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WO2000068216A1 - Fused 1,2,6-thiadiazine -n,n and n,x-disubstituted dioxide derivatives and corresponding production method - Google Patents

Fused 1,2,6-thiadiazine -n,n and n,x-disubstituted dioxide derivatives and corresponding production method Download PDF

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Publication number
WO2000068216A1
WO2000068216A1 PCT/ES2000/000165 ES0000165W WO0068216A1 WO 2000068216 A1 WO2000068216 A1 WO 2000068216A1 ES 0000165 W ES0000165 W ES 0000165W WO 0068216 A1 WO0068216 A1 WO 0068216A1
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independently selected
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general formula
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aryl
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French (fr)
Inventor
Ana Martinez Gil
Carmen Gil Ayuso-Gontan
Ana Morera Castro
Mª Concepción PEREZ MARTIN
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Consejo Superior de Investigaciones Cientificas CSIC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide

Definitions

  • the invention describes the preparation of a series of compounds N, N- and
  • CMV cytomegalovirus
  • lobucavir drugs such as lobucavir are being developed (Tenney, DJ; Yamanaka, G .; Voss, SM; Cianci, CW; Tuomari, AV; Sheafer, AK; Alam, M .; Colonno, RJ "Lobucavir is Phosphorylated in Human Cytomegalovirus-lnfected and Uninfected Cells and Inhibits the Viral DNA Polymerase ", Antimicrob. Agents Chem., 1997, 41, 2680-2685.) And adefovir, both nucleoside analogues.
  • Antisense oligonucleotides with activity against CMV have also been developed which in vitro are capable of inhibiting gene expression (Kirk Field, A. "Viral targets for antisense oligonucleotides: a mini review", Antiviral Res., 1998, 37, 67- 81.).
  • We still do not have an ideal or absolutely safe formulation from the point of view of toxicity leaving the resistance problems unresolved.
  • the invention is directed to the synthesis of the compounds of general formula II and III:
  • R6, R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (0) tR 10 , - N (R 10 ) R 11 , - N (R 10 ) C (O) (R 10 ), -NO 2 , cyano, -C (O) R 10 , -C (O) OR 10 Z. Z1.
  • Ri ⁇ and Ri ⁇ are independently selected from the group consisting of hydrogen, alkyl, aryl
  • Alkyl refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms that do not contain unsaturations, having one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, by ex .: methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
  • alkyl radicals may be optionally substituted by one or more substituents independently selected from the group consisting of halogens, hydroxyl, alkoxides, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • "Alkoxy” refers to a radical of formula -OR a where R a is an alkyl radical as described above, eg .: methoxy, ethoxy, propoxy, etc.
  • Alkoxycarbonyl refers to a radical of formula -C (O) OR where R a is an alkyl radical as described above, eg .: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.
  • Alkylthio refers to a radical of the formula -SR where R a is an alkyl radical as described above, eg .: methylthio, ethylthio, propylthio, etc.
  • Amino refers to a radical of the formula -NH2.
  • Aryl refers to a phenyl or naphthyl radical.
  • the aryl radical may be optionally substituted by one or more substituents selected from the group consisting of hydroxy, mercapto, halogens, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl as defined herein.
  • Acyl refers to a radical of the formula -C (O) -R a and -C (O) -R D where R a is an alkyl radical as described above, and R is an aryl radical as described. previously, for example: acetyl, propionyl, benzoyl, and the like.
  • Carbocycle refers to a cyclic system consisting only of carbon and hydrogen atoms.
  • the carbocycle may be a monocyclic, bicyclic or tricyclic system and may include fused systems and the cycle may be totally or partially saturated or aromatic.
  • these carbocycles include, but are not limited to, cycloalkyl, as defined herein, phenyl, naphthyl, anthracenyl, indanyl and the like.
  • the carbocycle may be substituted by R 10 and R 11 as described in the summary of the invention.
  • Carboxy refers to a radical of formula -C (O) OH.
  • Cycloalkyl refers to stable cycles of 3- to 10-monocyclic or bicyclic members that are saturated or partially saturated and that are formed exclusively of carbon and hydrogen atoms. This term also includes cycloalkyl radicals that may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl. “Halogens” refers to bromine, chlorine, iodine or fluorine.
  • Haloalkyl refers to an alkyl radical, as defined above, which is substituted by one or more halogens, as they have also been defined, for example: trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1- fluoromethyl-2-fluoroethyl, and the like.
  • Heterocycle refers to a stable 3- to 15-membered cycle consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic system that may include fused rings, and that the nitrogen, carbon, or sulfur atoms may be optionally oxidized, the nitrogen atom may be optionally quaternized, and
  • the heterocycle may be partially or fully saturated or aromatic.
  • heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.
  • the heterocycle may be optionally substituted by R 10 and R 11 as defined in the summary of the invention.
  • Niro refers to a radical of formula -NO2
  • the compounds of this invention may be useful in the treatment of opportunistic viral infections, especially those produced by cytomegalovirus or varicella zoster virus. Its antiviral action is equipotent to ganciclovir, usually marketed for the treatment of cytomegalovirus, but its mechanism of action is totally different, which makes these compounds suitable candiestes in patients infected with viral resistance developed to ganciclovir.
  • the compounds of the invention can be synthesized by a two-step general procedure shown in reaction scheme 1. It is understood that the rest of the compounds can be prepared in a similar manner.
  • the compounds of the general formula (III) are first prepared by adding an equivalent of the compound of the general formula (IV) to a solution of an equivalent of the compound of the general formula (V) having at least two centers susceptible to nucleophilic attack and a sodium bicarbonate base equivalent in a polar and protic solvent such as water to originate the compounds of general formula (III). Sometimes the reaction has to be heated for at least 12 hours. When the reaction is complete, the compounds of general formula (III) are isolated by pre-dissipation of the aqueous phase.
  • the products of general formula (I) and (II) are prepared by adding an equivalent of the compound of general formula (IV) to a solution of an equivalent of the compound of general formula (III) having at least one center susceptible to nucleophilic attack and a sodium hydride base equivalent in a polar and aprotic dimethylformamide solvent to originate the compounds of general formula (I) and (II) in proportions dependent on the substituents X, Z, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R, R1, R2, R 3 , R 4 - R5, R 6 , R 7 , R 8 and R 9 of the values of n, o, p, q, r and s.
  • the usual chromatographic techniques are used in the separation and isolation of the products of general formula (I) and (II).
  • reaction scheme 2 A specific synthesis of the general method is shown in reaction scheme 2 and is applied to obtain 1,3-dibenzyl-2,1, 3- benzothiadiazin-4-one 2,2-dioxide and 2,2- 1-benzyl-4-benzyloxy-2,1,3-benzothiadiazine dioxide.
  • the 2,2,3-benzothiadiazin-4 (1 H, 3 / - /) - one (666 mg, 3.3 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution. Next, an equivalent and a half of benzyl bromide (862 mg, 4.9 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and washed with dichloromethane (1x10 ml).
  • the 2,2,3-3-benzothiadiazin-4 (1 rV, 3 / - /) - one (398 mg, 2.0 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution.
  • an equivalent of 4-chlorophenylmethyl chloride (603 mg, 2.0 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and washed with dichloromethane (1x10 ml).
  • the 2,2,3-3-benzothiadiazin-4 (1 H, 3H) -one (500 mg, 2.5 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution. Next, an equivalent and a half of 4-cyanophenylmethyl bromide (741 mg, 3.7 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and the alkaline aqueous phase is extracted with ethyl acetate (10 x 10 mL).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to compounds of general formula (I, II and III) and to a method for the production thereof, whereby compounds (III) are initially obtained in a first step and compounds (I and II) are obtained in a second step. Said compounds can be applied in the field of opportunistic viral infections in immunocompromised patients.

Description

1. Título1. Title

DERIVADOS DE DIÓXIDOS N,N- Y NX-DISUSTITUIDOS DE 1 ,2,6-TIADIAZINA FUSIONADAS Y PROCEDIMIENTO DE OBTENCIÓNDERIVATIVES OF N, N- AND NX-DISUSTITUTED DIOXIDES OF 1, 2,6-TIADIAZINE FUSED AND PROCEDURE OF OBTAINING

2. Sector de la técnica2. Technical sector

La invención describe la preparación de una serie de compuestos N,N- yThe invention describes the preparation of a series of compounds N, N- and

Λ/,X-disustituidos de dióxidos de 1 ,2,6-tiadiazina fusionadas con posible aplicación dentro del ámbito de la industria farmacéutica, fundamentalmente en el campo de las infecciones virales oportunistas en pacientes inmunocomprometidos.Λ /, X-disubstituted dioxides of 1, 2,6-thiadiazine fused with possible application within the scope of the pharmaceutical industry, primarily in the field of opportunistic viral infections in immunocompromised patients.

