WO2014154921A1 - Method for the synthesis of homologous compounds of azanucleosides - Google Patents

Method for the synthesis of homologous compounds of azanucleosides Download PDF

Info

Publication number
WO2014154921A1
WO2014154921A1 PCT/ES2014/070214 ES2014070214W WO2014154921A1 WO 2014154921 A1 WO2014154921 A1 WO 2014154921A1 ES 2014070214 W ES2014070214 W ES 2014070214W WO 2014154921 A1 WO2014154921 A1 WO 2014154921A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
compounds
treatment
phenyl
intermediate compound
Prior art date
Application number
PCT/ES2014/070214
Other languages
Spanish (es)
French (fr)
Inventor
Carmen NÁJERA DOMINGO
José Miguel SANSANO GIL
Juan MANCEBO ARACIL
Luis Miguel CASTELLÓ MONCAYO
Original Assignee
Universidad De Alicante
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidad De Alicante filed Critical Universidad De Alicante
Publication of WO2014154921A1 publication Critical patent/WO2014154921A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen

Definitions

  • the present invention falls in general within the field of pharmaceutical chemistry and in particular relates to a method of synthesis of homologous azanucleoside compounds.
  • Microorganisms following their evolutionary development, adapt a series of mechanisms that allow them to be resistant to drugs that inhibit their life in a mammalian organism. To a greater extent bacteria (DM Livermore, Kor. J. Intern. Med. 2012, 27, 128) and viruses (and to a lesser extent fungi) are the pathogens most exposed to mutations and therefore those that exhibit resistance mechanisms much more advanced and effective.
  • nucleoside antibiotics that directly attack different control phases during the formation of the bacterial and fungal membranes.
  • the common denominator of all of them is a part that consists of a nucleoside that has the function of directing the drug towards its biological target (Winn, M. et. Al. Nat. Prod. Rep. 2010, 27, 279).
  • proline derivatives or pyrrolidine derivatives are very effective in inhibiting retroviruses such as the cause of hepatitis C or even the one that causes human immunodeficiency (Nájera, C. et. Al . I updated Chim. 2013, 28.).
  • HIV / AIDS is a pandemic that continues to affect the world and has a high risk of coinfection with other diseases such as Hepatitis C, which increases the possibility that patients with both viruses have up to ten times more likely to have liver cirrhosis. It is known that the resistance of a virus to a drug that contains a nucleoside structure takes a long time to occur.
  • the present invention in a first aspect, relates to a process for the synthesis of compounds of general formula (X) (hereafter referred to as the process of the present invention):
  • FCFR is a pyrimidine or pyrimidine base selected from adenine, guanine, thymine, cytosine or uracil.
  • R 1 is selected from Me, Et, Pr 1 , Bu 1 , or Bn
  • R 2 is selected from H, Me, P, Bu ⁇ , Bn or CH 2 OH.
  • Z is selected from C0 2 Me, C0 2 Et, C0 2 Bu ⁇ , S0 2 Ph, N0 2 , CN, COPh or COMe.
  • R 3 is selected from H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ⁇ or S0 2 Ph.
  • R 4 is selected from C0 2 H or CH 2 OH
  • Ar is selected from among phenyl, p-tolyl, p-isopropylphenyl, 4-tert-butyl-3-methyl-phenyl,
  • X is selected from O or H
  • Z 1 -R 3 is selected from / v-methyl, / V-ethyl, / V-benzyl, / V-Phenyl and / V-arylmaleimides.
  • the compound (III) is obtained from the treatment of a nitrogen base in medium basic with formalin or paraformaldehyde to give rise to the nitrogenous base aldehyde derivative.
  • the present invention relates to compounds of general formula (VI) obtained from step a) of the process of the present invention.
  • the present invention relates to compounds of general formula (VIII) obtained from step b) of the process of the present invention.
  • the present invention relates to compounds of general formula (IX) obtained from step c) of the process of the present invention.
  • the present invention relates to compounds of general formula (X) obtained by the process of the present invention.
  • the present invention relates to the use of the compounds of general formula (VI), (VIII), (IX) and (X), for the preparation of medicaments. More particularly for the preparation of a medicament for the treatment of viral diseases.
  • the present invention relates to the use of the compounds of general formula (VI), (VIII), (IX) and (X), for the preparation of a medicament for the treatment of bacterial diseases.
  • the present invention relates to the use of the compounds of general formula (VI), (VIII), (IX) and (X), for the preparation of a medicament for the treatment of cancer.
  • the aldehydes (III) were synthesized.
  • the pyric and pyrimidine bases (I) were treated in basic medium with hot formalin or paraformaldehyde giving rise to the corresponding hydroxymethylated derivatives (II).
  • FCFR pharmacoforo group
  • FCFR Adenine, guanine, thymine, cytosine and uracil.
  • Compounds II would be 8-hydroxymethyladenine, 8-hydroxymethylguanine, 6-hydroxymethylthimine and 5-hydroxymethylcytosine [CAS 1123-95-1].
  • Aldehydes III would be 8-formyladenine [CAS 1369342-17-5], 8-formylguanine [CAS 1130298-86], 6-formylimine [CAS 14161-00-3] and 5-formylcytosine.
  • the synthesis of the products (VI) took place from a 1,3-dipolar multicomponent-domino reaction (or by using the corresponding preformed mine) between an aldehyde (III) incorporating the pharmacophore (FCFR), an amino ester (IV) and the dipoolophil (V).
  • the multi-component reaction took place in the presence of toluene as a solvent, at room temperature, and with a catalytic amount of a silver salt. After mixing the three components the reaction was stopped after one day stirring at 25 ° C and the product was isolated after evaporation of the solvent and subsequent precipitation.
  • FCFR Adenine, guanine, thymine, cytosine and uracil.
  • R 1 Me, Et. Pr ⁇ , Bu ', Bn.
  • R 2 H, Me, Pr ⁇ , Bu ⁇ , Bn, CH 2 OH.
  • Z 1 C0 2 Me, C0 2 Et, C0 2 Bu ⁇ , S0 2 Ph, N0 2 , CN, COPh, COMe.
  • R 3 H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ⁇ , S0 2 Ph.
  • V, Z 1 -R 3 / V-methyl, A / -ethyl, / V-benzyl, / V-Phenyl and / V-arylmaleimides
  • X Acetate, trifluoroacetate, benzoate, carbonate, triflate, perchlorate, hexafluoroantimoniate.
  • the above multi-component reaction can be carried out starting from the corresponding previously prepared mine (VII) starting from aldehyde (III) and iminoester (IV) using the same reaction conditions.
  • FCFR Adenine, guanine, thymine, cytosine and uracil.
  • R 1 Me, Et. Pr ⁇ , Bu ', Bn.
  • R 2 H, Me, Pr ⁇ , Bu ⁇ , Bn, CH 2 OH.
  • Z 1 C0 2 Me, C0 2 Et, C0 2 Bu ⁇ , S0 2 Ph, N0 2 , CN, COPh, COMe.
  • R 3 H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ⁇ , S0 2 Ph.
  • V, Z 1 -R 3 / V-methyl, A / -ethyl, / V-benzyl, / V-Phenyl and / V-arylmaleimides
  • X Acetate, trifluoroacetate, benzoate, carbonate, triflate, perchlorate, and hexafluoroantimoniate.
  • FCFR Adenine, guanine, thymine, cytosine and uracil.
  • R 2 H, Me, Pr ⁇ , Bu ⁇ , Bn, CH 2 OH.
  • R 3 H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ⁇ , S0 2 Ph.
  • R 4 C0 2 H, CH 2 OH
  • V, Z 1 -R 3 / V-methylmaleimide, / V-ethylmaleimide, / V-benzylmaleimide, / V-Phenylmaleimide and / V-arylmaleimides
  • Ar Phenyl, p-tolyl, p-isopropylphenyl, 4-tert-butyl-3-methyl-phenyl, 4 (trifluoromethyl) phenyl.
  • X H, O
  • HSV-1 Herpes Simplex Virus
  • E. coli Escherichia coli (E. coli) (a mean inhibition of 13%) 5.6 ⁇ .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention relates to the method for the synthesis of homologous compounds of azanucleosides, to the compounds produced by said method, and to the use of same for developing drugs for treating viral and bacterial diseases and cancer.

