAL DE NUEVOS ANÁLOGOS DEEXPERIMENTAL PROCEDURE OF NEW ANALOGS OF
OXOISOAPORFINAS Los siguientes ejemplos ilustran la invención de compuestos con actividad antimalárica, y deben de ser considerados para una mejor comprensión de la misma sin que supongan una limitación: OXOISOAPORFINS The following examples illustrate the invention of compounds with antimalarial activity, and should be considered for a better understanding thereof without involving a limitation:
Ejemplo 1  Example 1
7-hidroxi-l ,2,3,l lb-tetrahidro-7H-dibenzo[<ie, A] quino lina (OXO 9)  7-hydroxy-l, 2,3, l lb-tetrahydro-7H-dibenzo [<ie, A] quinine lino (OXO 9)
Figure imgf000033_0001
Figure imgf000033_0001
Sobre una suspensión de OXO 1 (2,37 g, 10,0 mmol) en MeOH (150 mL) en un baño de hielo-agua se adicionaron 12g de NaBH4 de forma cuidadosa para evitar generar demasiada efervescencia dentro de la solución, agitándose continuamente por 2 horas. Posteriormente se diluyó la mezcla de reacción con agua (100 mL) y se ajustó el pH de la solución acuosa con AcOH a 8-9. La mezcla fue finalmente extraída con CH2CI2, los extractos orgánicos secados con Na2S04 y filtrados para ser luego concentrados al vacío generando un residuo color beige de OXO 9 [2,36 g, 100% de rendimiento]. Para evitar la re-oxidación del producto se generó el clorhidrato respectivo. 2,3 g de la carbinolamina (9,7 mmol) se disolvió en 10 mL de i-PrOH en caliente y se adicionó HC1 al 37% (0,8 mL), precipitando la sal respectiva al añadir una pequeña cantidad de éter etílico. El producto se filtró al vacío dando un sólido color amarillo claro del clorhidrato de OXO 9 On a suspension of OXO 1 (2.37 g, 10.0 mmol) in MeOH (150 mL) in an ice-water bath, 12g of NaBH 4 were added carefully to avoid generating too much effervescence inside the solution, stirring continuously for 2 hours. Subsequently, the reaction mixture was diluted with water (100 mL) and the pH of the aqueous solution was adjusted with AcOH to 8-9. The mixture was finally extracted with CH 2 CI 2 , the organic extracts dried with Na 2 S0 4 and filtered to be then concentrated in vacuo to generate a beige residue of OXO 9 [2.36 g, 100% yield]. To prevent re-oxidation of the product, the respective hydrochloride was generated. 2.3 g of the carbinolamine (9.7 mmol) was dissolved in 10 mL of hot i-PrOH and 37% HC1 (0.8 mL) was added, the respective salt precipitating by adding a small amount of ethyl ether . The product was filtered under vacuum giving a light yellow solid of OXO 9 hydrochloride.
[1 ,8 g, 66%o de rendimiento]. [1.8 g, 66% or yield].
