CA2096239A1 - Use of 2h-1,2,4-benzothiadiazine-3(4h)-thione 1,1-dioxides as antiviral medicaments - Google Patents
Use of 2h-1,2,4-benzothiadiazine-3(4h)-thione 1,1-dioxides as antiviral medicamentsInfo
- Publication number
- CA2096239A1 CA2096239A1 CA002096239A CA2096239A CA2096239A1 CA 2096239 A1 CA2096239 A1 CA 2096239A1 CA 002096239 A CA002096239 A CA 002096239A CA 2096239 A CA2096239 A CA 2096239A CA 2096239 A1 CA2096239 A1 CA 2096239A1
- Authority
- CA
- Canada
- Prior art keywords
- thione
- benzothiadiazine
- alkyl
- radical
- dioxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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
- A61K31/33—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
-
- 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
-
- 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
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
Abstract
Summary ABSTRACT
The invention concerns the new use of compounds of the formula I
The invention concerns the new use of compounds of the formula I
Description
Use of 2H-1~2 4-benzothiadiazine-3(4~)-thione 1,1-dioxides ac antiviral medicaments The subject of the present invention iE the new use of 2H-1,2,4-benzothiadiazine-3(4H)-thione 1,1-dioxidec 8S antiviral medicamentc.
In the Application JP 60 97,970 is described, inter alia, 2-propyl-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide with antifungal action.
6-Chloro-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide is used in U.S. 3,838,119 as starting material for the preparation of dihydrofurano-~2't3':4,57thiazolo/2,2-c7-/I,2,47benzothiadiazine derivatives.
Furthermore, 2-(2-methylphenyl)-2H-1,2,4-benzo-thiadiazine-3(4H)-thione l,l-dioxide is known from the Application Fr. M4279 with tranqillising, h~pnotic and hyp~ten~ive action.
In further publications, for this substance clAss could be demonstrated a cardiovascular action ((Phsrmazie, 43, 37, 1988), sn anti-inflammatory activity (Pharmazie, 44, 601, 1989, Boll. Chim.
Farm., 126, 239, 1987), an anti-hypertensive and possible diabetogenic action (Arzneimittelforschung 31, 279, 1981) and anti-microbial properties (Farmaco, Ed. Sci., 34, 189, 1979; ditto, 34, 81, 1979; ditto, 411, 1973; ditto, 27, 990, 1972;
ditto, 38, 366, 1983).
~ he s~nthesis of this substance cl~ss i~
described inter eli~ in Fsrmaco, Ed. Sci , 38, 466, 1983 snd in J. Med. Chem. ~, 524, 1976.
The present invention concerns the new use of compounds of the genersl formuls I, O~ ~O
_ Z~ ,Rl in which Rl signif~es a h~drogen stom, 8 Cl-C6-slk~l rsdicsl or a phen~l radicsl possibl~ substit-uted b~ Cl-C6-alkgl, R2 ~ R4 sre the ssme or different snd, independentl~ of one ~nother, signif~ a h~drogen or hslogen stom, e Cl-C6-alk~l, Cl-C6-slkox~, -trifluorometh~l or sminosulphon~l radicel snd R ~
h~drogen etom, 8 C~-C6-alk~l or phen~l-Cl-C6-slk~l group, or of their t~utomers for the prepsration of medicaments for the treatment of virel or retrovirsl infections~
The "Cl-C6-alk~l parts" in the definition of the slk~l or slkox~ groups can be straight-cheined or brsnched, such 89 e.g. the methyl, eth~l, isoprop~l, n-butJl, isobut~l or hex~l group.
Halogen signifies fluorine, chlorine, bromine or iodine, prefersbl7 chlorine or bromine Phen~l-C}-C6-elk~l groups sre, for exsmple, the benz~l or phen~leth~l group~
In the Application JP 60 97,970 is described, inter alia, 2-propyl-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide with antifungal action.
6-Chloro-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide is used in U.S. 3,838,119 as starting material for the preparation of dihydrofurano-~2't3':4,57thiazolo/2,2-c7-/I,2,47benzothiadiazine derivatives.
Furthermore, 2-(2-methylphenyl)-2H-1,2,4-benzo-thiadiazine-3(4H)-thione l,l-dioxide is known from the Application Fr. M4279 with tranqillising, h~pnotic and hyp~ten~ive action.
In further publications, for this substance clAss could be demonstrated a cardiovascular action ((Phsrmazie, 43, 37, 1988), sn anti-inflammatory activity (Pharmazie, 44, 601, 1989, Boll. Chim.