Description

PROCEDIMIENTO DE SINTESIS DE COMPUESTOS HOMÓLOGOS DE AZANUCLEÓSIDOS  SYNTHESIS PROCEDURE OF HOMOLOGICAL COMPOUNDS OF AZANUCLEOSIDES
Campo de la invención Field of the Invention
La presente invención se encuadra en general dentro del campo de la química farmacéutica y en particular se refiere a un procedimiento de síntesis de compuestos homólogos de azanucleósidos.  The present invention falls in general within the field of pharmaceutical chemistry and in particular relates to a method of synthesis of homologous azanucleoside compounds.
Estado de la técnica State of the art
Los microorganismos, siguiendo con su desarrollo evolutivo, adaptan una serie de mecanismos que les permite ser resistentes a los fármacos inhibidores de su vida en el organismo de un mamífero. En mayor medida bacterias (D. M. Livermore, Kor. J. Intern. Med. 2012, 27, 128) y virus (y en menor medida los hongos) son los agentes patógenos más expuestos a mutaciones y por consiguiente aquellos que exhiben mecanismos de resistencia mucho más avanzados y eficaces.  Microorganisms, following their evolutionary development, adapt a series of mechanisms that allow them to be resistant to drugs that inhibit their life in a mammalian organism. To a greater extent bacteria (DM Livermore, Kor. J. Intern. Med. 2012, 27, 128) and viruses (and to a lesser extent fungi) are the pathogens most exposed to mutations and therefore those that exhibit resistance mechanisms much more advanced and effective.
Por esta razón, se deben de poner en el mercado urgentemente nuevos fármacos capaces de combatirlos o inhibirlos ya que son, por ejemplo, la fuente de infección más importante entre los pacientes que han precisado cualquier tipo de intervención quirúrgica.  For this reason, new drugs capable of combating or inhibiting them should be urgently placed on the market since they are, for example, the most important source of infection among patients who have required any type of surgical intervention.
Se ha demostrado recientemente que existe una amplia familia de antibióticos nucleosídicos que atacan directamente a distintas fases de control durante la formación de la membrana bacteriana y la de los hongos. El denominador común de todos ellos es una parte que consiste en un nucleósido que tiene la función de dirigir al fármaco hacia su diana biológica (Winn, M. et. al. Nat. Prod. Rep. 2010, 27, 279).  It has recently been shown that there is a large family of nucleoside antibiotics that directly attack different control phases during the formation of the bacterial and fungal membranes. The common denominator of all of them is a part that consists of a nucleoside that has the function of directing the drug towards its biological target (Winn, M. et. Al. Nat. Prod. Rep. 2010, 27, 279).
Desde el punto de vista antiviral, los derivados de prolina o bien los derivados de pirrolidina son muy eficaces en la inhibición de los retrovirus tales como el causante de la hepatitis C o incluso el que origina la inmunodeficiencia humana (Nájera, C. et. al. Actualité Chim. 2013, 28.). El VIH/ SIDA es una pandemia que sigue afectando al mundo y que tiene un gran riesgo de coinfección con otras enfermedades como la Hepatitis C, que aumenta la posibilidad de que los enfermos con ambos virus tengan hasta diez veces más probabilidades de padecer cirrosis hepática. Se conoce que la resistencia de un virus a un fármaco que contiene una estructura nucleosídica tarda bastante tiempo en producirse. From an antiviral point of view, proline derivatives or pyrrolidine derivatives are very effective in inhibiting retroviruses such as the cause of hepatitis C or even the one that causes human immunodeficiency (Nájera, C. et. Al . I updated Chim. 2013, 28.). HIV / AIDS is a pandemic that continues to affect the world and has a high risk of coinfection with other diseases such as Hepatitis C, which increases the possibility that patients with both viruses have up to ten times more likely to have liver cirrhosis. It is known that the resistance of a virus to a drug that contains a nucleoside structure takes a long time to occur.
En el apartado correspondiente al uso de estos derivados como agentes anticancerígenos hay que recordar que determinados virus (aparte del comentado virus de la hepatitis C) ocasionan cánceres con el paso del tiempo. Este tratamiento, aunque no está tan estudiado, se podría intentar abordar con estos nuevos productos, pero quizás la mayor ventaja de estas estructuras reside en que puede ser intercalada en hebras de ADN y producir inhibiciones en el desarrollo de las células tumorales. In the section corresponding to the use of these derivatives as anticancer agents, it should be remembered that certain viruses (apart from the commented hepatitis C virus) cause cancers over time. This treatment, although not as studied, could be attempted with these new products, but perhaps the greatest advantage of these structures is that it can be intercalated in strands of DNA and produce inhibitions in the development of tumor cells.