RMN-1H δ (DMSO-Í/6, ppm): 3,02 (m, 1H, CHH), 3,39 (m, 2Η, CH2), 3,75 (m, 1Η, CHH), 5,35 (m, 1Η, CHH), 5,40 (s, 1Η, CH), 7, 16 (d, J = 7,5 Hz, 1H, Ar-H), 7,39 (m, 3H, Ar-H), 7,60 (d, J = 7,5 Hz, 1H, Ar-H), 7,67 (d, J = 7,3 Hz, 1H, Ar-H), 7,76 (d, J = 7,2 Hz, 1H, Ar-H), 9,87 (sa, 1H, OH), 1 1 ,41 (sa, 1H, NH). RMN-13C δ (DMSO-¿/6, ppm): 23,98 (CH2), 40,49 (CH2), 51 ,30 (CH), 65,53 (CH), 121 ,21 (CH), 122,55 (CH), 123,01 (CH), 125,67 (C), 126, 17 (CH), 126,70 (CH), 126,87 (CH), 129,96 (C), 130, 18 (C), 139,48 (C), 139,56 (C). IR (KBr,v, cm"1): 3367 (NH, OH), 1450 (OH). P.f. 1 17°C (descomposición). AE: calculado para Ci6Hi6NOCl ' 0,3 H20, C: 68,83; H: 6,49; N: 5,01. encontrado, C: 68,92; H: 5,77; N: 4,95. Ejemplo 2 1 H NMR δ (DMSO-Í / 6 , ppm): 3.02 (m, 1H, CHH), 3.39 (m, 2Η, CH 2 ), 3.75 (m, 1Η, CHH), 5, 35 (m, 1Η, CHH), 5.40 (s, 1Η, CH), 7, 16 (d, J = 7.5 Hz, 1H, Ar-H), 7.39 (m, 3H, Ar- H), 7.60 (d, J = 7.5 Hz, 1H, Ar-H), 7.67 (d, J = 7.3 Hz, 1H, Ar-H), 7.76 (d, J = 7.2 Hz, 1H, Ar-H), 9.87 (sa, 1H, OH), 1, 41 (sa, 1H, NH). 13 C NMR δ (DMSO-¿/ 6 , ppm): 23.98 (CH 2 ), 40.49 (CH 2 ), 51, 30 (CH), 65.53 (CH), 121, 21 (CH ), 122.55 (CH), 123.01 (CH), 125.67 (C), 126, 17 (CH), 126.70 (CH), 126.87 (CH), 129.96 (C) , 130, 18 (C), 139.48 (C), 139.56 (C). IR (KBr, v, cm "1 ): 3367 (NH, OH), 1450 (OH). Mp 1 17 ° C (decomposition). AE: calculated for Ci 6 Hi 6 NOCl ' 0.3 H 2 0, C : 68.83; H: 6.49; N: 5.01. Found, C: 68.92; H: 5.77; N: 4.95. Example 2
4-bromo-5-metoxi-7H-dibenzo[ e,A]quinolin-7-ona (OXO 16) y 3-bromo-5-metoxi- 7H-dibenzo[<¾A]quinolin-7-ona (OXO 15)  4-bromo-5-methoxy-7H-dibenzo [e, A] quinolin-7-one (OXO 16) and 3-bromo-5-methoxy-7H-dibenzo [<¾A] quinolin-7-one (OXO 15)
Figure imgf000034_0001
Figure imgf000034_0001
Sobre una disolución de OXO 5 (960 mg, 3,68 mmol) en CH3CN (40 mL) se añadió gota a gota una solución de Br2 0,5M en CH3CN (51 mL, 25 mmol), siendo agitada constantemente a 80°C por 2 horas. Después de enfriar la mezcla de reacción, se concentró al vacío dando un residuo que fue purificado mediante cromatografía en gel de sílice (hexanos/CH2Cl2 3 :7), obteniéndose OXO 16 como agujas de color amarillo brillante [235 mg, 18% de rendimiento] y OXO 15 como pelillos de color amarillo pardusco [354 mg, 28% de rendimiento] en ciclohexano. On a solution of OXO 5 (960 mg, 3.68 mmol) in CH 3 CN (40 mL) a solution of 0.5 M Br 2 in CH 3 CN (51 mL, 25 mmol) was added dropwise, being stirred constantly at 80 ° C for 2 hours. After cooling the reaction mixture, it was concentrated in vacuo to give a residue that was purified by silica gel chromatography (hexanes / CH 2 Cl 2 3: 7), obtaining OXO 16 as bright yellow needles [235 mg, 18 % yield] and OXO 15 as brownish-yellow hairs [354 mg, 28% yield] in cyclohexane.