Farm., 126, 239, 1987), an anti-hypertensive and possible diabetogenic action (Arzneimittelforschung 31, 279, 1981) and anti-microbial properties (Farmaco, Ed. Sci., 34, 189, 1979; ditto, 34, 81, 1979; ditto, 411, 1973; ditto, 27, 990, 1972;
ditto, 38, 366, 1983).
~ he s~nthesis of this substance cl~ss i~
described inter eli~ in Fsrmaco, Ed. Sci , 38, 466, 1983 snd in J. Med. Chem. ~, 524, 1976.
The present invention concerns the new use of compounds of the genersl formuls I, O~ ~O
_ Z~ ,Rl in which Rl signif~es a h~drogen stom, 8 Cl-C6-slk~l rsdicsl or a phen~l radicsl possibl~ substit-uted b~ Cl-C6-alkgl, R2 ~ R4 sre the ssme or different snd, independentl~ of one ~nother, signif~ a h~drogen or hslogen stom, e Cl-C6-alk~l, Cl-C6-slkox~, -trifluorometh~l or sminosulphon~l radicel snd R ~
h~drogen etom, 8 C~-C6-alk~l or phen~l-Cl-C6-slk~l group, or of their t~utomers for the prepsration of medicaments for the treatment of virel or retrovirsl infections~
The "Cl-C6-alk~l parts" in the definition of the slk~l or slkox~ groups can be straight-cheined or brsnched, such 89 e.g. the methyl, eth~l, isoprop~l, n-butJl, isobut~l or hex~l group.
Halogen signifies fluorine, chlorine, bromine or iodine, prefersbl7 chlorine or bromine Phen~l-C}-C6-elk~l groups sre, for exsmple, the benz~l or phen~leth~l group~
In psrticulsr, for the prepsrstion of medi-csments with sntiviral or anti-retrovirsl action, those compounds sre u~ed of the formuls II
0~ 0 ~4~ ~ ~N~ ~1 3 ~ N ~ S (II) in which Rl signifies 8 h~drogen stom, 8 Cl-C3-slk~l radical or a 2-meth~lphen~l rsdical, R2 8 h~drogen, chlorine or bromine atom, R3 8 h~drogen, chlorine or bromine atom or 8 methox~, meth~l or trifluorometh~l radicsl and R4 8 h~drogen,. chlorine or bromine atom or sn sminosulphonJl rsdicsl, Surprisingl~, it hss now been found that these 2~ 2,4-benzothiszine-3(4H.)_thione l,l-dioxide~
displs~ sn out~tsnding sntiviral sction snd sret therefore, especiall~ well suited for the trestment o~ virsl or retroviral infections. ~irsl infections of msmmals, especisllJ of humsns, are ver~ wide spresd. In spite of intensive endeavours, hitherto it hss not been possible to mske svsilable chemo-therspeutics which interfere csusativel~ or sJmptomsticsllJ with occursnces of disea~es caused virsll~ or retrovirsllJ with recognisable succes~.
At present, it i9 not possible to cure or chemo-therspeuticsll~ to influence fsvourabl~ the s~mptoms Or certsin viral diseases, such 0~ for ~xsmple the acquired immune deficiency s~ndrome (AIDS), the AIDS-related complex (ARC) and their preliminar~
steges, herpes, c~tomegslovirus (CMV), influenza snd other viral infections. At pre~ent, for exsmple, for the treatment of AIDS, there is almost exclusivel~
svailable 3'-ezido-3'-deox~th~midine (AZ~), known as zidovudine or Retrovir R~ ~owever, AZT i8 charscter-ised b~ e ver~ narrow therspeutic index or bg ver~
severe toxicities slread~ occurring in the thera-peutic rsnge (Hirsch, M.D (1988) J. Infect~ Dis.
157, 427-431). The compounds of the genersl formuls I
do not possess these disadvantages The~ act snti-virsll~ without being c~totoxic in phsrmscologicsll~
relevant doses.
~ he compounds of the formula I and II displs~
vsluable pharmacological properties In psrticular, the~ are suitable for the ther~p~ and proph~laxis of infections which sre csused b~ DNA viruses, such 89 e,g. the herpes simplex virus, the c~tomegslo-virus, papillomsviruses, the vsricells zoster virus or Epstein-Bsrr virus, or RNA viruses, such ss togaviruses, or especiallg retroviruses, such ss the oncoviruses HTLV-L snd II, as well ~8 the lenti-viruses visns and humsn immune deficiency virusHIV-l snd -2.