Existe pues la necesidad de proporcionar nuevos compuestos con actividad antimicrobiana, antiviral o anticancerígena que proporcione una solución a los problemas anteriormente descritos. There is therefore a need to provide new compounds with antimicrobial, antiviral or anticancer activity that provides a solution to the problems described above.
Descripción de la invención Description of the invention
Así pues, la presente invención, en un primer aspecto se refiere a un procedimiento para la síntesis de compuestos de fórmula general (X) (de ahora en adelante procedimiento de la presente invención):  Thus, the present invention, in a first aspect, relates to a process for the synthesis of compounds of general formula (X) (hereafter referred to as the process of the present invention):
Figure imgf000003_0001
Figure imgf000003_0001
(X)  (X)
caracterizado por que comprende los siguientes pasos: characterized in that it comprises the following steps:
a) obtención de un compuesto intermediario de fórmula general (VI) a) obtaining an intermediate compound of general formula (VI)
Figure imgf000003_0002
Figure imgf000003_0002
(VI) a partir de la reacción de un derivado aldehídico de base nitrogenada (III) con un aminoéster (IV) y un dipolarófilo (V),
Figure imgf000004_0001
(VI) from the reaction of a nitrogenous base aldehyde derivative (III) with an amino ester (IV) and a dipoolophil (V),
Figure imgf000004_0001
(I II) (IV) (V)  (I II) (IV) (V)
b) obtención de un compuesto intermediario de fórmula general (VIII) a partir del compuesto intermediario obtenido en el paso a) y cloruro de aroílo en presencia de piridina b) obtaining an intermediate compound of general formula (VIII) from the intermediate compound obtained in step a) and aroyl chloride in the presence of pyridine
Figure imgf000004_0002
Figure imgf000004_0002
(VIII)  (VIII)
c) obtención de un compuesto intermediario de fórmula general (IX) a partir de la hidrólisis de los ésteres metílicos del compuesto intermediario obtenido en el paso b) a ácido mediante tratamiento con hidróxido de potasio en metanol c) obtaining an intermediate compound of general formula (IX) from the hydrolysis of the methyl esters of the intermediate compound obtained in step b) to acid by treatment with potassium hydroxide in methanol
Figure imgf000004_0003
Figure imgf000004_0003
d) reducción del compuesto obtenido en el paso c) en presencia de borano donde:d) reduction of the compound obtained in step c) in the presence of borane where:
FCFR es una base púrica o pirimidínica seleccionada de entre adenina, guanina, timina, citosina o uracilo. FCFR is a pyrimidine or pyrimidine base selected from adenine, guanine, thymine, cytosine or uracil.
R1 es seleccionado de entre Me, Et, Pr1, Bu1, o Bn R 1 is selected from Me, Et, Pr 1 , Bu 1 , or Bn
R2 es seleccionado de entre H, Me, P , Bu¡, Bn o CH2OH. R 2 is selected from H, Me, P, Bu ¡ , Bn or CH 2 OH.
Z es seleccionado de entre C02Me, C02Et, C02Bu¡, S02Ph, N02, CN, COPh o COMe. R3 es seleccionado de entre H, Me, Ph, Arilo, C02Me, C02Bu¡ o S02Ph. Z is selected from C0 2 Me, C0 2 Et, C0 2 Bu ¡ , S0 2 Ph, N0 2 , CN, COPh or COMe. R 3 is selected from H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ¡ or S0 2 Ph.
R4 es seleccionado de entre C02H o CH2OH R 4 is selected from C0 2 H or CH 2 OH
Ar es seleccionado de entre fenilo, p-tolilo, p-isopropilfenilo, 4-tercbutil-3-metil-fenilo, Ar is selected from among phenyl, p-tolyl, p-isopropylphenyl, 4-tert-butyl-3-methyl-phenyl,
4(trifluorometil)fenilo. 4 (trifluoromethyl) phenyl.
X es seleccionado de entre O o H, X is selected from O or H,
Z1-R3 es seleccionado de entre /v-metil, /V-etil, /V-bencil, /V-Fenil y /V-arilmaleimidas.Z 1 -R 3 is selected from / v-methyl, / V-ethyl, / V-benzyl, / V-Phenyl and / V-arylmaleimides.
En un aspecto más en particular, en el procedimiento de la presente invención, el compuesto (III) se obtiene a partir del tratamiento de una base nitrogenada en medio básico con formalina o paraformaldehído para dar lugar al derivado aldehídico de base nitrogenada. In a more particular aspect, in the process of the present invention, the compound (III) is obtained from the treatment of a nitrogen base in medium basic with formalin or paraformaldehyde to give rise to the nitrogenous base aldehyde derivative.
En otro aspecto, la presente invención se refiere a compuestos de fórmula general (VI) obtenidos a partir de la etapa a) del procedimiento de la presente invención.  In another aspect, the present invention relates to compounds of general formula (VI) obtained from step a) of the process of the present invention.