RMN-1H (OXO 16) δ (CDC13, ppm): 4,17 (s, 3H, 0-5-CH3), 7,63 (ddd, J = J' = 7,6 Hz, J" = 1 ,2 Hz, 1H, H-10), 7,78 (ddd, J = J' = 7,9 Hz, J" = 1 ,4 Hz, 1H, H-9), 7,94 (d, J = 5,9 Hz, 1H, H-3), 8,23 (s, 1H, H-6), 8,33 (dd, J = 7,8 Hz, J' = 1 ,1 Hz, 1H, H- 11), 8,69 (d, J = 5,9 Hz, 1H, H-2), 8,81 (dd, J = 7,9 Hz, J' = 0,9 Hz, 1H, H-8). RMN- 13C (OXO 17) δ (CDC13, ppm): 57,21 (0-5-CH3), 1 15,0 (C-3), 1 15,27 (C-6), 1 19,21 (C-4), 1 19,38 (C-3b), 125,60 (C-1 1), 127,53 (C-8), 129,69 (C-6a), 130,54 (C-9), 131 ,86 (C-3a), 134,32 (C-10), 136,22 (C-7a), 136,42 (C-l la), 145, 18 (C-2), 148,69 (C-l lb), 157, 15 (C-5), 182,77 (C-7). IR (OXO 16) (KBr,v, cm 1): 1689 (C=0). P.f. (OXO 16) 215-218°C. EMBR (OXO 16) {miz): 340,1 (M+, 33,2), 339,1 (100). AE: calculado para Ci7Hi0BrNO2, C: 60,02; H: 2,96; N: 4,12. encontrado, C: 60,07; H: 2,92; N: 3,96. 1H NMR (OXO 16) δ (CDC1 3 , ppm): 4.17 (s, 3H, 0-5-CH 3 ), 7.63 (ddd, J = J '= 7.6 Hz, J "= 1, 2 Hz, 1H, H-10), 7.78 (ddd, J = J '= 7.9 Hz, J "= 1, 4 Hz, 1H, H-9), 7.94 (d, J = 5.9 Hz, 1H, H-3), 8.23 (s, 1H, H-6), 8.33 (dd, J = 7.8 Hz, J '= 1, 1 Hz, 1H, H - 11), 8.69 (d, J = 5.9 Hz, 1H, H-2), 8.81 (dd, J = 7.9 Hz, J '= 0.9 Hz, 1H, H-8 ). NMR- 1 3 C (OXO 17) δ (CDC1 3 , ppm): 57.21 (0-5-CH 3 ), 1 15.0 (C-3), 1 15.27 (C-6), 1 19.21 (C-4), 1 19.38 (C-3b), 125.60 (C-1 1), 127.53 (C-8), 129.69 (C-6a), 130.54 (C-9), 131, 86 (C-3a), 134.32 (C-10), 136.22 (C-7a), 136.42 (Cl la), 145, 18 (C-2), 148.69 (Cl lb), 157, 15 (C-5), 182.77 (C-7). IR (OXO 16) (KBr, v, cm 1 ): 1689 (C = 0). Mp (OXO 16) 215-218 ° C. LRMS (OXO 16) {miz): 340.1 (M + , 33.2), 339.1 (100). AE: calculated for Ci 7 Hi 0 BrNO 2 , C: 60.02; H: 2.96; N: 4.12. found, C: 60.07; H: 2.92; N: 3.96.