The compound~ of the formula I snd II appear to be especisll~ suitsble for the trestment of the 2~96239 clinical manifeststions of the retrovirsl ~IV
infection in humans~ ~uch as the persistent, teneralised l~mphadenopath~ (PG~), the ~dvanc~d stage of the AIDS_related complex (ARC) and the clinicall~ complete manifestation of AIDS.
It could now be demonstrated that compounds of the general formula I and II inhibit the multi-plication of DNA or RNA viruses, respectivel~, st the stage of the virus-specific D~A or RNA
transcription, respectivel~. Via the inhibition of the enz~me reverse transcriptase, the substances can influence the multiplicstion of ~etroviru~e~
(cf. Proc. Natl. Acad. Sci. USA 83, l911t 1986 and Nature t- 325, 773, 1987).
Since a very great need exists for chemothera-peutics with interfere as specifically as possible with retrovirall~-cau~ed diseases or their s~mptoms without influencing tbe normall~ occurring n0tural bod~ function, the said compounds could be sdvant-ageousl~ uEed proph~lscticall~ or therspeuticall~ in the treatment of diseases in which a retroviral infection is of pathoph~siologica~ s~mptomatic or clinical relevance.
~he medicsments conta^ining compound~ of the formula I or II for the treatment of viral infections can be admini~tered enterall~ or parenterall~ in liquid or solid form. There hereb~ come into question the usual forms of administration, such a8 for ~7~
example tablets, capsules, coated tablets, ~rups, solutions Qr suspensions. As injection medium, wster is preferabl~ used which contains the sdditives usual in the case of injection solutions, such as stabilising agents, solubilising agents and buffers.
Such additives sre e.g. tartrate and citrate buffer, ethanol, complex formers, such as eth~lenediamine-tetraacetic acid and its non-toxic salt~ high molecular pol~mers, such as li~uid polgeth~lene oxide, for viscosit~ regulstion Liquid carrier materials for in~ection Eolutions must be sterile and are preferabl~ filled into ampoules. Solid carrier materials are, for example, starch, lactose, mannitol, meth~l cellulose, talc, highlg-dispersed silicic scids, high molecular fatt~ acids, such as stearic ecid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular pol~mers, such as pol~eth~lene gl~col~, etc. COm~ositions suitable for oral administration can, if desired, contain flavo~ring and sweetening materials.
~ he dosaging can depend upon variouE factors, such a8 mode of administration, species, age or individual Etate of health. The compoundE according to the invention are usuall~ administered in amounts of 0.1 - 100 mg, preferabl~ 0.2 - 8~ mg per dag and per kg of bod~ weight. It is preferred to divide up the daily dose into 2 - 5 admini~trations, whereb~
in the case of each administration 1 - 2 teblets with an active materisl content of 0.5 - 500 mg are given. The tablets can also be ret~rded, whereb~
the number of administrations per dag i9 reduced to 1 - ~. The active material content of the retsrded tablets can amount to 2 - 1000 mg, The active msterial csn also be given by continuous infusion, whereb~ the amounts of 5 - 1000 mg per da~ normallg suffice~
~or the production of the final forms of administration, the medicements produced according to per se known methods are individuall~ confectioned snd provided with the instruction (as 8 rule in the form of a package leaflet) that the~e medicsments are suitable for the treatment of viral or retro-viral infections.
~ he compounds of the general formuls I sccording to the invention csn be prepared according to instructions of the patent applications and ~itèr-ature references mentioned in the prior art.
In the mesning of the present invention, spartfrom the compounds possible b~ combination of all claims, the following mentioned derivatives especiall~ come into question.