En otro aspecto, la presente invención se refiere a compuestos de fórmula general (VIII) obtenidos a partir de la etapa b) del procedimiento de la presente invención. In another aspect, the present invention relates to compounds of general formula (VIII) obtained from step b) of the process of the present invention.
En otro aspecto, la presente invención se refiere a compuestos de fórmula general (IX) obtenidos a partir de la etapa c) del procedimiento de la presente invención. In another aspect, the present invention relates to compounds of general formula (IX) obtained from step c) of the process of the present invention.
En otro aspecto, la presente invención se refiere a compuestos de fórmula general (X) obtenidos por el procedimiento de la presente invención.  In another aspect, the present invention relates to compounds of general formula (X) obtained by the process of the present invention.
En otro aspecto, la presente invención se refiere al uso de los compuestos de fórmula general (VI), (VIII), (IX) y (X), para la elaboración de medicamentos. Más en particular para la elaboración de un medicamento para el tratamiento de enfermedades virales. In another aspect, the present invention relates to the use of the compounds of general formula (VI), (VIII), (IX) and (X), for the preparation of medicaments. More particularly for the preparation of a medicament for the treatment of viral diseases.
En otro aspecto, la presente invención se refiere al uso de los compuestos de fórmula general (VI), (VIII), (IX) y (X), para la elaboración de un medicamento para tratamiento de enfermedades bacterianas. In another aspect, the present invention relates to the use of the compounds of general formula (VI), (VIII), (IX) and (X), for the preparation of a medicament for the treatment of bacterial diseases.
En otro aspecto, la presente invención se refiere al uso de los compuestos de fórmula general (VI), (VIII), (IX) y (X), para la elaboración de un medicamento para el tratamiento del cáncer.  In another aspect, the present invention relates to the use of the compounds of general formula (VI), (VIII), (IX) and (X), for the preparation of a medicament for the treatment of cancer.
Descripción detallada de la invención Detailed description of the invention
Por un lado, se sintetizaron los aldehidos (III). En este caso las bases púricas y pirimidínicas (I) se trataron en medio básico con formalina o paraformaldehído en caliente dando lugar a los correspondientes derivados hidroximetilados (II). De ahora en adelante se designará a las bases púricas o pirimidínicas como grupo farmacoforo (FCFR).  On the one hand, the aldehydes (III) were synthesized. In this case, the pyric and pyrimidine bases (I) were treated in basic medium with hot formalin or paraformaldehyde giving rise to the corresponding hydroxymethylated derivatives (II). From now on, the pyrimidine or pyrimidine bases will be designated as a pharmacoforo group (FCFR).
Formalina  Formalin
o (CH2CO)n [Ox] ,CHO or (CH 2 CO) n [Ox], CHO
FCFR FCFR FCFR  FCFR FCFR FCFR
base  base
(I)  (I)
FCFR = Adenina, guanina, timina, citosina y uracilo. Los compuestos II serían la 8- hidroximetiladenina, 8-hidroximetilguanina, 6-hidroximetiltimina y 5-hidroximetilcitosina [CAS 1123-95-1]. Los aldehidos III serían 8-formiladenina [CAS 1369342-17-5], 8- formilguanina [CAS 1130298-86], 6-formiltimina [CAS 14161-00-3] y 5-formilcitosina. FCFR = Adenine, guanine, thymine, cytosine and uracil. Compounds II would be 8-hydroxymethyladenine, 8-hydroxymethylguanine, 6-hydroxymethylthimine and 5-hydroxymethylcytosine [CAS 1123-95-1]. Aldehydes III would be 8-formyladenine [CAS 1369342-17-5], 8-formylguanine [CAS 1130298-86], 6-formylimine [CAS 14161-00-3] and 5-formylcytosine.
En la actualidad existe solo un aldehido, derivado del uracilo [6-formiluracilo monohidrato CAS 36327-91-0], descrito en la bibliografía (Chiacchio, U. et. al. Tetrahedron 2003, 59, 4733). There is currently only one aldehyde, derived from uracil [6-formyluracil monohydrate CAS 36327-91-0], described in the literature (Chiacchio, U. et. Al. Tetrahedron 2003, 59, 4733).
La síntesis de los productos (VI) tuvo lugar a partir de una reacción 1 ,3-dipolar multicomponente-dominó (o bien empleando la ¡mina correspondiente ya preformada) entre un aldehido (III) que incorpora el farmacóforo (FCFR), un aminoéster (IV) y el dipolarófilo (V). La reacción multicomponente tuvo lugar en presencia de tolueno como disolvente, a temperatura ambiente, y con una cantidad catalítica de una sal de plata. Tras mezclar los tres componentes la reacción se detuvo al cabo de un día agitando a 25 °C y se aisló el producto tras evaporación del disolvente y posterior precipitación.  The synthesis of the products (VI) took place from a 1,3-dipolar multicomponent-domino reaction (or by using the corresponding preformed mine) between an aldehyde (III) incorporating the pharmacophore (FCFR), an amino ester (IV) and the dipoolophil (V). The multi-component reaction took place in the presence of toluene as a solvent, at room temperature, and with a catalytic amount of a silver salt. After mixing the three components the reaction was stopped after one day stirring at 25 ° C and the product was isolated after evaporation of the solvent and subsequent precipitation.