3. Estado de la Técnica3. State of the Art

Más de la mitad de los adultos presentan una serología positiva para el citomegalovirus (CMV). En los pacientes inmunocompetentes la infección aguda por CMV puede ser asintomática o provocar un síndrome mononucleosídico; en cualquiera de los casos, la agresividad de CMV en estos pacientes es escasa. Sin embargo, su capacidad para provocar enfermedad invasiva es elevada entre la población inmunodeprimida, especialmente entre las mujeres embarazadas, los receptores de transplantes de órganos y entre los infectados por el virus de la inmunodeficiencia humana (VIH). De hecho, la infección por CMV es casi universal en estos pacientes, causándoles retinitis o enfermedad diseminada, ceguera y contribuyendo además a su muerte. No hay que olvidar que los virus de la familia herpes persisten de forma latente, y pueden reactivarse en situaciones de inmunodepresión. Dados los grandes avances en las técnicas quirúrgicas que han aumentado notablemente el número de pacientes con transplante de órganos, y la gran extensión del SIDA entre la población mundial [Número estimado de adultos y niños viviendo con el VIH/SIDA a fines de 1998: 33,4 millones (Parras Vázquez, F. "Epidemiología actual de la infección por VIH/ SIDA", Medicine, Λ99o, 83, 3861-3867.)], el tratamiento de estas infecciones oportunistas es de gran urgencia y necesidad. Mas aún, cuando el empleo de agentes antirretrovirales ha convertido el SIDA en una enfermedad crónica de larga duración. En la actualidad se dispone de varios fármacos con actividad frente a CMV. El ganciclovir, el foscamet y el cidofovir están aprobados para su uso en E.E.U.U. Todos ellos, requieren una fosforilación previa intracelular para pasar a su forma activa, utilizando una fosfotransferasa del virus. El tratamiento prolongado con estos fármacos antivirales conlleva el problema de la aparición de resistencias (De Jong, M.D.; Boucher, C.A.B.; Danner, S.A.; Gazzard, B.; Griffiths, P.D.; Katlama, C; Lange, J.M.A.; Richman, D.D.; Vella, S. "Summary of the International Consensus Symposium on Management of HIV, CMV and hepatitis virus infection", Antiviral Res., 1998, 37, 1-16.). Mutaciones en el gen de la fosfotransferasa (UL-97), impiden que el CMV fosforile al ganciclovir haciéndose resistente al mismo. Asimismo, mutaciones en la ADN polimerasa pueden provocar la aparición de resistencias a los fármacos. Este último mecanismo es el responsable de las resistencias ya encontradas al foscamet (González-Lahoz, J.M.; Verdejo Ortés, J. "Infecciones víricas en pacientes VIH positivos", Medicine, 1998, 83, 3883-3888.) y al cidofovir (Reina, J. "Mecanismos de resistencia a los antivirales en el grupo herpesvirus", Enferm. Infecc Microbiol. Clin., 1997, 15, 329-334.). En el momento actual, se están desarrollando otros fármacos como el lobucavir (Tenney, D.J.; Yamanaka, G.; Voss, S.M.; Cianci, C.W.; Tuomari, A.V.; Sheafer, A.K.; Alam, M.; Colonno, R.J. "Lobucavir is Phosphorylated in Human Cytomegalovirus-lnfected and Uninfected Cells and Inhibits the Viral DNA Polymerase", Antimicrob. Agents Chem., 1997, 41, 2680-2685.) y el adefovir, ambos análogos de nucleósidos. También se han desarrollado oligonucleótidos antisentido con actividad frente al CMV que in vitro, son capaces de inhibir la expresión génica (Kirk Field, A. "Viral targets for antisense oligonucleotides: a mini review", Antiviral Res., 1998, 37, 67-81.). A pesar del arsenal terapéutico disponible, existen determinadas circunstancias clínicas en las que todavía no disponemos de una formulación ideal ni absolutamente segura desde el punto de vista de toxicidad, quedando sin resolver los problemas de resistencias. Hay por tanto una necesidad urgente de encontrar nuevos fármacos activos frente a CMV, menos tóxicos, con una buena biodisponibilidad y que además actúen por mecanismos de acción diferentes a los ya existentes. Dentro de la búsqueda de aciclonucleósidos de dióxidos de 1 ,2,6- tiadiazina con actividad antiviral [(Martinez, A.; Esteban, A.I.; Juanes, O.; Conde, S.; Goya, P,; De Clerq, E. "New 1 ,2,6-Thiadiazine Dioxide Acyclonucleosides: Synthesis and Antiviral Evaluation", Bioorg. Med. Chem., 1995, 3, 1527-1535.), (Esteban, A.I.; De Clerq, E.; Martinez, A. "Synthesis and Antiviral Activity of Modified 1 ,2,6-Thiadiazine Dioxide Acyclonucleosides", Nucleosides Nucleotides, 1997, 16, 265-276.)] recientemente se ha puesto a punto la síntesis de los primeros aciclonucleósidos de dióxidos de 2,1 ,3-benzotiadiazina. Se evaluó la actividad antiviral de estos compuestos contra CMV(cepas AD-169 y Davis) y WZ (cepas OKA, YS, 07/1 e YS/R) en células pulmonares de embrión humano (células HEL), encontrándose que algunos de los compuestos mostraron actividad contra CMV y WZ (Martinez, A.; Esteban, A.I.; De Clerq, E. "Benzothiadiazine Dioxides Acyclonucleosides as Lead Compounds for the Development of New Agents Against Human Cytomegalovirus and Varicella- Zoster Virus Infections", Bioorg. Med. Chem. Lett., 1997, 7, 1031-1032.), muy similar a la del patrón de ensayo ganciclovir. Además, fue también evaluada la actividad antiviral contra el VIH-1 (cepa IIIB) y VIH-2 (cepa ROD) en linfocitos T humanos (células CEM y MT-4). Alguno de los compuestos inhibe la replicación del VIH-1 y VIH-2 en células CEM a una concentración 15-20 μM. Además, alguno de los derivados inhibe la replicación del VIH-1 en células MT-4 con una IC50 = 3,7 μg/ml, siendo inactivo para el VIH-2 a concentraciones subtóxicas. Los estudios preliminares de relación estructura química-actividad biológica realizados en esta familia de compuestos (Martinez, A.; Esteban, A. I.; Castro, A.; Gil, C; Conde, S.; Andrei, G.; Snoeck, R.; Balzarini, J.; De Clerq, E. "Novel Potencial Agents for Human Cytomegalovirus Infection: Synthesis and Antiviral Evaluation of Benzothiadiazine Dioxides Acyclonucleosides", J. Med. Chem., 1999, en prensa.), pusieron de manifiesto la necesidad de una doble sustitución de los nitrógenos del sistema heterocíclico así como la preferencia de entornos lipófilos en las cadenas laterales unidas al núcleo de benzotiadiazina. A la vista de todos estos resultados, podemos considerar los aciclonucleósido modificados de benzotiadiazina, como nuevos cabeza de serie en la búsqueda de agentes antivirales activos frente a las infecciones oportunistas producidas por CMV y WZ, con una potencia semejante al ganciclovir, actualmente comercializado, pero con una estructura que sugiere un mecanismo de acción completamente diferente. La eliminación del grupo hidroxilo en el resto acíclico le impide actuar como terminador de cadena, no siendo susceptible de fosforilación. Este punto es especialmente interesante dadas las resistencias encontradas a los fármacos actualmente en uso y justifica las modificaciones posteriores de su estructura para obtener nuevos compuestos útiles en el tratamiento de la enfermedad.More than half of adults have a positive serology for cytomegalovirus (CMV). In immunocompetent patients, acute CMV infection may be asymptomatic or cause a mononucleoside syndrome; In either case, CMV aggressiveness in these patients is low. However, its ability to cause invasive disease is high among the immunocompromised population, especially among pregnant women, recipients of organ transplants and among those infected by the human immunodeficiency virus (HIV). In fact, CMV infection is almost universal in these patients, causing retinitis or disseminated disease, blindness and also contributing to their death. Do not forget that herpes family viruses persist latent, and can be reactivated in immunosuppression situations. Given the great advances in surgical techniques that have significantly increased the number of patients with organ transplants, and the large extent of AIDS among the world population [Estimated number of adults and children living with HIV / AIDS at the end of 1998: 33 , 4 million (Parras Vázquez, F. "Current epidemiology of HIV / AIDS infection", Medicine, Λ99o, 83, 3861-3867.)], The treatment of these opportunistic infections is of great urgency and necessity. Moreover, when the use of antiretroviral agents has turned AIDS into a chronic disease of long duration. There are currently several drugs with activity against CMV. Ganciclovir, foscamet and cidofovir are approved for use in the USA. All of them require prior intracellular phosphorylation to enter their active form, using a phosphotransferase from the virus. Prolonged treatment with these antiviral drugs leads to the problem of resistance (De Jong, MD; Boucher, CAB; Danner, SA; Gazzard, B .; Griffiths, PD; Katlama, C; Lange, JMA; Richman, DD; Vella, S. "Summary of the International Consensus Symposium on Management of HIV, CMV and hepatitis virus infection", Antiviral Res., 1998, 37, 1-16.). Mutations in the phosphotransferase gene (UL-97), prevent CMV from phosphorylating ganciclovir by becoming resistant to it. Also, mutations in DNA polymerase can cause drug resistance to occur. The latter mechanism is responsible for the resistance already found to foscamet (González-Lahoz, JM; Verdejo Ortés, J. "Viral infections in HIV positive patients", Medicine, 1998, 83, 3883-3888.) And cidofovir (Reina , J. "Mechanisms of antiviral resistance in the herpesvirus group", Enferm. Infecc Microbiol. Clin., 1997, 15, 329-334.). Currently, other drugs such as lobucavir are being developed (Tenney, DJ; Yamanaka, G .; Voss, SM; Cianci, CW; Tuomari, AV; Sheafer, AK; Alam, M .; Colonno, RJ "Lobucavir is Phosphorylated in Human Cytomegalovirus-lnfected and Uninfected Cells and Inhibits the Viral DNA Polymerase ", Antimicrob. Agents Chem., 1997, 41, 2680-2685.) And adefovir, both nucleoside analogues. Antisense oligonucleotides with activity against CMV have also been developed which in vitro are capable of inhibiting gene expression (Kirk Field, A. "Viral targets for antisense oligonucleotides: a mini review", Antiviral Res., 1998, 37, 67- 81.). Despite the available therapeutic arsenal, there are certain clinical circumstances in which we still do not have an ideal or absolutely safe formulation from the point of view of toxicity, leaving the resistance problems unresolved. There is therefore an urgent need to find new active drugs against CMV, less toxic, with good bioavailability and also acting by different mechanisms of action to those already existing. Within the search for acylonucleosides of dioxides of 1, 2,6-thiadiazine with antiviral activity [(Martinez, A .; Esteban, AI; Juanes, O .; Conde, S .; Goya, P; De Clerq, E. "New 1, 2,6-Thiadiazine Dioxide Acyclonucleosides: Synthesis and Antiviral Evaluation", Bioorg. Med. Chem., 1995, 3, 1527-1535.), (Esteban, AI; De Clerq, E .; Martinez, A. "Synthesis and Antiviral Activity of Modified 1, 2,6-Thiadiazine Dioxide Acyclonucleosides", Nucleosides Nucleotides, 1997, 16, 265-276.)] The synthesis of the first acylonucleosides of dioxides of 2,1 has recently been completed, 3-benzothiadiazine. The antiviral activity of these compounds against CMV (strains AD-169 and Davis) and WZ (strains OKA, YS, 07/1 and YS / R) in human embryonic lung cells (HEL cells) was evaluated, finding that some of the Compounds showed activity against CMV and WZ (Martinez, A .; Esteban, AI; De Clerq, E. "Benzothiadiazine Dioxides Acyclonucleosides as Lead Compounds for the Development of New Agents Against Human Cytomegalovirus and Varicella-Zoster Virus Infections", Bioorg. Med. Chem. Lett., 1997, 7, 1031-1032.), Very similar to that of the ganciclovir test pattern. In addition, the antiviral activity against HIV-1 (strain IIIB) and HIV-2 (strain ROD) in human T lymphocytes (CEM and MT-4 cells) was also evaluated. Some of the compounds inhibit the replication of HIV-1 and HIV-2 in EMF cells at a concentration of 15-20 μM. In addition, some of the derivatives inhibit the replication of HIV-1 in MT-4 cells with an IC50 = 3.7 μg / ml, being inactive for HIV-2 at sub-toxic concentrations. Preliminary studies of the relationship between chemical structure and biological activity carried out in this family of compounds (Martinez, A .; Esteban, AI; Castro, A .; Gil, C; Conde, S .; Andrei, G .; Snoeck, R .; Balzarini, J .; De Clerq, E. "Novel Potential Agents for Human Cytomegalovirus Infection: Synthesis and Antiviral Evaluation of Benzothiadiazine Dioxides Acyclonucleosides", J. Med. Chem., 1999, in press.), Highlighted the need for double substitution of the nitrogens of the heterocyclic system as well as the preference of lipophilic environments in the side chains attached to the benzothiadiazine nucleus. In view of all these results, we can consider the benzothiadiazine modified acylonucleoside as new standard in the search for active antiviral agents against infections opportunists produced by CMV and WZ, with a potency similar to ganciclovir, currently marketed, but with a structure that suggests a completely different mechanism of action. The elimination of the hydroxyl group in the acyclic moiety prevents it from acting as a chain terminator, not being susceptible to phosphorylation. This point is especially interesting given the resistance found to the drugs currently in use and justifies the subsequent modifications of its structure to obtain new compounds useful in the treatment of the disease.