RMN-1H (OXO 15) δ (CDC13, ppm): 3,96 (s, 3H, O-5-CH3), 7,48 (d, J = 2,5 Hz, 1H, H-4), 7,54 (ddd, J = J' = 7,6 Hz, J" = 1 ,2 Hz, 1H, H-10), 7,69 (ddd, J = J' = 7,6 Hz, J" = 1 ,0 Hz, 1H, H-9), 8,07 (d, J = 2,5 Hz, 1H, H-6), 8,22 (dd, J = 7,8 Hz, J' = 1 ,0 Hz, 1H, H-l l), 8,63 (s, 1H, H-2), 8,62 (dd, J = 7,9 Hz, J' = 0,8 Hz, 1H, H-8). RMN-13C (OXO 16) δ (CDC13, ppm): 56, 1 1 (0-5-CH3), 1 10,98 (C-4), 1 18,96 (C-3), 1 19,64 (C- 6), 122,07 (C-3b), 125,39 (C-l l), 127,65 (C-8), 130,47 (C-9), 131 ,10 (C-6a), 131 ,76 (C-3a), 134,30 (C-10), 136,35 (C-7a/C-l la), 146,01 (C-2), 147,27 (C-l lb), 161 ,71 (C- 5), 182,51 (C-7). IR (OXO 15) (KBr,v, cm"1): 1664 (C=0). P.f. (OXO 15) 203- 204°C. EMBR (OXO 15) (m/z): 340.95 (M+, 100). 1H NMR (OXO 15) δ (CDC1 3 , ppm): 3.96 (s, 3H, O-5-CH 3 ), 7.48 (d, J = 2.5 Hz, 1H, H-4) , 7.54 (ddd, J = J '= 7.6 Hz, J "= 1, 2 Hz, 1H, H-10), 7.69 (ddd, J = J' = 7.6 Hz, J" = 1.0 Hz, 1H, H-9), 8.07 (d, J = 2.5 Hz, 1H, H-6), 8.22 (dd, J = 7.8 Hz, J '= 1 , 0 Hz, 1H, Hl l), 8.63 (s, 1H, H-2), 8.62 (dd, J = 7.9 Hz, J '= 0.8 Hz, 1H, H-8) . NMR- 13 C (OXO 16) δ (CDC1 3 , ppm): 56, 1 1 (0-5-CH 3 ), 1 10.98 (C-4), 1 18.96 (C-3), 1 19.64 ( C- 6), 122.07 (C-3b), 125.39 (Cl l), 127.65 (C-8), 130.47 (C-9), 131, 10 (C-6a), 131 , 76 (C-3a), 134.30 (C-10), 136.35 (C-7a / Cl la), 146.01 (C-2), 147.27 (Cl lb), 161, 71 ( C-5), 182.51 (C-7). IR (OXO 15) (KBr, v, cm "1 ): 1664 (C = 0). Mp (OXO 15) 203- 204 ° C. LRMS (OXO 15) (m / z): 340.95 (M + , 100 ).
Ejemplo 3 Example 3
4-nitro-5-metoxi-7H-dibenzo[(ie,A]quinolin-7-ona (OXO 18)  4-nitro-5-methoxy-7H-dibenzo [(ie, A] quinolin-7-one (OXO 18)
Figure imgf000035_0001
Figure imgf000035_0001
OXO 5 OXO 18  OXO 5 OXO 18
Sobre una disolución de OXO 5 (200 mg, 0,76 mmol) en TFA (10 mL) se añadió gota a gota una solución de H2S04/HN03 1 : 1 (10 mL), siendo agitada constantemente a temperatura ambiente (22°C) por 4 horas. Después de diluir la mezcla de reacción con agua (50 mL), se basificó la solución con NH4OH a pH 8-9, extrayéndose con CH2C12. Los extractos orgánicos fueron secados con Na2S04, filtrados y concentrados al vacío obteniéndose OXO 18 como un sólido amorfo de color amarillo [167 mg, 71% de rendimiento]. On a solution of OXO 5 (200 mg, 0.76 mmol) in TFA (10 mL) a solution of H 2 S04 / HN0 3 1: 1 (10 mL) was added dropwise, being constantly stirred at room temperature ( 22 ° C) for 4 hours. After diluting the reaction mixture with water (50 mL), the solution was basified with NH 4 OH at pH 8-9, extracted with CH 2 C1 2 . The organic extracts were dried with Na 2 S0 4 , filtered and concentrated in vacuo to obtain OXO 18 as a yellow amorphous solid [167 mg, 71% yield].