Figure imgf000006_0001
Figure imgf000006_0001
FCFR = Adenina, guanina, timina, citosina y uracilo.  FCFR = Adenine, guanine, thymine, cytosine and uracil.
R1 = Me, Et. Pr¡, Bu', Bn. R 1 = Me, Et. Pr ¡ , Bu ', Bn.
R2 = H, Me, Pr¡, Bu¡, Bn, CH2OH. R 2 = H, Me, Pr ¡ , Bu ¡ , Bn, CH 2 OH.
Z1 = C02Me, C02Et, C02Bu¡, S02Ph, N02, CN, COPh, COMe. Z 1 = C0 2 Me, C0 2 Et, C0 2 Bu ¡ , S0 2 Ph, N0 2 , CN, COPh, COMe.
R3 = H, Me, Ph, Arilo, C02Me, C02Bu¡, S02Ph. R 3 = H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ¡ , S0 2 Ph.
(V, Z1-R3) = /V-metil, A/-etil, /V-bencil, /V-Fenil y /V-arilmaleimidas (V, Z 1 -R 3 ) = / V-methyl, A / -ethyl, / V-benzyl, / V-Phenyl and / V-arylmaleimides
X = Acetato, trifluoroacetato, benzoato, carbonato, triflato, perclorato, hexafluoroantimoniato.  X = Acetate, trifluoroacetate, benzoate, carbonate, triflate, perchlorate, hexafluoroantimoniate.
Como bien sabe un experto en la materia, la reacción multicomponente anterior puede realizar partiendo de la correspondiente ¡mina (VII) previamente preparada partir del aldehido (III) y del iminoéster (IV) empleando las mismas condiciones de reacción. As one skilled in the art knows, the above multi-component reaction can be carried out starting from the corresponding previously prepared mine (VII) starting from aldehyde (III) and iminoester (IV) using the same reaction conditions.
R1
Figure imgf000007_0001
R1
Figure imgf000007_0001
FCFR = Adenina, guanina, timina, citosina y uracilo. FCFR = Adenine, guanine, thymine, cytosine and uracil.
R1 = Me, Et. Pr¡, Bu', Bn. R 1 = Me, Et. Pr ¡ , Bu ', Bn.
R2 = H, Me, Pr¡, Bu¡, Bn, CH2OH. R 2 = H, Me, Pr ¡ , Bu ¡ , Bn, CH 2 OH.
Z1 = C02Me, C02Et, C02Bu¡, S02Ph, N02, CN, COPh, COMe. Z 1 = C0 2 Me, C0 2 Et, C0 2 Bu ¡ , S0 2 Ph, N0 2 , CN, COPh, COMe.
R3 = H, Me, Ph, Arilo, C02Me, C02Bu¡, S02Ph. R 3 = H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ¡ , S0 2 Ph.
(V, Z1-R3) = /V-metil, A/-etil, /V-bencil, /V-Fenil y /V-arilmaleimidas (V, Z 1 -R 3 ) = / V-methyl, A / -ethyl, / V-benzyl, / V-Phenyl and / V-arylmaleimides
X = Acetato, trifluoroacetato, benzoato, carbonato, triflato, perclorato, y hexafluoroantimoniato.  X = Acetate, trifluoroacetate, benzoate, carbonate, triflate, perchlorate, and hexafluoroantimoniate.
En otra etapa los cicloaductos (VI) se hicieron reaccionar con cloruros de aroílo en presencia de piridina con la intención de mejorar la solubilidad de los mismos en los sistemas vivos obteniéndose así los productos (VIII). Seguidamente se hidrolizaron los ésteres metílicos a sus correspondientes ácidos (IX) por tratamiento con hidróxido de potasio en metanol a temperatura ambiente (25 °C) pudiéndose realizar una reducción quimioselectiva en uno de los ácidos carboxílicos en presencia de borano generando los derivados (X) según se indica en el esquema. In another stage the cycloadducts (VI) were reacted with aroyl chlorides in the presence of pyridine with the intention of improving their solubility in living systems, thus obtaining the products (VIII). Subsequently, the methyl esters were hydrolyzed to their corresponding acids (IX) by treatment with potassium hydroxide in methanol at room temperature (25 ° C) and a chemoselective reduction could be carried out on one of the carboxylic acids in the presence of borane generating the derivatives (X) as indicated in the scheme.
Figure imgf000008_0001
Figure imgf000008_0001
FCFR = Adenina, guanina, timina, citosina y uracilo. FCFR = Adenine, guanine, thymine, cytosine and uracil.
R2 = H, Me, Pr¡, Bu¡, Bn, CH2OH. R 2 = H, Me, Pr ¡ , Bu ¡ , Bn, CH 2 OH.
Z = C02Me, C02Et, C02Bu¡, S02Ph, N02, CN, COPh, COMe. Z = C0 2 Me, C0 2 Et, C0 2 Bu ¡ , S0 2 Ph, N0 2 , CN, COPh, COMe.
R3 = H, Me, Ph, Arilo, C02Me, C02Bu¡, S02Ph. R 3 = H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ¡ , S0 2 Ph.
R4 = C02H, CH2OH R 4 = C0 2 H, CH 2 OH
(V, Z1-R3) = /V-metilmaleimida, /V-etilmaleimida, /V-bencilmaleimida, /V-Fenilmaleimida y /V-arilmaleimidas (V, Z 1 -R 3 ) = / V-methylmaleimide, / V-ethylmaleimide, / V-benzylmaleimide, / V-Phenylmaleimide and / V-arylmaleimides
Ar = Fenilo, p-tolilo, p-isopropilfenilo, 4-tercbutil-3-metil-fenilo, 4(trifluorometil)fenilo. X = H, O Ar = Phenyl, p-tolyl, p-isopropylphenyl, 4-tert-butyl-3-methyl-phenyl, 4 (trifluoromethyl) phenyl. X = H, O