4. Descripción de la invención4. Description of the invention

4.1. Breve descripción de la invención4.1. Brief Description of the Invention

La invención se dirige a la síntesis de los compuestos de fórmula general II y III:The invention is directed to the synthesis of the compounds of general formula II and III:

Figure imgf000006_0001
Figure imgf000007_0001
donde:
Figure imgf000006_0001
Figure imgf000007_0001
where:

R, R1, R2, R3, R4, R5 R, R 1 , R 2 , R 3 , R 4 , R 5

R6, R7, R8 y R9 son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, haloalquil, aril, -OR10, -S(0)t-R10, - N(R10)R11, -N(R10)C(O)(R10), -NO2, ciano, -C(O)R10, -C(O)OR10 Z. Z1. Z2R6, R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (0) tR 10 , - N (R 10 ) R 11 , - N (R 10 ) C (O) (R 10 ), -NO 2 , cyano, -C (O) R 10 , -C (O) OR 10 Z. Z1. Z2

Z3, Z4, Z3 son elegidos independientemente entre el grupo consistente en - C(R10)(R11)-, -C(O)-, -O-, -C(=NR10)-, -S(O)t-, N(R10)- n, o, p, q, r y s son cero, o un número entero comprendido entre 1 y 5, teniendo en cuenta que n, o y p no pueden ser cero simultáneamente, y q, r y s no pueden ser cero simultáneamente, t es cero, uno ó dos.Z 3 , Z 4 , Z 3 are independently selected from the group consisting of - C (R 10 ) (R 11 ) -, -C (O) -, -O-, -C (= NR 10 ) -, -S (O) t-, N (R 10 ) - n, o, p, q, rys are zero, or an integer between 1 and 5, taking into account that n, oyp cannot be zero simultaneously, and q, rys they cannot be zero simultaneously, t is zero, one or two.

Riθ y Riι son elegidos independientemente entre el grupo consistente en hidrógeno, alquil, arilRiθ and Riι are independently selected from the group consisting of hydrogen, alkyl, aryl

X son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, =O, =S, -N(R10)R11, aril A es un carbociclo o heterociclo fusionado opcionalmente sustituido deX are independently selected from the group consisting of hydrogen, halogen, alkyl, = O, = S, -N (R 10 ) R 11 , aryl A is an optionally substituted fused carbocycle or heterocycle of

5, 6 ó 7 miembros saturado o insaturado. 4.2. Descripción de la invención Definiciones:5, 6 or 7 members saturated or unsaturated. 4.2. Description of the invention Definitions:

A menos que se especifique lo contrario, los siguientes términos tienen el siguiente significado:Unless otherwise specified, the following terms have the following meaning:

"Alquil" se refiere a un radical de cadena hidrocarbonada lineal o ramificado consistente solamente en átomos de carbono e hidrogeno que no contienen insaturaciones, teniendo de uno a ocho átomos de carbonos y que está unido al resto de la molécula por un enlace sencillo, por ej.: metil, etil, n-propil, i-propil, n-butil, t-butil, n-pentil, etc. Los radicales alquilo pueden estar opcionalmente sustituidos por uno o mas sustituyentes independientemente seleccionados del grupo consistente en halógenos, hidroxilo, alcóxidos, carboxi, ciano, carbonil, acil, alcoxicarbonil, amino, nitro, mercapto y alquiltio. "Alcoxi" se refiere a un radical de formula -ORa donde Ra es un radical alquilo como se ha descrito arriba, por ej.: metoxi, etoxi, propoxi, etc. "Alcoxicarbonil" se refiere a un radical de formula -C(O)ORa donde Ra es un radical alquilo como se ha descrito arriba, por ej.: metoxicarbonil, etoxicarbonil, propoxicarbonil, etc. "Alquiltio" se refiere a un radical de formula -SRa donde Ra es un radical alquilo como se ha descrito arriba, por ej.: metiltio, etiltio, propiltio, etc."Alkyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms that do not contain unsaturations, having one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, by ex .: methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. The alkyl radicals may be optionally substituted by one or more substituents independently selected from the group consisting of halogens, hydroxyl, alkoxides, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio. "Alkoxy" refers to a radical of formula -OR a where R a is an alkyl radical as described above, eg .: methoxy, ethoxy, propoxy, etc. "Alkoxycarbonyl" refers to a radical of formula -C (O) OR where R a is an alkyl radical as described above, eg .: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc. "Alkylthio" refers to a radical of the formula -SR where R a is an alkyl radical as described above, eg .: methylthio, ethylthio, propylthio, etc.

"Amino" se refiere a un radical de formula -NH2."Amino" refers to a radical of the formula -NH2.

"Aril" se refiere a un radical fenilo o naftilo. El radical arilo puede estar opcionalmente sustituido por uno o mas sustituyentes seleccionados entre el grupo consistente en hidroxi, mercapto, halógenos, alquil, fenil, alcoxi, haloalquil, nitro, ciano, dialquilamino, aminoalquil, acil y alcoxicarbonil como son definidos aqui."Aryl" refers to a phenyl or naphthyl radical. The aryl radical may be optionally substituted by one or more substituents selected from the group consisting of hydroxy, mercapto, halogens, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl as defined herein.

"Acil" se refiere a un radical de formula -C(O)-Ra y -C(O)-RD donde Ra es un radical alquilo como se ha descrito arriba, y R es un radical arilo como se ha descrito anteriormente, por ej.: acetil, propionil, benzoil, y semejantes."Acyl" refers to a radical of the formula -C (O) -R a and -C (O) -R D where R a is an alkyl radical as described above, and R is an aryl radical as described. previously, for example: acetyl, propionyl, benzoyl, and the like.

"Carbociclo" se refiere a un sistema cíclico consistente solamente en átomos de carbono e hidrógeno. Para el proposito de esta invención el carbociclo puede ser un sistema monocíclico, bicíclico o tricíclico y puede incluir sistemas fusionados y el ciclo puede estar total o parcialmente saturado o aromático. Ejemplos de estos carbociclos incluyen, pero no limitan, a cicloalquilos, como se definen aqui, fenilo, naftilo, antracenil, indanil y semejantes. El carbociclo puede estar sustituido por R10 y R11 como se describen en el resumen de la invencción."Carbocycle" refers to a cyclic system consisting only of carbon and hydrogen atoms. For the purpose of this invention the carbocycle may be a monocyclic, bicyclic or tricyclic system and may include fused systems and the cycle may be totally or partially saturated or aromatic. Examples of these carbocycles include, but are not limited to, cycloalkyl, as defined herein, phenyl, naphthyl, anthracenyl, indanyl and the like. The carbocycle may be substituted by R 10 and R 11 as described in the summary of the invention.

"Carboxi" se refiere a un radical de formula -C(O)OH."Carboxy" refers to a radical of formula -C (O) OH.

"Ciano" se refiere a un radical de formula -CN"Cyano" refers to a radical of formula -CN

"Cicloalquil" se refiere a ciclos estables de 3- a 10- miembros monocídicos o bicíclicos que están saturados o parcialmente saturados y que están formados exclusivamente por átomos de carbono e hidrógeno. Este término también incluye radicales cicloalquilo que pueden estar opcionalmente sustituidos por uno o mas sustituyentes seleccionados independientemente del grupo consistente en alquil, halógeno, hydroxi, amino, ciano, nitro, alcoxi, carboxy y alcoxicarbonil. "Halógenos" se refiere a bromo, cloro, iodo o flúor."Cycloalkyl" refers to stable cycles of 3- to 10-monocyclic or bicyclic members that are saturated or partially saturated and that are formed exclusively of carbon and hydrogen atoms. This term also includes cycloalkyl radicals that may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl. "Halogens" refers to bromine, chlorine, iodine or fluorine.

"Haloalquil" se refiere a un radical alquilo, como ha sido definido arriba, que está sustituido por uno o mas halógenos, como también han sido definidos, por ej.: trifluorometil, triclorometil, 2,2,2-trifluoroetil, 1- fluorometil-2-fluoroetil, y semejantes."Haloalkyl" refers to an alkyl radical, as defined above, which is substituted by one or more halogens, as they have also been defined, for example: trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1- fluoromethyl-2-fluoroethyl, and the like.

"Heterociclo" se refiere a un ciclo estable de 3- a 15- miembros consistente en átomos de carbono y de uno a cinco heteroátomos seleccionados del grupo consistente en nitrógeno, oxigeno y azufre. Para los propósitos de esta invencción, el heterociclo puede ser un sistema monocíclcico, bicíclico o tricíclico que puede incluir anillos fusionados, y que los átomos de nitrógeno, carbono, o azufre puedan estar opcionalmente oxidados, el átomo de nitrógeno puede estar opcionalmente cuaternizado, y el heterociclo puede estar parcial o totalmente saturado o aromático. Ejemplos de estos heterociclos incluyen, pero no limitan, a azepinas, benzimidazol, benzotiazol, furano, isotiazol, imidazol, indol, piperidina, piperazina, purina, quinolina, tiadiazol, tetrahidrofurano. El heterociclo puede estar opcionalmente sustituido por R10 y R11 como se han definido en el resumen de la invención."Heterocycle" refers to a stable 3- to 15-membered cycle consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic system that may include fused rings, and that the nitrogen, carbon, or sulfur atoms may be optionally oxidized, the nitrogen atom may be optionally quaternized, and The heterocycle may be partially or fully saturated or aromatic. Examples of these heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran. The heterocycle may be optionally substituted by R 10 and R 11 as defined in the summary of the invention.