RMN-1H δ (DMSO-de, ppm): 4,24 (s, 3H, O-5-CH3), 7,65 (d, J = 5,9 Hz, 1H, H-3), 7,78 (dd, J = 8,1 Hz, J' = 1 ,2 Hz, 1H, H-10), 7,94 (dd, J = 8,0 Hz, J' = 1 ,3 Hz, 1H, H-1 H NMR δ (DMSO-de, ppm): 4.24 (s, 3H, O-5-CH 3 ), 7.65 (d, J = 5.9 Hz, 1H, H-3), 7, 78 (dd, J = 8.1 Hz, J '= 1, 2 Hz, 1H, H-10), 7.94 (dd, J = 8.0 Hz, J' = 1, 3 Hz, 1H, H -
9) , 8,28 (dd, J = 7,2 Hz, J' = 1 ,0 Hz, 1H, H-l l), 8,44 (s, 1H, H-6), 8,81 (m, 2H, H- 2/H-8). RMN-13C δ (DMSO-¿/6, ppm): 58,70 (0-5-CH3), 1 14,37 (C-6), 1 16,78 (C-3b),9), 8.28 (dd, J = 7.2 Hz, J '= 1.0 Hz, 1H, Hl), 8.44 (s, 1H, H-6), 8.81 (m, 2H , H- 2 / H-8). NMR- 13 C δ (DMSO-¿/ 6 , ppm): 58.70 (0-5-CH 3 ), 1 14.37 (C-6), 1 16.78 (C-3b),
1 17,54 (C-3), 126, 14 (C-l l), 128,22 (C-3a), 129,16 (C-8), 129,42 (C-9), 131 ,57 (C-1 17.54 (C-3), 126, 14 (Cl l), 128.22 (C-3a), 129.16 (C-8), 129.42 (C-9), 131, 57 (C -
10) , 132,17 (C-7a), 132,51 (C-6a), 135,13 (C-4), 135,78 (C-l la), 147,31 (C-2), 150,07 (C-5), 152,60 (C-l lb), 181 ,77 (C-7). IR (KBr,v, cm"1): 1673 (C=0), 1353 y 1530 (- N02). P.f. 231-233°C. EMBR (miz): 306,1 (M+, 100). EMAR calculado para Ci7HioN204 306,2802, encontrado 306,06240. AE: calculado para Ci7Hi0N2O4, C: 66,67: H: 3,29: N: 9, 15. encontrado, C: 66,41 : H: 3,27: N: 9,03. 10), 132.17 (C-7a), 132.51 (C-6a), 135.13 (C-4), 135.78 (Cl la), 147.31 (C-2), 150.07 (C-5), 152.60 (Cl lb), 181, 77 (C-7). IR (KBr, v, cm "1 ): 1673 (C = 0), 1353 and 1530 (- N0 2 ). Mp 231-233 ° C. LRMS (miz): 306.1 (M + , 100). EMAR calculated for Ci 7 HioN 2 0 4 306,2802, found 306,06240 AE: calculated for Ci 7 Hi 0 N 2 O 4 , C: 66.67: H: 3.29: N: 9, 15. found, C: 66.41: H: 3.27: N: 9.03.

Claims

REIVINDICACIONES
1. Uso de oxoaporfinas con la fórmula general I, II, III, IV, V, y VI, sus sales farmacéuticamente aceptables, hidratos, solvatos, tautómeros, esteroisómeros y N- óxidos, para la elaboración de una composición farmacéutica para el tratamiento de malaria,  1. Use of oxoaporphins with the general formula I, II, III, IV, V, and VI, their pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers and N-oxides, for the preparation of a pharmaceutical composition for the treatment of malaria,
Figure imgf000036_0001
Figure imgf000036_0001
independiente entre hidrógeno, halógeno, nitro, ciano, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y - NRaRb; independent between hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and - NR a R b ;
- R10 se selecciona entre hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -NRaRb, -S(0)mNRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, - NRaC(0)ORb, -NRaC(0)NRaRb; - R11 se selecciona entre hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -S(0)mNRaRb, -C(0)NRaRb; - R 10 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , -C (0) NR a R b , -NR a C (0) R b , - NR a C (0) OR b , -NR a C (0) NR a R b ; - R 11 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -S (0) m NR to R b , -C (0) NR to R b ;
Ra y Rb se seleccionan independientemente entre hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, heteroarilo sustituido o no sustituido, o, Ra y Rb conjuntamente forman un anillo de heterociclo sustituido o no sustituido, de 4 a 7 miembros conteniendo 0-2 heteroátomos adicionales independientemente seleccionados entre oxígeno, azufre y N-Rc, donde Rc se selecciona entre hidrógeno, alquilo sustituido o no sustituido, o -C(0)Rb. R a and R b are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or, R a and R b together form a substituted or unsubstituted heterocycle ring of 4 to 7 members containing additional 0-2 heteroatoms independently selected from oxygen, sulfur and NR c , where R c is selected from hydrogen, substituted or unsubstituted alkyl, or -C (0) R b .