Ejemplo 1: Preparación del compuesto VI [FCFR = 5-uracililmetilo, R1 = etilo, R2 = bencilo, Z-R3 = CON(Me)CO]. Example 1: Preparation of compound VI [FCFR = 5-uracilylmethyl, R 1 = ethyl, R 2 = benzyl, ZR 3 = CON (Me) CO].
En un balón opaco de 25 mi, se añadió 5-formiluracilo (70 mg, 0.5 mmol), acetato de plata (I) (4.15 mg, 0.025 mmol), éster etílico de L-fenilalanina (96.5 mg, 0.5 mmol) y N- metilmaleimida (55.6 mg, 0.5 mmol) y se diluye con tolueno (3 mL). La suspensión resultante se agitó vigorosamente durante 15 horas a una temperatura de 25 °C. Al cabo de este tiempo el disolvente se evaporó a vacío y el crudo de reacción se diluyó con 25 mi de etanol caliente. Una vez disuelto, se filtró con celita con rapidez, y calentando de nuevo si fuera necesario para evitar que el crudo precipite. Después se eliminó el etanol a vacío, obteniéndose 198.1 mg (93% de rendimiento) del producto puro VI como una mezcla de diasteroisómeros en relación 3.5: 1. In a 25 ml opaque balloon, 5-formyluracil (70 mg, 0.5 mmol), silver acetate (I) (4.15 mg, 0.025 mmol), L-phenylalanine ethyl ester (96.5 mg, 0.5 mmol) and N were added - methylmaleimide (55.6 mg, 0.5 mmol) and diluted with toluene (3 mL). The resulting suspension was vigorously stirred for 15 hours at a temperature of 25 ° C. After this time the solvent was evaporated in vacuo and the reaction crude was diluted with 25 ml of hot ethanol. Once dissolved, it was filtered with Celite quickly, and heating again if necessary to prevent oil from precipitating. The ethanol was then removed in vacuo, obtaining 198.1 mg (93% yield) of pure product VI as a mixture of diastereomers in a 3.5: 1 ratio.
Ejemplo 2: Preparación del compuesto VIII [FCFR = 5-uracililmetilo, R1 = etilo, R2 = bencilo, Z-R3 = CON(Me)CO, Ar = 4-(trifluorometil)fenilo]. Example 2: Preparation of compound VIII [FCFR = 5-uracylmethyl, R 1 = ethyl, R 2 = benzyl, ZR 3 = CON (Me) CO, Ar = 4- (trifluoromethyl) phenyl].
El compuesto VI sintetizado anteriormente (206 mg, 0.5 mmol,) se suspendió en piridina seca (2 ml_) y trietilamina (0.2 mmol, 166 μΙ_), y seguidamente se añadió cloruro de 4-(trifluorometil)benzoilo (0.6 mmol, 92 μΙ_). La mezcla se dejó a reflujo durante una noche y el disolvente se evaporó a presión reducida. El compuesto obtenido se lavó con éter (3x5 mL) hasta obtener un sólido blanco (260 mg, 89%). Compound VI synthesized above (206 mg, 0.5 mmol,) was suspended in dry pyridine (2 ml_) and triethylamine (0.2 mmol, 166 μΙ_), and then 4- (trifluoromethyl) benzoyl chloride (0.6 mmol, 92 μΙ_) was added ). The mixture was allowed to reflux overnight and the solvent was evaporated under reduced pressure. The compound obtained was washed with ether (3x5 mL) until a white solid (260 mg, 89%) was obtained.
Ejemplo 3: Preparación del compuesto IX [FCFR = 5-uracililmetilo, R1 = H, R2 = bencilo, COX-R3 = CON(Me)CO, Ar = 4-(trifluorometil)fenilo]. Example 3: Preparation of compound IX [FCFR = 5-uracilylmethyl, R 1 = H, R 2 = benzyl, COX-R 3 = CON (Me) CO, Ar = 4- (trifluoromethyl) phenyl].
El compuesto VIII (292 mg, 0.5 mmol) se suspendió en una disolución de KOH 1 M en una mezcla 4/1 MeOH/H20 (50 mL) y la mezcla resultante se sometió a un reflujo 16 horas y se evaporó el metanol a presión reducida. La solución resultante se acidificó con HCI acuoso 0,5 M, observándose un precipitado blanco. Dicho sólido se lavó con éter (3x5 mL) hasta obtener un sólido blanco (228 mg, 79%). Compound VIII (292 mg, 0.5 mmol) was suspended in a solution of 1 M KOH in a 4/1 MeOH / H 2 mixture (50 mL) and the resulting mixture was refluxed 16 hours and methanol was evaporated under reduced pressure. The resulting solution was acidified with 0.5 M aqueous HCI, a white precipitate being observed. Said solid was washed with ether (3x5 mL) until a white solid was obtained (228 mg, 79%).
Se realizaron ensayos preliminares para comprobar la actividad de los compuestos de la presente invención, los resultados de los mismos demostraron que dichos compuestos (derivados de 5-formiluracilo, glicinato de metilo y /V-metilmaleimida): Preliminary tests were carried out to verify the activity of the compounds of the present invention, the results thereof demonstrated that said compounds (derivatives of 5-formyluracil, methyl glycinate and / V-methylmaleimide):
- reducción de Herpes Simplex Virus (HSV-1) un 15% en 50 μg/ml, CC50 >200 μg/mL, EC50 36. - reduction of Herpes Simplex Virus (HSV-1) by 15% in 50 μg / ml, CC 50 > 200 μg / mL, EC 50 36.
- Escherichia coli (E. coli) (una media de inhibición del 13%) 5.6 μΜ.  - Escherichia coli (E. coli) (a mean inhibition of 13%) 5.6 μΜ.
- una inhibición del crecimiento de la línea celular de cáncer de mama MCF-7, en 8%, 1 mg/ml.  - an inhibition of the growth of the MCF-7 breast cancer cell line, in 8%, 1 mg / ml.