"Mercapto" se refiere a un radical de formula -SH"Mercapto" refers to a radical of formula -SH

"Nitro" se refiere a un radical de fórmula -NO2"Nitro" refers to a radical of formula -NO2

Utilidad de los compuestos de la invención: Los compuestos de esta invención pueden ser útiles en el tratamiento de infecdones virales oportunistas, especialmente las producidas por citomegalovirus o virus de tipo varicela zoster. Su acción antiviral es equipotente al ganciclovir, adualmente comercializado para el tratamiento de citomegalovirus, pero su mecanismo de acción es totalmente diferente lo que hace a estos compuestos unos candiadtos idóneos en pacientes infectados con resistencias virales desarrolladas a ganciclovir.Usefulness of the compounds of the invention: The compounds of this invention may be useful in the treatment of opportunistic viral infections, especially those produced by cytomegalovirus or varicella zoster virus. Its antiviral action is equipotent to ganciclovir, usually marketed for the treatment of cytomegalovirus, but its mechanism of action is totally different, which makes these compounds suitable candiestes in patients infected with viral resistance developed to ganciclovir.

Preparación de los compuestos de la invención:Preparation of the compounds of the invention:

Los compuestos de la invención pueden ser sintetizados por un procedimiento general en dos etapas mostrado en el esquema de reacción 1. Se entiende que el resto de los compuestos pueden prepararse de manera similar.

Figure imgf000011_0001
The compounds of the invention can be synthesized by a two-step general procedure shown in reaction scheme 1. It is understood that the rest of the compounds can be prepared in a similar manner.
Figure imgf000011_0001

Esquema de reacción 1 Reaction Scheme 1

En general, los compuestos de fórmula general (III) se preparan primero añadiendo un equivalente del compuesto de fórmula general (IV) a una solución de un equivalente del compuesto de fórmula general (V) que tenga al menos dos centros susceptibles de ataque nucleófilo y un equivalente de base tipo bicarbonato sódico en un disolvente polar y prótico como agua para originar los compuestos de fórmula general (III). En ocasiones la reacción tiene que ser calentada al menos 12 horas. Cuando la reacción se ha completado, los compuestos de fórmula general (III) se aislan por precipatación de la fase acuosa. En una segunda etapa, los productos de fórmula general (I) y (II) se preparan añadiendo un equivalente del compuesto de fórmula general (IV) a una solución de un equivalente del compuesto de fórmula general (III) que tenga al menos un centro susceptible de ataque nucleófilo y un equivalente de base tipo hidruro sódico en un disolvente polar y aprótico tipo dimetilformamida para originar los compuestos de formula general (I) y (II) en proporciones dependientes de los sustituyentes X, Z, Z1 , Z2, Z3, Z4, Z5, R, R1, R2, R3, R4- R5, R6, R7, R8 y R9 de los valores de n, o, p, q, r y s. Las técnicas cromatográficas habituales se emplean en la separación y aislamiento de los productos de fórmula general (I) y (II).In general, the compounds of the general formula (III) are first prepared by adding an equivalent of the compound of the general formula (IV) to a solution of an equivalent of the compound of the general formula (V) having at least two centers susceptible to nucleophilic attack and a sodium bicarbonate base equivalent in a polar and protic solvent such as water to originate the compounds of general formula (III). Sometimes the reaction has to be heated for at least 12 hours. When the reaction is complete, the compounds of general formula (III) are isolated by pre-dissipation of the aqueous phase. In a second stage, the products of general formula (I) and (II) are prepared by adding an equivalent of the compound of general formula (IV) to a solution of an equivalent of the compound of general formula (III) having at least one center susceptible to nucleophilic attack and a sodium hydride base equivalent in a polar and aprotic dimethylformamide solvent to originate the compounds of general formula (I) and (II) in proportions dependent on the substituents X, Z, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , R, R1, R2, R 3 , R 4 - R5, R 6 , R 7 , R 8 and R 9 of the values of n, o, p, q, r and s. The usual chromatographic techniques are used in the separation and isolation of the products of general formula (I) and (II).

Una síntesis específica del método general se muestra en el esquema de reacción 2 y se aplica a la obtención del 2,2-dióxido de 1 ,3-dibencil-2,1 ,3- benzotiadiazin-4-ona y del 2,2-dióxido de 1-bencil-4-bencilox¡-2,1,3- benzotiadiazina. A specific synthesis of the general method is shown in reaction scheme 2 and is applied to obtain 1,3-dibenzyl-2,1, 3- benzothiadiazin-4-one 2,2-dioxide and 2,2- 1-benzyl-4-benzyloxy-2,1,3-benzothiadiazine dioxide.

Figure imgf000013_0001
Figure imgf000013_0001

Esquema de reacción 2Reaction Scheme 2

Se disuelve el 2,2-dióxido de 2,1,3-benzotiadiazin-4(1 H,3/-/)-ona (666 mg, 3,3 mmol) en 20 mi de una solución acuosa de bicarbonato sódico saturada. A continuación, se añade un equivalente y medio de bromuro de bencilo (862 mg, 4.9 mmol) y se mantiene a reflujo 2 horas. Se enfría hasta temperatura ambiente, y se lava con diclorometano (1x10 mi). La fase acuosa alcalina se enfría a -4 °C y el producto buscado (2,2-dióxido de 1 -bencil-2.1.3-benzotiadiazin-4(3/-/)-ona) se aisla de esta fase por filtración, y se purifica por recristalización de tolueno/metanol (788 mg, 81 %) obteniéndose como un sólido cristalino blanco. P.f: 285-287 °C. 1H RMN (DMSO-d6): δ 7.88 (dd, 1 H), 6.87 (t, 1 H), 6.74 (dd, 1 H), 7.23 (t, 1 H), 7.27-7.42 (m, 5H), 4.95 (s, 2H).13C RMN (DMSO-d6): 546.47, 113.80, 119.28, 119.70, 126.93, 126.98, 128.44, 128.85, 131.93, 137.88, 142.22, 165.91 Análisis calculado para C14H12N2O3S: C, 58,32; H, 4,16; N, 9,71 ; S, 11 ,12. Encontrado: C, 58,41 ; H, 4,05; N, 9,77; S, 11 ,31. A una suspensión equimolecular de hidruro sódico en dimetilformamida (20 mi), se le añade el 2,2-dióxido de 1-bencil-2,1 ,3-benzotiadiazin-4(3/-/)-ona (250 mg, 0,8 mmol), y un equivalente y medio de bromuro de bencilo (222 mg, 1 ,3 mmol). La mezcla de reacción se calienta a reflujo durante dos horas. Una vez concluida la reacción, se evapora el disolvente a presión reducida y a continuación, tras adición de agua (10 mi), se extrae con diclorometano (2x1 Oml). La fase orgánica, se seca sobre sulfato sódico anhidro, y el disolvente se elimina a vacío. Por cromatografía en columna de gel de sílice del residuo utilizando como eluyente diclorometano: hexano 2:1 , se obtienen los productos buscados. De la primera fracción se aisla el 2,2-dióxido de 1 ,3-dibencil-2,1 ,3-benzotiadiazin- 4-ona (144 mg, 44 %) como un sóido blanco. P.f: 120-122 °C. 1H RMN (CDCI3): δ 8.04 (dd, 1 H), 7.04 (dd, 1 H), 7.47 (t, 1 H), 6.99-7.42 (m, 11 H), 4.83 (s, 2H), 4.93 (s, 2H).13C RMN (CDCI3): δ 46.54, 56.21 , 122.18, 122.81 , 126.43, 128.00, 128.16, 128.50, 128.56, 128.72, 128.91 , 133.82, 134.65, 135.64, 139.79, 162.09. Análisis calculado para C21H18N2O3S: C, 66,65; H, 4,78; N, 7,40; S, 8,46. Encontrado: C, 66,42; H, 4,80; N, 7,35; S, 8,25.The 2,2,3-benzothiadiazin-4 (1 H, 3 / - /) - one (666 mg, 3.3 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution. Next, an equivalent and a half of benzyl bromide (862 mg, 4.9 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and washed with dichloromethane (1x10 ml). The alkaline aqueous phase is cooled to -4 ° C and the desired product (1-benzyl-2.1.3-benzothiadiazin-4 (3 / - /) - one) is isolated from this phase by filtration, and purified by recrystallization from toluene / methanol (788 mg, 81%) to obtain a white crystalline solid. Mp: 285-287 ° C. 1 H NMR (DMSO-d 6 ): δ 7.88 (dd, 1 H), 6.87 (t, 1 H), 6.74 (dd, 1 H), 7.23 (t, 1 H), 7.27-7.42 (m, 5H ), 4.95 (s, 2H). 13 C NMR (DMSO-d 6 ): 546.47, 113.80, 119.28, 119.70, 126.93, 126.98, 128.44, 128.85, 131.93, 137.88, 142.22, 165.91 Analysis calculated for C14H12N2O3S: C, 58.32; H, 4.16; N, 9.71; S, 11, 12. Found: C, 58.41; H, 4.05; N, 9.77; S, 11, 31. To an equimolecular suspension of sodium hydride in dimethylformamide (20 ml), 1-benzyl-2,1,3-benzothiadiazin-4 (3 / - /) -one 2,2-dioxide (250 mg, 0 , 8 mmol), and an equivalent and a half of benzyl bromide (222 mg, 1.3 mmol). The reaction mixture is heated at reflux for two hours. Once the reaction is over, the solvent is evaporated under reduced pressure and then, after the addition of water (10 ml), it is extracted with dichloromethane (2x1 Oml). The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. By silica gel column chromatography of the residue using dichloromethane: hexane 2: 1 as eluent, the desired products are obtained. From the first fraction, 1,3-dibenzyl-2,1,3-benzothiadiazin-4-one 2,2-dioxide (144 mg, 44%) is isolated as a white solid. Mp: 120-122 ° C. 1 H NMR (CDCI 3 ): δ 8.04 (dd, 1 H), 7.04 (dd, 1 H), 7.47 (t, 1 H), 6.99-7.42 (m, 11 H), 4.83 (s, 2H), 4.93 (s, 2H). 13 C NMR (CDCI3): δ 46.54, 56.21, 122.18, 122.81, 126.43, 128.00, 128.16, 128.50, 128.56, 128.72, 128.91, 133.82, 134.65, 135.64, 139.79, 162.09. Analysis calculated for C21H18N2O3S: C, 66.65; H, 4.78; N, 7.40; S, 8.46. Found: C, 66.42; H, 4.80; N, 7.35; S, 8.25.