2. Uso de compuestos con la fórmula general (I), según la reivindicación 1, donde2. Use of compounds with the general formula (I) according to claim 1, wherein
- R1 y R2 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, - ORb y -NRaRb; - R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, - OR b and -NR a R b ;
- R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted alkenyl or unsubstituted, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ;
donde Ra y Rb son como se definieron en la reivindicación 1. wherein R a and R b are as defined in claim 1.
3. Uso de compuestos con la fórmula general (I), según la reivindicación 2, donde3. Use of compounds with the general formula (I) according to claim 2, wherein
R1 y R2 son hidrógeno y R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, y -ORb; R 1 and R 2 are hydrogen and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, and -OR b ;
donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
4. Uso de compuestos con la fórmula general (II), según la reivindicación 1, donde4. Use of compounds with the general formula (II) according to claim 1, wherein
R1, R2, R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, nitro, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, arilo sustituido o no sustituido o -ORb; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, nitro, substituted or unsubstituted alkyl, substituted cycloalkyl or unsubstituted, substituted or unsubstituted aryl or -OR b ;
donde Rb es como se definió en la reivindicación 1. wherein R b is as defined in claim 1.
5. Uso de compuestos con la fórmula general (II), según la reivindicación 4, donde R1 y R2 se seleccionan entre hidrógeno o halógeno, y R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, nitro, y - ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. 5. Use of compounds with the general formula (II) according to claim 4, wherein R 1 and R 2 are selected from hydrogen or halogen, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen, nitro, and - OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
6. Uso de compuestos con la fórmula general (III), según la reivindicación 1, donde6. Use of compounds with the general formula (III) according to claim 1, wherein
R1, R2, R3, R4, R5, R6, R7, R8 y R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno y -ORb; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, halogen and -OR b ;
donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
7. Uso de compuestos con la fórmula general (IV), según la reivindicación 1, donde7. Use of compounds with the general formula (IV) according to claim 1, wherein
1 2 6 7 8 9 1 2 6 7 8 9
- R , R¿ R , R', R° y R" son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -ORb y -NRaRb; - R, R ¿ R, R ', R ° and R "are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR a R b ;
- R3, R4, R5 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ;
donde Ra y Rb son como se definieron en la reivindicación 1. wherein R a and R b are as defined in claim 1.
8. Uso de compuestos con la fórmula general (IV), según la reivindicación 7, donde8. Use of compounds with the general formula (IV) according to claim 7, wherein
R1, R2, R6, R7, R8 y R9 son hidrógeno y R3, R4, R5 son cada uno de ellos seleccionados de forma independiente entre hidrógeno o -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. R 1 , R 2 , R 6 , R 7 , R 8 and R 9 are hydrogen and R 3 , R 4 , R 5 are each independently selected from hydrogen or -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
9. Uso de compuestos con la fórmula general (V), según la reivindicación 1, donde 9. Use of compounds with the general formula (V) according to claim 1, wherein
1 2 6 7 8 9  1 2 6 7 8 9
- R , R , R , R , R y R son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -ORb y -NRaRb; - R, R, R, R, R and R are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR a R b ;
- R3, R4, R5 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R10 es hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -NRaRb, -S(0)mNRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, - NRaC(0)NRaRb; - R 3 , R 4 , R 5 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloheteroalkyl, substituted aryl or unsubstituted, -OR b and -NR a R b ; - R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , - C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , - NR a C (0) NR a R b ;
donde Ra y Rb son como se definieron en la reivindicación 1. wherein R a and R b are as defined in claim 1.