Claims

REIVINDICACIONES
1. Procedimiento para la síntesis de compuestos de fórmula general (X) 1. Procedure for the synthesis of compounds of general formula (X)
Figure imgf000010_0001
Figure imgf000010_0001
(X)  (X)
caracterizado por que comprende los siguientes pasos: characterized in that it comprises the following steps:
a) obtención de un compuesto intermediario de fórmula general (VI) a) obtaining an intermediate compound of general formula (VI)
Figure imgf000010_0002
Figure imgf000010_0002
(VI) a partir de la reacción de un derivado aldehídico de base nitrogenada (III) con un aminoéster (IV) y un dipolarófilo (V),
Figure imgf000010_0003
(VI) from the reaction of a nitrogenous base aldehyde derivative (III) with an amino ester (IV) and a dipoolophil (V),
Figure imgf000010_0003
(I II) (IV) (V)  (I II) (IV) (V)
b) obtención de un compuesto intermediario de fórmula general (VIII) a partir del compuesto intermediario obtenido en el paso a) y cloruro de aroílo en presencia de piridina b) obtaining an intermediate compound of general formula (VIII) from the intermediate compound obtained in step a) and aroyl chloride in the presence of pyridine
Figure imgf000010_0004
Figure imgf000010_0004
(VIII)  (VIII)
c) obtención de un compuesto intermediario de fórmula general (IX) a partir de la hidrólisis de los ésteres metílicos del compuesto intermediario obtenido en el paso b) a ácido mediante tratamiento con hidróxido de potasio en metanol
Figure imgf000011_0001
c) obtaining an intermediate compound of general formula (IX) from the hydrolysis of the methyl esters of the intermediate compound obtained in step b) to acid by treatment with potassium hydroxide in methanol
Figure imgf000011_0001
(IX) d) reducción del compuesto obtenido en el paso c) en presencia de borano donde: (IX) d) reduction of the compound obtained in step c) in the presence of borane where:
FCFR es una base púrica o pirimidínica seleccionada de entre adenina, guanina, timina, citosina o uracilo. FCFR is a pyrimidine or pyrimidine base selected from adenine, guanine, thymine, cytosine or uracil.
R1 es seleccionado de entre Me, Et, Pr1, Bu1, o Bn R 1 is selected from Me, Et, Pr 1 , Bu 1 , or Bn
R2 es seleccionado de entre H, Me, Pr\ Bu¡, Bn o CH2OH. R 2 is selected from H, Me, Pr \ Bu ¡ , Bn or CH 2 OH.
Z es seleccionado de entre C02Me, C02Et, C02Bu¡, S02Ph, N02, CN, COPh o COMe. R3 es seleccionado de entre H, Me, Ph, Arilo, C02Me, C02Bu¡ o S02Ph. Z is selected from C0 2 Me, C0 2 Et, C0 2 Bu ¡ , S0 2 Ph, N0 2 , CN, COPh or COMe. R 3 is selected from H, Me, Ph, Arilo, C0 2 Me, C0 2 Bu ¡ or S0 2 Ph.
R4 es seleccionado de entre C02H o CH2OH R 4 is selected from C0 2 H or CH 2 OH
Ar es seleccionado de entre fenilo, p-tolilo, p-isopropilfenilo, 4-tercbutil-3-metil-fenilo, 4(trifluorometil)fenilo. Ar is selected from among phenyl, p-tolyl, p-isopropylphenyl, 4-tert-butyl-3-methyl-phenyl, 4 (trifluoromethyl) phenyl.
X es seleccionado de entre O o H, X is selected from O or H,
Z1-R3 es seleccionado de entre /V-metil, N-et\\, /V-bencil, /V-Fenil y /V-arilmaleimidas. Z 1 -R 3 is selected from / V-methyl, N-et \\, / V-benzyl, / V-Phenyl and / V-arylmaleimides.
2. Procedimiento según la reivindicación 1 donde el compuesto (III) se obtiene a partir del tratamiento de una base nitrogenada en medio básico con formalina o paraformaldehído para dar lugar al derivado aldehídico de base nitrogenada. 2. The method according to claim 1 wherein the compound (III) is obtained from the treatment of a nitrogenous base in basic medium with formalin or paraformaldehyde to give rise to the nitrogenous base aldehyde derivative.
3. Compuestos de fórmula general (VI) obtenidos a partir de la etapa a) del procedimiento según la reivindicación 1.  3. Compounds of general formula (VI) obtained from step a) of the process according to claim 1.
4. Compuestos de fórmula general (VIII) obtenidos a partir de la etapa b) del procedimiento según la reivindicación 1. 4. Compounds of general formula (VIII) obtained from step b) of the process according to claim 1.
5. Compuestos de fórmula general (IX) obtenidos a partir de la etapa c) del procedimiento según la reivindicación 1.  5. Compounds of general formula (IX) obtained from step c) of the process according to claim 1.
6. Compuestos de fórmula general (X) obtenido por el procedimiento según la reivindicación 1.  6. Compounds of general formula (X) obtained by the process according to claim 1.
7. Uso de los compuestos según cualquiera de las reivindicaciones 3-6 para la elaboración de medicamentos.  7. Use of the compounds according to any of claims 3-6 for the manufacture of medicaments.
8. Uso según la reivindicación 7 para la elaboración de un medicamento para el tratamiento de enfermedades virales. 8. Use according to claim 7 for the preparation of a medicament for the treatment of viral diseases.
9. Uso según la reivindicación 7 para la elaboración de un medicamento para el tratamiento de enfermedades bacterianas. 9. Use according to claim 7 for the preparation of a medicament for the treatment of bacterial diseases.
10. Uso según la reivindicación 7 para la elaboración de un medicamento para el tratamiento del cáncer.  10. Use according to claim 7 for the preparation of a medicament for the treatment of cancer.
PCT/ES2014/070214 2013-03-27 2014-03-21 Method for the synthesis of homologous compounds of azanucleosides WO2014154921A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES201300304A ES2499965B2 (en) 2013-03-27 2013-03-27 Synthesis procedure of homologous azanucleoside compounds
ESP201300304 2013-03-27