De la segunda fracción se aisla el 2,2-dióxido de 1 -bencil-4-(benciloxi)- 2.1.3-benzotiadiazina (26 mg, 8 %) como un sólido blanco. P.f.: 110-111 °C. 1H RMN (CDCI3): δ 713C RMN (CDCI3): δ Análisis calculado para C21H18N2O3S: C, 66,65; H, 4,78; N, 7,40; S, 8,46. Encontrado: C, 66,86; H, 4,62; N, 7,50; S, 8,70. Otro ejemplo específico de la síntesis de los compuestos de fórmula general (I), y (III) es el siguiente:From the second fraction, 1-benzyl-4- (benzyloxy) -2,2-benzothiadiazine 2,2-dioxide (26 mg, 8%) is isolated as a white solid. Mp: 110-111 ° C. 1 H NMR (CDCI3): δ 7 13 C NMR (CDCI3): δ Analysis calculated for C21H18N2O3S: C, 66.65; H, 4.78; N, 7.40; S, 8.46. Found: C, 66.86; H, 4.62; N, 7.50; S, 8.70. Another specific example of the synthesis of the compounds of general formula (I), and (III) is as follows:

Se disuelve el 2,2-dióxido de 2,1 ,3-benzotiadiazin-4(1 rV,3/-/)-ona (398 mg, 2,0 mmol) en 20 mi de una solución acuosa de bicarbonato sódico saturada. A continuación, se añade un equivalente de cloruro de 4-clorofenilmetilo (603 mg, 2,0 mmol) y se mantiene a reflujo 2 horas. Se enfría hasta temperatura ambiente, y se lava con diclorometano (1x10 mi). La fase acuosa alcalina se enfría a -4 °C y el producto buscado (2.2-dióxido de 1-f(4-clorofenil)met¡π-2,1 ,3-benzotiadiazin- 4(3H)-ona) se aisla de esta fase por filtración, y se purifica por recristalización de tolueno/metanol (407 mg, 63 %) obteniéndose como un sólido cristalino blanco. P.f.: 285-287 °C. 1H RMN (DMSO-d6): δ 7.86 (dd, 1 H), 6.92 (t, 1 H), 6.75 (dd, 1 H), 7.30 (t, 1 H), 7.27-7.39 (m, 4H), 4.93 (s, 2H). 13C RMN (DMSCxle): δ 46.51 , 114.54, 119.74, 120.64, 129.01 , 129.37, 129.52, 133.17, 137.05, 132.35, 142.30, 167.29. Análisis calculado para C14H11N2O3SCI : C, 52,11 ; H, 3,41 ; N, 8,68; S, 9,93. Encontrado: C, 52,34; H, 3,52; N, 8,47; S, 9,85.The 2,2,3-3-benzothiadiazin-4 (1 rV, 3 / - /) - one (398 mg, 2.0 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution. Next, an equivalent of 4-chlorophenylmethyl chloride (603 mg, 2.0 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and washed with dichloromethane (1x10 ml). The alkaline aqueous phase is cooled to -4 ° C and the desired product (2.2-1-f (4-chlorophenyl) met¡π-2,1, 3-benzothiadiazin-4 (3H) -one) is isolated from this phase by filtration, and is purified by recrystallization from toluene / methanol (407 mg, 63%) to obtain a white crystalline solid. Mp: 285-287 ° C. 1 H NMR (DMSO-d 6 ): δ 7.86 (dd, 1 H), 6.92 (t, 1 H), 6.75 (dd, 1 H), 7.30 (t, 1 H), 7.27-7.39 (m, 4H ), 4.93 (s, 2H). 13 C NMR (DMSCxle): δ 46.51, 114.54, 119.74, 120.64, 129.01, 129.37, 129.52, 133.17, 137.05, 132.35, 142.30, 167.29. Analysis calculated for C14H11N2O3SCI: C, 52.11; H, 3.41; N, 8.68; S, 9.93. Found: C, 52.34; H, 3.52; N, 8.47; S, 9.85.

A una suspensión equimolecular de hidruro sódico en dimetilformamida (20 mi), se le añade el 2,2-dióxido de 1-[(4-clorofenil)metil]-2,1 ,3-benzotiadiazin- 4(3H)-ona (100 mg, 0,3 mmol), y un equivalente y medio de bromuro de bencilo (77 mg, 0,4 mmol). La mezcla de reacción se calienta a reflujo durante dos horas. Una vez concluida la reacción, se evapora el disolvente a presión reducida y a continuación, tras adición de agua (10 mi), se extrae con diclorometano (2x1 Oml). La fase orgánica, se seca sobre sulfato sódico anhidro, y el disolvente se elimina a vacío. Por cromatografía circular centrífuga del residuo utilizando como eluyente diclorometano, se obtiene el producto buscado 2.2-dióxido de 1-f(4-clorofenil)met¡n-3-bencil-2.1.3-benzotiadiazin-4-ona (35 mg, 29 %) como un si pe. "Η RMN (CDCI3): δ 8.05 (dd, 1 H), 6.91 (dd, 1 H), 7.45 (t, 1H), 7.06 (t, 1H), 7.16-7.38 (m, 9H), 4.78 (s, 2H), 4.94 (s, 2H). 13C RMN (CDCI3): δ 46.46, 55.37, 121.98, 122.71 , 126.55, 128.08, 128.56, 128.91 , 129.49, 129.98, 130.57, 132.36, 134.44, 134.77, 135.55, 139.56, 161.98. Análisis calculado para C21H17N2O3SCI : C, 61 ,09; H, 4,15; N, 6,78; S, 7,77. Encontrado: C, 60,87; H, 4,28; N, 6,68; S, 7,88. Otro ejemplo específico de la síntesis de los compuestos de fórmula general (I), (II) y (III) es el siguiente:To an equimolecular suspension of sodium hydride in dimethylformamide (20 ml), the 2,2-dioxide of 1 - [(4-chlorophenyl) methyl] -2,1, 3-benzothiadiazine-4 (3H) -one ( 100 mg, 0.3 mmol), and an equivalent and a half of benzyl bromide (77 mg, 0.4 mmol). The reaction mixture is heated at reflux for two hours. Once the reaction is over, the solvent is evaporated under reduced pressure and then, after the addition of water (10 ml), it is extracted with dichloromethane (2x1 Oml). The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. By centrifugal circular chromatography of the residue using dichloromethane as eluent, the desired product is obtained 2.2-dioxide of 1-f (4-chlorophenyl) metin-3-benzyl-2.1.3-benzothiadiazin-4-one (35 mg, 29 %) as a yes pe. " Η NMR (CDCI3): δ 8.05 (dd, 1 H), 6.91 (dd, 1 H), 7.45 (t, 1H), 7.06 (t, 1H), 7.16-7.38 (m, 9H), 4.78 (s , 2H), 4.94 (s, 2H) .1 3 C NMR (CDCI3): δ 46.46, 55.37, 121.98, 122.71, 126.55, 128.08, 128.56, 128.91, 129.49, 129.98, 130.57, 132.36, 134.44, 134.77, 135.55, 139.56, 161.98 Analysis calculated for C21H17N2O3SCI: C, 61, 09; H, 4.15; N, 6.78; S, 7.77. Found: C, 60.87; H, 4.28; N, 6 , 68; S, 7.88 Another specific example of the synthesis of the compounds of general formula (I), (II) and (III) is as follows:

Se disuelve el 2,2-dióxido de 2,1 ,3-benzotiadiazin-4(1 H,3H)-ona (500 mg, 2,5 mmol) en 20 mi de una solución acuosa de bicarbonato sódico saturada. A continuación, se añade un equivalente y medio de bromuro de 4-cianofenilmetilo (741 mg, 3,7 mmol) y se mantiene a reflujo 2 horas. Se enfría hasta temperatura ambiente, y la fase acuosa alcalina se extrae con acetato de etilo (10 x 10 mi). La fase orgánica se seca sobre sulfato sódico, y el disolvente se evapora apresión reducida para originar el producto buscado (2,2-dióxido de 1-f(4-cianofenil)metill- 2,1.3-benzotiadiazin-4(3H)-ona). Se purifica por recristalización de tolueno/metanol (566 mg, 72 %) obteniéndose como un sólido cristalino blanco. P.f.: 298-300 °C, 1H RMN (DMSO-d6): δ 7.87 (dd, 1 H), 6.88 (t, 1 H), 6.66 (dd, 1 H), 7.25 (t, 1 H), 7.58 (d, 2H?), 7.78 (d, 2H), 5.03 (s, 2H). 13C RMN (DMSO-d6): δ 46.28, 109.72, 119.42, 119.60, 113.47, 127.83, 128.92, 131.98, 132.30, 141.87, 144.01 , 165.67. Análisis calculado para C15H11N3O3S: C, 57,52; H, 3,51 ; N, 13,40; S, 10,23. Encontrado: C, 57,75; H, 3,21 ; N, 13,22; S, 10,09.The 2,2,3-3-benzothiadiazin-4 (1 H, 3H) -one (500 mg, 2.5 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution. Next, an equivalent and a half of 4-cyanophenylmethyl bromide (741 mg, 3.7 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and the alkaline aqueous phase is extracted with ethyl acetate (10 x 10 mL). The organic phase is dried over sodium sulfate, and the solvent evaporates reduced pressure to give rise to the desired product (1-f (4-cyanophenyl) methyl-2,1,3-benzothiadiazin-4 (3H) -one 2,2-dioxide ). It is purified by recrystallization from toluene / methanol (566 mg, 72%) to obtain a white crystalline solid. Mp: 298-300 ° C, 1 H NMR (DMSO-d 6 ): δ 7.87 (dd, 1 H), 6.88 (t, 1 H), 6.66 (dd, 1 H), 7.25 (t, 1 H) , 7.58 (d, 2H?), 7.78 (d, 2H), 5.03 (s, 2H). 13 C NMR (DMSO-d 6 ): δ 46.28, 109.72, 119.42, 119.60, 113.47, 127.83, 128.92, 131.98, 132.30, 141.87, 144.01, 165.67. Analysis calculated for C15H11N3O3S: C, 57.52; H, 3.51; N, 13.40; S, 10.23. Found: C, 57.75; H, 3.21; N, 13.22; S, 10.09.