10. Uso de compuestos con la fórmula general (V), según la reivindicación 9, donde10. Use of compounds with the general formula (V) according to claim 9, wherein
R1, R2, R6, R7, R8, R9 y R10 son hidrógeno, y R3, R4, R5 se seleccionan preferentemente entre hidrógeno y -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. R 1 , R 2 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen, and R 3 , R 4 , R 5 are preferably selected from hydrogen and -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
11. Uso de compuestos con la fórmula general (VI), según la reivindicación 1, donde11. Use of compounds with the general formula (VI) according to claim 1, wherein
- R1 y R2 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, ciano, alquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, -ORb y -NRaRb; - R 1 and R 2 are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR b and -NR to R b ;
- R3, R4, R5, R6, R7, R8, R9 son cada uno de ellos seleccionados de forma independiente entre hidrógeno, halógeno, alquilo sustituido o no sustituido, cicloalquilo sustituido o no sustituido, alquenilo de sustituido o no sustituido, cicloheteroalquilo sustituido o no sustituido, arilo sustituido o no sustituido, -ORb y -NRaRb; - R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted alkenyl or unsubstituted, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, -OR b and -NR a R b ;
- R10 es hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -NRaRb, -S(0)mNRaRb, -C(0)Rb, -C02Rb, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, o -- R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -NR to R b , -S (0) m NR to R b , -C (0) R b , -C0 2 R b , - C (0) NR a R b , -NR a C (0) R b , -NR a C (0) OR b , or -
NRaC(0)NRaRb; donde Ra y Rb son como se definieron anteriormente. NR to C (0) NR to R b ; where R a and R b are as defined above.
- R11 es hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, -S(0)mNRaRb, o -C(0)NRaRb; - R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -S (0) m NR to R b , or -C (0) NR to R b ;
donde Ra y Rb son como se definieron en la reivindicación 1. wherein R a and R b are as defined in claim 1.
12. Uso de compuestos con la fórmula general (VI), según la reivindicación 11, donde R1, R2, R5, R6, R7, R8, R9, R10 y R11 son hidrógeno y R3, R4, R5, son cada uno de ellos seleccionados preferentemente entre hidrógeno o -ORb; donde Rb se selecciona preferentemente entre hidrógeno y alquilo sustituido o no sustituido. 12. Use of compounds with the general formula (VI) according to claim 11, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen and R 3 , R 4 , R 5 , are each preferably selected from hydrogen or -OR b ; where R b is preferably selected from hydrogen and substituted or unsubstituted alkyl.
13. Uso de compuestos de fórmula general I, II, III, IV, V y VI, según la reivindicación 1, seleccionados preferentemente entre: 13. Use of compounds of general formula I, II, III, IV, V and VI according to claim 1, preferably selected from:
- 2,3-dihidro-7H-dibenzo[de,A]quinolin-7-ona  - 2,3-dihydro-7H-dibenzo [de, A] quinolin-7-one
- 5 -metoxi-2,3 -dihidro-7H-dibenzo [de, /z]quinolin-7-ona - 5-metoxi-6-hidroxi-2,3-dihidro-7H-dibenzo[(ie,A]quinolin-7-ona - 5 -methoxy-2,3-dihydro-7H-dibenzo [de, / z] quinolin-7-one - 5-methoxy-6-hydroxy-2,3-dihydro-7H-dibenzo [(ie, A] quinolin-7-one