Publications (1)

Publication Number Publication Date
WO2014154921A1 true WO2014154921A1 (en) 2014-10-02

Family

ID=51587135

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/ES2014/070214 WO2014154921A1 (en) 2013-03-27 2014-03-21 Method for the synthesis of homologous compounds of azanucleosides

Country Status (2)

Country Link
ES (1) ES2499965B2 (en)
WO (1) WO2014154921A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999019338A1 (en) * 1997-10-14 1999-04-22 Albert Einstein College Of Medicine Of Yeshiva University Inhibitors of nucleoside metabolism
WO2006002231A1 (en) * 2004-06-22 2006-01-05 Biocryst Pharmaceuticals, Inc. Aza nucleosides, preparation thereof and use as inhibitors of rna viral polymerases
WO2011061139A1 (en) * 2009-11-17 2011-05-26 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999019338A1 (en) * 1997-10-14 1999-04-22 Albert Einstein College Of Medicine Of Yeshiva University Inhibitors of nucleoside metabolism
WO2006002231A1 (en) * 2004-06-22 2006-01-05 Biocryst Pharmaceuticals, Inc. Aza nucleosides, preparation thereof and use as inhibitors of rna viral polymerases
WO2011061139A1 (en) * 2009-11-17 2011-05-26 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ELBORAY, E.E. ET AL.: "X=Y=ZH compounds as potential 1,3-dipoles. Part 65: atom economic cascade synthesis of highly Functionalized pyrimidinylpyrrolidines''.", TETRAHEDRON, vol. 67, 2011, pages 5700 - 5710 *
KAWASHIMA, K. ET AL.: "Reaction of functionalized azomethine ylides with olefinic dipolarophiles''.", HETEROCYCLES, vol. 70, 2006, pages 647 - 654 *
QIU, X.-L. K. ET AL.: "Synthesis of 3'-Deoxy-3'-difluoromethyl Azanucleosides from trans-4-Hydroxy-L-proline''.", JOURNAL OF ORGANIC CHEMISTRY, vol. 70, 2005, pages 3826 - 3837 *

Also Published As

Publication number Publication date
ES2499965A1 (en) 2014-09-29
ES2499965B2 (en) 2015-03-31

Similar Documents

Publication Publication Date Title
AU2018217236B2 (en) Synthesis of polycyclic-carbamoylpyridone compounds
ES2622703T3 (en) New compounds of inverse code mimetic structures and their use
JP2006528162A (en) Compound
TW201823266A (en) Di-sulfide containing cell penetrating peptides and methods of making and using thereof
JPS5896097A (en) Erythromycin b derivative
WO2014154921A1 (en) Method for the synthesis of homologous compounds of azanucleosides
EP0096870B1 (en) Ester of metronidazole with n,n-dimethylglycine and acid addition salt thereof
WO2014022975A1 (en) N-(4-(3-amino-1h-indazol-4-yl)phenyl)-n'-(2-fluoro-5-methylphenyl)carbamide and preparation method for intermediate thereof
JP2021515046A (en) Vitamin C coupling platinum complex, its intermediate, its production method, pharmaceutical composition and use
ES2807558T3 (en) Procedure for preparing oxathiazine-type compounds
RU2656614C2 (en) Derivatives of oxalic acid, their use as chemosensitizers in combined anti-tumor therapy with cytostastics in the treatment of leukemia and drug-resistant leukemia, a method for production derivatives of oxalic acid
Shilenkov et al. SYNTHESIS OF 2, 6-DIISOPROPYlOXYCARBONIL-3, 5-DIMETHYL-4-(N-ACETAMIDOBENZENESULFONIL)-4-AMINOPHENOL AND THE EVIDENCE OF ITS STRUCTURE
RU2298556C1 (en) Cis-cis-[4-nitraminopyridin-n]tetrachloroplatinum (iv) trimethylolaminomethane salt and method for its preparing
Bakhtiyarova et al. Synthesis of carboxylate arsenobetaines based on (carboxyalkyl) triphenylarsonium halides
EA016532B1 (en) Sulfanyl derivatives and their use as synthesis intermediates
JPS63275567A (en) Novel quinoline derivative, ester and salt thereof
RU2477272C2 (en) Ketimine based on 4,4'-dichlorobenzophenone and guanidine and method for production thereof
SU1213726A1 (en) 3-dimethylaminopropylamide benzthiazino[2,3-b] phenothiazine-6-carboxylic acid possessing antitumoral activity
RU2271352C2 (en) 3-(4-nitrobenzoylmethylene)-1h,4h-hexahydro-2-quinoxalone eliciting anti-inflammatory activity
CN104341367B (en) One class tetrazoleacetic acid compounds, Preparation Method And The Use
RU2493158C2 (en) SODIUM SALT OF 2-METHYL-6-FLUORO-1,2,4-TRIAZOLO[5,1-c]-1,2,4-TRIAZIN-7(4H)-ONE DIHYDRATE, HAVING ANTIVIRAL ACTIVITY
JP2989865B2 (en) Pyrroloquinoline derivatives, esters and salts thereof
CN102731410B (en) Preparation and application of pyridazine human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor
DK160827B (en) PTERIDIN DERIVATIVES, PROCEDURES FOR PREPARING THEM AND PHARMACEUTICAL PREPARATION
JPH10310568A (en) N-alkoxycarbonyl-l-asparagine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14773449

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14773449

Country of ref document: EP

Kind code of ref document: A1