A una suspensión equimolecular de hidruro sódico en dimetilformamida (20 mi), se le añade el 2,2-dióxido de 1-[(4-cianofenil)metil]-2,1 ,3-benzotiadiazin- 4(3H)-ona (200 mg, 0,6 mmol), y un equivalente y medio de bromuro de bencilo (153 mg, 0,9 mmol). La mezcla de reacción se calienta a reflujo durante dos horas. Una vez concluida la reacción, se evapora el disolvente a presión reducida y a continuación, tras adición de agua (10 mi), se extrae con diclorometano (2x1 Oml). La fase orgánica, se seca sobre sulfato sódico anhidro, y el disolvente se elimina a vacío. Por cromatografía en capa fina preparativa del residuo utilizando como eluyente diclorometano: hexano 1 :1 , se obtienen los productos buscados. De la primera fracción se aisla el 2.2-dióxido de 1-[(4- cianofenil)met¡π-3-bencil-2, 1 ,3-benzotiadiazin-4-ona (30 mg, 12 %) como un sóido blanco. P.f.: 45-47 °C. 1H RMN (CDCI3): δ 8.09 (dd, 1 H), 7.03 (dd, 1H), 7.52 (t, 1 H), 7.11-7.42 (m, 10H), 4.97 (s, 2H), 4.88 (s, 2H). "<3C RMN (CDCI3): δ 46.42, 55.19, 112.38, 121.27, 122.34, 126.66, 128.23, 128.44, 128.61 , 129.11 , 130.76, 132.51 , 135.39, 139.30, 135.01 , 139.40, 161.43. Análisis calculado para C22H17N3O3S: C, 65,51 ; H, 4,21 ; N, 10,41 ; S, 7,94. Encontrado: C, 65,43; H, 4,00; N, 10,60; S, 7,74.To an equimolecular suspension of sodium hydride in dimethylformamide (20 ml), the 2,2-dioxide of 1 - [(4-cyanophenyl) methyl] -2,1, 3-benzothiadiazine-4 (3H) -one ( 200 mg, 0.6 mmol), and an equivalent and a half of benzyl bromide (153 mg, 0.9 mmol). The reaction mixture is heated at reflux for two hours. Once the reaction is over, the solvent is evaporated under reduced pressure and then, after the addition of water (10 ml), it is extracted with dichloromethane (2x1 Oml). The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. By preparative thin layer chromatography of the residue using dichloromethane: hexane 1: 1 as eluent, the desired products are obtained. From the first fraction, 1 - [(4- cyanophenyl) meti-3-benzyl-2, 1, 3-benzothiadiazin-4-one (30 mg, 12%) is isolated as a white solid. Mp: 45-47 ° C. 1 H NMR (CDCI3): δ 8.09 (dd, 1 H), 7.03 (dd, 1H), 7.52 (t, 1 H), 7.11-7.42 (m, 10H), 4.97 (s, 2H), 4.88 (s , 2H). " < 3 C NMR (CDCI3): δ 46.42, 55.19, 112.38, 121.27, 122.34, 126.66, 128.23, 128.44, 128.61, 129.11, 130.76, 132.51, 135.39, 139.30, 135.01, 139.40, 161.43. Analysis calculated for C22H17N3O3S: C , 65.51; H, 4.21; N, 10.41; S, 7.94. Found: C, 65.43; H, 4.00; N, 10.60; S, 7.74.

De la segunda fracción se aisla el 2,2-dióxido de 2,2-dióxido de 1 -f(4- cianofenil)metin-4-(benciloxi)-2.1.3-benzotiadiazina (4 mg, 2 %) como un sirupe. 1H RMN (CDCI3): δ 7.97 (d, 1 H), 6.84 (d, 1 H), 7.10 (t, 1 H), 7.30-7.65 (m, 10H), 5.24 (s, 2H), 5.50 (s, 2H). 13C RMN (CDCI3): δ 49.04, 71.05, 111.27, 115.35, 111.91 , 122.40, 127.47, 128.36, 128.86, 129.08, 132.79, 135.98, 140.98, 142.57, 165.76. Análisis calculado para C22H17N3O3S: C, 65,51 ; H, 4,21; N, 10,41 ; S, 7,94. Encontrado: C, 65,48; H, 4,27; N, 10,71 ; S, 7,63.From the second fraction, 2,2-dioxide of 2,2-dioxide of 1-f (4- cyanophenyl) metin-4- (benzyloxy) -2.1.3-benzothiadiazine (4 mg, 2%) is isolated as a sirupe . 1 H NMR (CDCI3): δ 7.97 (d, 1 H), 6.84 (d, 1 H), 7.10 (t, 1 H), 7.30-7.65 (m, 10H), 5.24 (s, 2H), 5.50 ( s, 2H). 13 C NMR (CDCI3): δ 49.04, 71.05, 111.27, 115.35, 111.91, 122.40, 127.47, 128.36, 128.86, 129.08, 132.79, 135.98, 140.98, 142.57, 165.76. Analysis calculated for C22H17N3O3S: C, 65.51; H, 4.21; N, 10.41; S, 7.94. Found: C, 65.48; H, 4.27; N, 10.71; S, 7.63.

Los siguientes compuestos, mostrados en las tablas 1 y 2 son representativos de los compuestos objeto de la invención y han sido preparados a partir de los métodos anteriormente descritos. Todos ellos han mostrado actividad antiviral a concentraciones menores de 25 mg.ml-1.The following compounds, shown in Tables 1 and 2 are representative of the compounds object of the invention and have been prepared. from the methods described above. All of them have shown antiviral activity at concentrations below 25 mg.ml -1 .

Figure imgf000017_0001
Figure imgf000017_0001

Tabla 2Table 2

Figure imgf000017_0002
(REGLA 26) c o
Figure imgf000017_0002
(RULE 26) co

OOR

O (0O (0

Figure imgf000018_0001
c o o
Figure imgf000018_0001
coo

Figure imgf000019_0001
Figure imgf000019_0001

HOJA DE SUSTITUCIÓN (REGLA 26) c oSUBSTITUTE SHEET (RULE 26) co

O CO

Figure imgf000020_0001
Or CO
Figure imgf000020_0001

J2 .Ω reJ2 .Ω re

HOJA DE SUSTITUCIÓN (REGLA 26) SUBSTITUTE SHEET (RULE 26)