- 7H-dibenzo[<¾A]quinolin-7-ona  - 7H-dibenzo [<¾A] quinolin-7-one
- 5 -metoxi-7H-dibenzo [de, h] quino lin-7-ona  - 5 -methoxy-7H-dibenzo [de, h] quino lin-7-one
- 5-metoxi-6-hidroxi-7H-dibenzo[ e,A]qumolin-7-ona  - 5-methoxy-6-hydroxy-7H-dibenzo [e, A] qumolin-7-one
- 5-hidroxi-7H-dibenzo[de,A]quinolin-7-ona  - 5-hydroxy-7H-dibenzo [de, A] quinolin-7-one
- 3 -bromo-7H-dibenzo [de, h] quino lin-7-ona  - 3-bromo-7H-dibenzo [de, h] quino lin-7-one
- 3 -bromo-5 -metoxi-7H-dibenzo [de, h] quino lin-7-ona  - 3-bromo-5-methoxy-7H-dibenzo [de, h] quino lin-7-one
- 4-bromo-5-metoxi-7H-dibenzo[(ie,A]quinolin-7-ona  - 4-bromo-5-methoxy-7H-dibenzo [(ie, A] quinolin-7-one
- 9-nitro-7H-dibenzo[ e,A]quinolin-7-ona  - 9-nitro-7H-dibenzo [e, A] quinolin-7-one
- 4-nitro-5-metoxi-7H-dibenzo[ e,A]qumolin-7-ona  - 4-nitro-5-methoxy-7H-dibenzo [e, A] qumolin-7-one
- 5 -metoxi-6H-dibenzo [de, h] quino lin-6-ona  - 5 -methoxy-6H-dibenzo [de, h] quino lin-6-one
- 5-metoxi-2,3,8,9,10,l l-hexahidro-7H-dibenzo[(ie,A]quinolin-7-ona  - 5-methoxy-2,3,8,9,10, l-hexahydro-7H-dibenzo [(ie, A] quinolin-7-one
- 2,3,8,9,10,1 l-hexahidro-7H-dibenzo[de,A]quinolm-7-ona  - 2,3,8,9,10,1 l-hexahydro-7H-dibenzo [de, A] quinolm-7-one
-5-metoxi-6-hidroxi-l,2,3,7a,8,9,10,l 1,1 la,l lb-decahidro-7H- dibenzo[<¾/z] quino lin-7-ona  -5-methoxy-6-hydroxy-l, 2,3,7a, 8,9,10, l 1,1 la, l lb-decahydro-7H- dibenzo [<¾ / z] quino lin-7-one
- 5 -metoxi-7-hidroxi- 1 ,2,3 , 11 b-tetrahidro-7H-dibenzo [de, h] quino lina  - 5 -methoxy-7-hydroxy-1, 2,3, 11 b-tetrahydro-7H-dibenzo [de, h] quino lina
- 7-hidroxi-l,2,3,l lb-tetrahidro-7H-dibenzo[(ie,A]quinolina  - 7-hydroxy-l, 2,3, l lb-tetrahydro-7H-dibenzo [(ie, A] quinoline
14. Una composición farmacéutica que comprende un compuesto de fórmula general I, II, III, IV, V ó VI, como se definieron en las reivindicaciones de 1 a 13, y un vehículo farmacéuticamente aceptable para su uso en el tratamiento de malaria. 14. A pharmaceutical composition comprising a compound of general formula I, II, III, IV, V or VI, as defined in claims 1 to 13, and a pharmaceutically acceptable carrier for use in the treatment of malaria.
15. Uso de un compuesto de fórmula general I, II, III, IV, V ó VI, como se definieron en las reivindicaciones de 1 a 13, para la preparación de un medicamento para administrar por vía oral en el tratamiento de malaria. 15. Use of a compound of general formula I, II, III, IV, V or VI, as defined in claims 1 to 13, for the preparation of a medicament for oral administration in the treatment of malaria.
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CN103130803B (en) * 2013-03-04 2015-04-22 广西师范大学 Oxidized iso-aporphine alkaloid derivative, synthetic method and application
CN116813546A (en) * 2023-06-30 2023-09-29 中国药科大学 Nitric oxide donor type oxidation iso-aporphine alkaloid derivative, preparation method and antidepressant application thereof
CN116813546B (en) * 2023-06-30 2024-04-05 中国药科大学 Nitric oxide donor type oxidation iso-aporphine alkaloid derivative, preparation method and antidepressant application thereof

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