Claims

5. Revindicaciones 5. Revindications 1. DERIVADOS DE DIÓXIDOS N,N- Y NX-DISUSTITUIDOS DE 1 ,2,6- TIADIAZINA FUSIONADAS Y PROCEDIMIENTO DE OBTENCIÓN, compuestos de fórmula general I:1. N, N- AND NX-DISPOSED DIOXID DERIVATIVES OF 1, 2,6- FUSIONED TIADIAZINE AND PROCEDURE FOR OBTAINING, compounds of general formula I:
Figure imgf000021_0001
donde:
Figure imgf000021_0001
where: R, R1, R2,R, R 1 , R 2 , R3, R4, R5 R6, R7, R8 y R9 son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, haloalquil, aril, -OR10, -S(O)t-R10, - N(R10)R11, -N(R1°)C(0)(R1°), -NO2, ciano, -C(O)R10, -C(O)OR10 Z. Z1. Z2 Z3, Z4, Z3 son elegidos independientemente entre el grupo consistente en -R 3 , R 4 , R5 R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (O) tR 10 , - N (R10) R 11 , -N (R1 °) C (0) (R 1 °), -NO 2 , cyano, -C (O) R 10 , -C (O) OR 10 Z. Z1. Z2 Z 3 , Z 4 , Z 3 are independently selected from the group consisting of - C(R10)(R11)-, -C(O)-, -O-, -C(=NR1°)-, -S(O)t-, N(R )- n, o, p, q, r y s son cero, o un número entero comprendido entre 1 y 5, teniendo en cuenta que n, o y p no pueden ser cero simultáneamente, y q, r y s no pueden ser cero simultáneamente, t es cero, uno ó dos. RiO y Rii son elegidos independientemente entre el grupo consistente en hidrógeno, alquil, arilC (R 10 ) (R 11 ) -, -C (O) -, -O-, -C (= NR1 °) -, -S (O) t-, N (R) - n, o, p, q, r and r are zero, or an integer between 1 and 5, taking into account that n, o and p cannot be zero simultaneously, and q, r and r cannot be zero simultaneously, t is zero, one or two. RiO and Rii are independently selected from the group consisting of hydrogen, alkyl, aryl X son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, =O, =S, -N(R10)R11, arilX are independently selected from the group consisting of hydrogen, halogen, alkyl, = O, = S, -N (R 10 ) R 11 , aryl A es un carbociclo o heterociclo fusionado opcionalmente sustituido de 5, 6 ó 7 miembros saturado o insaturado.A is an optionally substituted 5, 6 or 7 membered saturated or unsaturated carbocycle or heterocycle. 2. DERIVADOS DE DIÓXIDOS N,N- Y NX-DISUSTITUIDOS DE 1 ,2,6- TIADIAZINA FUSIONADAS Y PROCEDIMIENTO DE OBTENCIÓN, compuestos de fórmula general II:2. DERIVATIVES OF DIOXIDES N, N- AND NX-DISUSTITUTED OF 1, 2,6- TIADIAZINE FUSED AND PROCEDURE OF OBTAINING, compounds of general formula II:
Figure imgf000022_0001
donde:
Figure imgf000022_0001
where: R, R1, R2R, R 1 , R2 R3, R4, R5 R 3 , R 4 , R 5 R6, R7, Rδ y R9 son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, haloalquil, aril, -OR10, -S(O)t-R10, - N(R10)R11, -N(Ri°)C(O)(R10), -NO2, ciano, -C(O)R10, -C(O)OR10 R6, R7, Rδ and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (O) tR 10 , - N (R 10 ) R 11 , -N ( Ri °) C (O) (R 10 ), -NO 2 , cyano, -C (O) R 10 , -C (O) OR 10 Z. Z1. Z2 Z3, Z4, Z3 son elegidos independientemente entre el grupo consistente enZ. Z1. Z2 Z 3 , Z 4 , Z 3 are independently selected from the group consisting of C(R10)(R11)-, -C(O)-, -O-, -C(=NR10)-, -S(O)t-, N(R10)- n, o, p, q, r y s son cero, o un número entero comprendido entre 1 y 5, teniendo en cuenta que n, o y p no pueden ser cero simultáneamente, y q, r y s no pueden ser cero simultáneamente, t es cero, uno ó dos.C (R 10 ) (R 11 ) -, -C (O) -, -O-, -C (= NR 10 ) -, -S (O) t-, N (R 10 ) - n, o, p , q, rys are zero, or an integer between 1 and 5, taking into account that n, o and p cannot be zero simultaneously, and q, r and r cannot be zero simultaneously, t is zero, one or two. Rio y Riι Son elegidos independientemente entre el grupo consistente en hidrógeno, alquil, aril X son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, =O, =S, -N(R10)R1 1, aril A es un carbociclo o heterociclo fusionado opcionalmente sustituido de 5, 6 ó 7 miembros saturado o insaturado. Rio and Riι S on independently selected from the group consisting of hydrogen, alkyl, aryl X are independently selected from the group consisting of hydrogen, halogen, alkyl, = O, = S, -N (R 10 ) R 1 1 , aryl A it is an optionally substituted 5, 6 or 7 membered saturated or unsaturated carbocycle or heterocycle. 3. DERIVADOS DE DIÓXIDOS N,N- Y /V,X-DISUSTITUIDOS DE 1 ,2,6- TIADIAZINA FUSIONADAS Y PROCEDIMIENTO DE OBTENCIÓN, compuestos de fórmula general III:3. DERIVATIVES OF DIOXIDES N, N- Y / V, X-DISUSTITUTES OF 1, 2,6- TIADIAZINE FUSED AND PROCEDURE OF OBTAINING, compounds of general formula III:
Figure imgf000023_0001
donde:
Figure imgf000023_0001
where: R, R1, R2, R3, R4, R5 R6, R7, R8 y R9 son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, haloalquil, aril, -OR10, -S(O)t-R10, - N(R10)R11, -N(R10)C(O)(R10), -NO2, daño, -C(O)R10, -C(O)OR10 R, R 1 , R 2 , R 3 , R 4 , R 5 R6, R7, R8 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (O) tR 10 , - N (R 10 ) R 11 , -N (R 10 ) C ( O) (R 10 ), -NO 2 , damage, -C (O) R 10 , -C (O) OR 10 Z. Z1. Z2 Z3, Z4, Z3 son elegidos independientemente entre el grupo consistente en -Z. Z1. Z2 Z 3 , Z 4 , Z 3 are independently selected from the group consisting of - C(R10)(R11)-, -C(O)-, -O-, -C(=NR1°)-, -S(O)t-, N(R™)- n, o, p, q, r y s son cero, o un número entero comprendido entre 1 y 5, teniendo en cuenta que n, o y p no pueden ser cero simultáneamente, y q, r y s no pueden ser cero simultáneamente. t es cero, uno ó dos.C (R 10 ) (R 11 ) -, -C (O) -, -O-, -C (= NR1 °) -, -S (O) t-, N (R ™) - n, o, p , q, rys are zero, or an integer between 1 and 5, taking into account that n, o and p cannot be zero simultaneously, and q, r and r cannot be zero simultaneously. t is zero, one or two. RiO y Rii sor-| elegidos independientemente entre el grupo consistente en hidrógeno, alquil, arilRiO and Rii sor - | independently selected from the group consisting of hydrogen, alkyl, aryl X son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, =O, =S, -N(R10)R11, arilX are independently selected from the group consisting of hydrogen, halogen, alkyl, = O, = S, -N (R 10 ) R 11 , aryl A es un carbociclo o heterociclo fusionado opdonalmente sustituido deA is an optionally substituted fused carbocycle or heterocycle of 5, 6 ó 7 miembros saturado o insaturado.5, 6 or 7 members saturated or unsaturated. 4. Procedimiento de obtención de compuestos según reivindicaciones 1 y 2 caracterizado porque se preparan añadiendo un equivalente del compuesto de fórmula general (IV) a una soludón de un equivalente del compuesto de fórmula general (III) que tenga al menos un centro susceptible de ataque nucleófilo y un equivalente de base tipo hidruro sódico en un disolvente polar y aprótico tipo dimetilformamida para originar los compuestos de formula general (I) y (II) en proporciones dependientes de los sustituyentes X, Z, Z1,4. Procedure for obtaining compounds according to claims 1 and 2 characterized in that they are prepared by adding an equivalent of the compound of general formula (IV) to a soludon of an equivalent of the compound of general formula (III) having at least one center susceptible to attack nucleophile and a sodium hydride base equivalent in a polar and aprotic solvent dimethylformamide type to originate the compounds of general formula (I) and (II) in proportions dependent on the substituents X, Z, Z 1 , Z2, Z3, Z4 Z5, R, R1, R2, R3, R4- R5, R6, R7, R8 y R9 de los valores de n, o, p, q, r y s; se emplean en la separación y aislamiento de los productos de fórmula general (I) y (II) técnicas cromatográficas.Z 2 , Z 3 , Z 4 Z 5 , R, R 1 , R 2 , R 3 , R 4 - R 5 , R 6 , R 7 , R 8 and R 9 of the values of n, o, p, q , rys; they are used in the separation and isolation of the products of general formula (I) and (II) chromatographic techniques. 5. Procedimiento de obtención de compuestos según reivindicación 3, caracterizado porque se preparan primero añadiendo un equivalente del compuesto de fórmula general (IV) a una solución de un equivalente del compuesto de fórmula general (V)5. Process for obtaining compounds according to claim 3, characterized in that they are first prepared by adding an equivalent of compound of general formula (IV) to a solution of an equivalent of the compound of general formula (V)
Figure imgf000025_0001
Figure imgf000025_0001
 que tenga al menos dos centros susceptibles de ataque nudeófilo y un equivalente de base tipo bicarbonato sódico en un disolvente polar y prótico como agua para originar los compuestos de fórmula general (III); ocasionalmente, la reacción tiene que ser calentada al menos 12 horas; finalmente cuando la reacción se ha completado, los compuestos de fórmula general (III) se aislan por predpatación de la fase acuosa.having at least two centers susceptible to nudeophilic attack and a sodium bicarbonate base equivalent in a polar and protic solvent such as water to originate the compounds of general formula (III); occasionally, the reaction has to be heated for at least 12 hours; finally when the reaction is complete, the compounds of general formula (III) are isolated by predpatation of the aqueous phase. 6. Procedimiento de obtención del 2,2-dióxido de 1 ,3-dibencil-2,1 ,3- benzotiadiazin-4-ona y del 2,2-dióxido de 1-bencil-4-bencilox¡-2,1 ,3- benzotiadiazina, caracterizado por los siguientes pasos: Se disuelve el 2,2-dióxido de 2,1 ,3-benzotiadiazin^(1H,3H)-ona (398 mg, 2,0 mmol) en 20 mi de una solución acuosa de bicarbonato sódico saturada. A continuación, se añade un equivalente de cloruro de 4-clorofenilmetilo (603 mg, 2,0 mmol) y se mantiene a reflujo 2 horas. Se enfría hasta temperatura ambiente, y se lava con diclorometano (1x10 mi). La fase acuosa alcalina se enfría a -4 °C y el produdo buscado (2.2-dióxido de 1-í(4-clorofenil)metil1- 2.1.3-benzotiadiazin-4(3H)-ona) se aisla de esta fase por filtración, y se purifica por recristalización de tolueno/metanol (407 mg, 63 %) obteniéndose como un sólido cristalino blanco. P.f.: 285-287 °C. 1H RMN (DMSO-dβ): δ 7.86 (dd, 1H), 6.92 (t, 1 H), 6.75 (dd, 1 H), 7.30 (t, 1 H), 7.27-7.39 (m, 4H), 4.93 (s, 2H). 13C RMN (DMSO-d6): 846.51 , 114.54, 119.74, 120.64, 129.01 , 129.37, 129.52, 133.17, 137.05, 132.35, 142.30, 167.29. Análisis calculado para C14H11N2O3SCI : C, 52,11 ; H, 3,41 ; N, 8,68; S, 9,93. Encontrado: C, 52,34; H, 3,52; N, 8,47; S, 9,85. A una suspensión equimolecular de hidruro sódico en dimetilformamida (20 mi), se le añade el 2,2-dióxido de 1-[(4- clorofenil)metil]-2,1 ,3-benzotiadiazin-4(3H)-ona (100 mg, 0,3 mmol), y un equivalente y medio de bromuro de bencilo (77 mg, 0,4 mmol). La mezcla de reacción se calienta a reflujo durante dos horas. Una vez concluida la reacción, se evapora el disolvente a presión reducida y a continuación, tras adición de agua (10 mi), se extrae con diclorometano (2x1 Oml). La fase orgánica, se seca sobre sulfato sódico anhidro, y el disolvente se elimina a vacío. Por cromatografía circular centrífuga del residuo utilizando como eluyente diclorometano, se obtiene el producto buscado 2.2-dióxido de 1-f(4- clorofenil)metill-3-bencil-2.1.S-benzotiadiazin^-ona (35 mg, 29 %) como un si pe.6. Procedure for obtaining 2,2-dioxide of 1,3-dibenzyl-2,1, 3- benzothiadiazin-4-one and 2,2-dioxide of 1-benzyl-4-benzyloxy-2,1, 3- benzothiadiazine, characterized by the following steps: 2,2-3, 3-benzothiadiazin ^ (1H, 3H) -one (398 mg, 2.0 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous solution of saturated sodium bicarbonate. Next, an equivalent of 4-chlorophenylmethyl chloride (603 mg, 2.0 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and washed with dichloromethane (1x10 ml). The alkaline aqueous phase is cooled to -4 ° C and the desired product (2,2-1-yl (4-chlorophenyl) methyl1-2,1,3-benzothiadiazin-4 (3H) -one) is isolated from this phase by filtration. , and is purified by recrystallization from toluene / methanol (407 mg, 63%) to obtain a white crystalline solid. Mp: 285-287 ° C. 1 H NMR (DMSO-dβ): δ 7.86 (dd, 1H), 6.92 (t, 1 H), 6.75 (dd, 1 H), 7.30 (t, 1 H), 7.27-7.39 (m, 4H), 4.93 (s, 2H). 13 C NMR (DMSO-d 6 ): 846.51, 114.54, 119.74, 120.64, 129.01, 129.37, 129.52, 133.17, 137.05, 132.35, 142.30, 167.29. Analysis calculated for C14H11N2O3SCI: C, 52.11; H, 3.41; N, 8.68; S, 9.93. Found: C, 52.34; H, 3.52; N, 8.47; S, 9.85. To an equimolecular hydride suspension Sodium in dimethylformamide (20 ml), 1 - [(4-chlorophenyl) methyl] 2,2-dioxide, -2,1, 3-benzothiadiazin-4 (3 H) -one (100 mg, 0.3 mmol), and an equivalent and a half of benzyl bromide (77 mg, 0.4 mmol). The reaction mixture is heated at reflux for two hours. Once the reaction is over, the solvent is evaporated under reduced pressure and then, after the addition of water (10 ml), it is extracted with dichloromethane (2x1 Oml). The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. By centrifugal circular chromatography of the residue using dichloromethane as eluent, the desired product is obtained 2.2-dioxide of 1-f (4- chlorophenyl) methyl-3-benzyl-2.1.S-benzothiadiazin ^ -one (35 mg, 29%) as yes yes 7. Procedimiento de obtención del 2.2-dióxido de 1-f(4-cianofenil)metiπ-3-bencil- 2, 1 ,3-benzotiadiazin-4-ona y del 2,2-dióxido de 1-í(4-cianofenil)met¡π-4- (benciloxi)-2.1 ,3-benzotiadiazina caracterizado por los siguientes pasos:7. Procedure for obtaining 2.2-dioxide of 1-f (4-cyanophenyl) metiπ-3-benzyl-2, 1, 3-benzothiadiazin-4-one and 2,2-dioxide of 1-y (4-cyanophenyl) ) met¡π-4- (benzyloxy) -2.1, 3-benzothiadiazine characterized by the following steps: Se disuelve el 2,2-dióxido de 2,1,3-benzotiadiazin-4(1 H,3/- )-ona (500 mg, 2,5 mmol) en 20 mi de una solución acuosa de bicarbonato sódico saturada. A continuación, se añade un equivalente y medio de bromuro de 4- cianofenilmetilo (741 mg, 3,7 mmol) y se mantiene a reflujo 2 horas. Se enfría hasta temperatura ambiente, y la fase acuosa alcalina se extrae con acetato de etilo (10 x 10 mi). La fase orgánica se seca sobre sulfato sódico, y el disolvente se evapora a presión reducida para originar el producto buscado (2.2-dióxido de 1-f(4-cianofenil)metill-2.1.3-benzotiadiazin-4(3H)-ona). Se purifica por recristalización de tolueno/metanol (566 mg, 72 %) obteniéndose como un sólido cristalino blanco. P.f.: 298-300 °C, H RMN (DMSO-d6): δThe 2,2,3-benzothiadiazin-4 (1 H, 3 / -) -one (500 mg, 2.5 mmol) 2,2-dioxide is dissolved in 20 ml of an aqueous saturated sodium bicarbonate solution. Then, an equivalent and a half of 4- cyanophenylmethyl bromide (741 mg, 3.7 mmol) is added and refluxed for 2 hours. It is cooled to room temperature, and the alkaline aqueous phase is extracted with ethyl acetate (10 x 10 mL). The organic phase is dried over sodium sulfate, and the solvent is evaporated under reduced pressure to give rise to the desired product (2.2-1-f (4-cyanophenyl) methyl-2.1.3-benzothiadiazin-4 (3H) -one) . It is purified by recrystallization from toluene / methanol (566 mg, 72%) to obtain a white crystalline solid. Mp: 298-300 ° C, NMR H (DMSO-d 6 ): δ 7.87 (dd, 1H), 6.88 (t, 1 H), 6.66 (dd, 1 H), 7.25 (t, 1H), 7.58 (d, 2H?), 7.78 (d, 2H), 5.03 (s, 2H). 13C RMN (DMSO-d6): δ 46.28, 109.72, 119.42, 119.60, 113.47, 127.83, 128.92, 131.98, 132.30, 141.87, 144.01 , 165.67. Análisis calculado para C15H11N3O3S: C, 57,52; H, 3,51 ; N, 13,40; S, 10,23. Encontrado: C, 57,75; H, 3,21 ; N, 13,22; S, 10,09. A una suspensión equimolecular de hidruro sódico en dimetilformamida (20 mi), se le añade el 2,2-dióxido de 1-[(4-cianofenil)metil]-2,1 ,3-benzotiadiazin-4(3H)-ona (200 mg, 0,6 mmol), y un equivalente y medio de bromuro de bencilo (153 mg, 0,9 mmol). La mezcla de reacción se calienta a reflujo durante dos horas. Una vez concluida la reacción, se evapora el disolvente a presión reducida y a continuación, tras adición de agua (10 mi), se extrae con diclorometano (2x1 Oml). La fase orgánica, se seca sobre sulfato sódico anhidro, y el disolvente se elimina a vacío. Por cromatografía en capa fina preparativa del residuo utilizando como eluyente diclorometano:hexano 1 :1 , se obtienen los productos buscados. De la primera fracción se aisla el 2.2-dióxido de 1-IY4- cianofenil)met¡n-3-bencil-2.1.3-benzotiadiazin-4-ona (30 mg, 12 %) como un sóido blanco. P.f.: 45-47 °C. 1 H RMN (CDCI3): δ 8.09 (dd, 1 H), 7.03 (dd, 1 H),7.87 (dd, 1H), 6.88 (t, 1 H), 6.66 (dd, 1 H), 7.25 (t, 1H), 7.58 (d, 2H?), 7.78 (d, 2H), 5.03 (s, 2H ). 13 C NMR (DMSO-d 6 ): δ 46.28, 109.72, 119.42, 119.60, 113.47, 127.83, 128.92, 131.98, 132.30, 141.87, 144.01, 165.67. Analysis calculated for C15H11N3O3S: C, 57.52; H, 3.51; N, 13.40; S, 10.23. Found: C, 57.75; H, 3.21; N, 13.22; S, 10.09. To an equimolecular suspension of sodium hydride in dimethylformamide (20 ml), the 2,2-dioxide of 1 - [(4-cyanophenyl) methyl] -2,1, 3-benzothiadiazin-4 (3H) -one ( 200 mg, 0.6 mmol), and an equivalent and a half of benzyl bromide (153 mg, 0.9 mmol). The reaction mixture is heated at reflux for two hours. Once the reaction is over, the solvent is evaporated under reduced pressure and then, after the addition of water (10 ml), it is extracted with dichloromethane (2x1 Oml). The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. By preparative thin layer chromatography of the residue using dichloromethane: hexane 1: 1 as eluent, the desired products are obtained. 1-IY4-cyanophenyl) met-3-benzyl-2.1.3-benzothiadiazin-4-one (30 mg, 12%) is isolated from the first fraction as a white solid. Mp: 45-47 ° C. 1 H NMR (CDCI3): δ 8.09 (dd, 1 H), 7.03 (dd, 1 H), 7.52 (t, 1 H), 7.11-7.42 (m, 10H), 4.97 (s, 2H), 4.88 (s, 2H). 13C RMN (CDCI3): δ 46.42, 55.19, 112.38, 121.27, 122.34, 126.66, 128.23, 128.44, 128.61 , 129.11 , 130.76, 132.51 , 135.39, 139.30, 135.01 , 139.40, 161.43. Análisis calculado para C22H17N3O3S: C, 65,51 ; H, 4,21 ; N, 10,41 ; S, 7,94. Encontrado: C, 65,43; H, 4,00; N, 10,60; S, 7,74. De la segunda fracción se aisla el 2,2-dióxido de 2.2-dióxido de 1-r(4-cianofeniDmet¡π-4-(bencilox¡)-2.1.3- benzotiadiazina (4 mg, 2 %) como un si pe.7.52 (t, 1 H), 7.11-7.42 (m, 10H), 4.97 (s, 2H), 4.88 (s, 2H). 13 C NMR (CDCI3): δ 46.42, 55.19, 112.38, 121.27, 122.34, 126.66, 128.23, 128.44, 128.61, 129.11, 130.76, 132.51, 135.39, 139.30, 135.01, 139.40, 161.43. Analysis calculated for C22H17N3O3S: C, 65.51; H, 4.21; N, 10.41; S, 7.94. Found: C, 65.43; H, 4.00; N, 10.60; S, 7.74. From the second fraction, 2,2-dioxide of 2,2-dioxide of 1-r (4-cyanopheniDmet¡π-4- (benzyloxy) -2.1.3-benzothiadiazine (4 mg, 2%) is isolated as a pe . 8. Uso de los compuestos según reivindicaciones 1 , 2 y 3 en el tratamiento de infecciones virales oportunistas, especialmente las producidas por citomegalovirus o virus de tipo varicela zoster. 8. Use of the compounds according to claims 1, 2 and 3 in the treatment of opportunistic viral infections, especially those produced by cytomegalovirus or varicella zoster virus. REIVINDICACIONES MODIFICADASMODIFIED CLAIMS [recibidas por la O icina International el 16 de octubre de 2000 (16.10.00); reivindicación 1 modificada; otras reivindicaciones no cambian (3 páginas)] 5. Reivindicaciones[received by the International Office on October 16, 2000 (16.10.00); modified claim 1; other claims do not change (3 pages)] 5. Claims 1. DERIVADOS DE DIÓXIDOS N,N- Y NX-DISUSTITUIDOS DE 1 ,2,6-1. DERIVATIVES OF N, N- AND NX-DISPOSED DIOXIDES OF 1, 2,6- TIADIAZINA FUSIONADAS Y PROCEDIMIENTO DE OBTENCIÓN, compuestos de fórmula general I:FUSIONATED TIADIAZINE AND OBTAINING PROCEDURE, compounds of general formula I:
Figure imgf000028_0001
Figure imgf000028_0001
 donde:where: R, R , R ,R, R, R, R3, R4, R5,R 3 , R 4 , R 5 , R6, R7, R8 y R9 son elegidos independientemente entre el grupo consistente en hidrógeno, halógeno, alquil, haloalquil, aril, -OR10, -S(O)t-R10, - N(R10)R11, -N(R10)C(O)(R10), -NO2, ciano, -C(O)R10, -C(0)OR1° z, z1, z2 R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (O) t -R 10 , - N (R 10 ) R 11 , -N (R 10 ) C (O) (R 10 ), -NO 2 , cyano, -C (O) R 10 , -C (0) OR 1 ° z, z 1 , z 2 Z3, Z4, Z5 son elegidos independientemente entre el grupo consistente en - C(R10) (R11)-, -C(O)-, -C(=NR10)-, -S(O)r, N(R10)- n, o, p, q, r y s son cero, o un número entero comprendido entre 1 y 5, teniendo en cuenta que n, o y p no pueden ser cero simultáneamente, y q, r y s no pueden ser cero simultáneamente. t es cero, uno ó dos. RiO y RH son elegidos independientemente entre el gmpo consistente en hidrógeno, alquil, aril X son elegidos independientemente entre el gmpo consistente en hidrógeno, halógeno, alquil, =O, =S, -N(R10)R11, aril A es un carboddo o heterociclo fusionado opcionalmente sustituido deZ 3 , Z 4 , Z 5 are independently selected from the group consisting of - C (R 10 ) (R 11 ) -, -C (O) -, -C (= NR 10 ) -, -S (O) r , N (R 10 ) - n, o, p, q, rys are zero, or an integer between 1 and 5, taking into account that n, oyp cannot be zero simultaneously, and q, rys cannot be zero simultaneously . t is zero, one or two. RiO and RH are independently selected from the group consisting of hydrogen, alkyl, aryl X are independently selected from the group consisting of hydrogen, halogen, alkyl, = O, = S, -N (R 10 ) R 11 , aryl A is a optionally substituted carboddo or fused heterocycle of 5, 6 ó 7 miembros saturado o insaturado.5, 6 or 7 members saturated or unsaturated. 2. DERIVADOS DE DIÓXIDOS N,N- Y NX-DISUSTITUIDOS DE 1 ,2,6- TIADIAZINA FUSIONADAS Y PROCEDIMIENTO DE OBTENCIÓN, compuestos de fórmula general II:2. DERIVATIVES OF DIOXIDES N, N- AND NX-DISUSTITUTED OF 1, 2,6- TIADIAZINE FUSED AND PROCEDURE OF OBTAINING, compounds of general formula II:
Figure imgf000029_0001
donde:
Figure imgf000029_0001
where: R, R1, R2, R3 R4, R5R, R 1 , R 2 , R 3 R 4 , R5 R6, R7, R8 y R9 son elegidos independientemente entre el gmpo consistente en hidrógeno, halógeno, alquil, haloalquil, aril, -OR10, -S(O)t-R10, - N(R10)R11, -N(R10)C(O)(R10), -NO2, daño, -C(O)R10, -C(O)OR10 R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, aryl, -OR 10 , -S (O) tR 10 , - N (R10) R11, -N (R10) C (O) (R 10 ), -NO 2 , damage, -C (O) R 10 , -C (O) OR 10 Z, Z1, Z2 Z, Z1, Z 2
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