1. 2-eth~1-2H-1,2-4-benzothiadiazine-3(4~)-thione l,l-dioxide, m.p. 143C
~9~.,23:g _9_ 2. 5-chloro-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 125-126C
3. 6-meth~1-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p~ 176-177C
4. 6-chloro-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 176-177C
0~ 0 ~4~ ~ ~N~ ~1 3 ~ N ~ S (II) in which Rl signifies 8 h~drogen stom, 8 Cl-C3-slk~l radical or a 2-meth~lphen~l rsdical, R2 8 h~drogen, chlorine or bromine atom, R3 8 h~drogen, chlorine or bromine atom or 8 methox~, meth~l or trifluorometh~l radicsl and R4 8 h~drogen,. chlorine or bromine atom or sn sminosulphonJl rsdicsl, Surprisingl~, it hss now been found that these 2~ 2,4-benzothiszine-3(4H.)_thione l,l-dioxide~
displs~ sn out~tsnding sntiviral sction snd sret therefore, especiall~ well suited for the trestment o~ virsl or retroviral infections. ~irsl infections of msmmals, especisllJ of humsns, are ver~ wide spresd. In spite of intensive endeavours, hitherto it hss not been possible to mske svsilable chemo-therspeutics which interfere csusativel~ or sJmptomsticsllJ with occursnces of disea~es caused virsll~ or retrovirsllJ with recognisable succes~.
At present, it i9 not possible to cure or chemo-therspeuticsll~ to influence fsvourabl~ the s~mptoms Or certsin viral diseases, such 0~ for ~xsmple the acquired immune deficiency s~ndrome (AIDS), the AIDS-related complex (ARC) and their preliminar~
steges, herpes, c~tomegslovirus (CMV), influenza snd other viral infections. At pre~ent, for exsmple, for the treatment of AIDS, there is almost exclusivel~
svailable 3'-ezido-3'-deox~th~midine (AZ~), known as zidovudine or Retrovir R~ ~owever, AZT i8 charscter-ised b~ e ver~ narrow therspeutic index or bg ver~
severe toxicities slread~ occurring in the thera-peutic rsnge (Hirsch, M.D (1988) J. Infect~ Dis.
157, 427-431). The compounds of the genersl formuls I
do not possess these disadvantages The~ act snti-virsll~ without being c~totoxic in phsrmscologicsll~
relevant doses.
~ he compounds of the formula I and II displs~
vsluable pharmacological properties In psrticular, the~ are suitable for the ther~p~ and proph~laxis of infections which sre csused b~ DNA viruses, such 89 e,g. the herpes simplex virus, the c~tomegslo-virus, papillomsviruses, the vsricells zoster virus or Epstein-Bsrr virus, or RNA viruses, such ss togaviruses, or especiallg retroviruses, such ss the oncoviruses HTLV-L snd II, as well ~8 the lenti-viruses visns and humsn immune deficiency virusHIV-l snd -2.
The compound~ of the formula I snd II appear to be especisll~ suitsble for the trestment of the 2~96239 clinical manifeststions of the retrovirsl ~IV
infection in humans~ ~uch as the persistent, teneralised l~mphadenopath~ (PG~), the ~dvanc~d stage of the AIDS_related complex (ARC) and the clinicall~ complete manifestation of AIDS.
It could now be demonstrated that compounds of the general formula I and II inhibit the multi-plication of DNA or RNA viruses, respectivel~, st the stage of the virus-specific D~A or RNA
transcription, respectivel~. Via the inhibition of the enz~me reverse transcriptase, the substances can influence the multiplicstion of ~etroviru~e~
(cf. Proc. Natl. Acad. Sci. USA 83, l911t 1986 and Nature t- 325, 773, 1987).
Since a very great need exists for chemothera-peutics with interfere as specifically as possible with retrovirall~-cau~ed diseases or their s~mptoms without influencing tbe normall~ occurring n0tural bod~ function, the said compounds could be sdvant-ageousl~ uEed proph~lscticall~ or therspeuticall~ in the treatment of diseases in which a retroviral infection is of pathoph~siologica~ s~mptomatic or clinical relevance.
~he medicsments conta^ining compound~ of the formula I or II for the treatment of viral infections can be admini~tered enterall~ or parenterall~ in liquid or solid form. There hereb~ come into question the usual forms of administration, such a8 for ~7~
example tablets, capsules, coated tablets, ~rups, solutions Qr suspensions. As injection medium, wster is preferabl~ used which contains the sdditives usual in the case of injection solutions, such as stabilising agents, solubilising agents and buffers.
Such additives sre e.g. tartrate and citrate buffer, ethanol, complex formers, such as eth~lenediamine-tetraacetic acid and its non-toxic salt~ high molecular pol~mers, such as li~uid polgeth~lene oxide, for viscosit~ regulstion Liquid carrier materials for in~ection Eolutions must be sterile and are preferabl~ filled into ampoules. Solid carrier materials are, for example, starch, lactose, mannitol, meth~l cellulose, talc, highlg-dispersed silicic scids, high molecular fatt~ acids, such as stearic ecid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular pol~mers, such as pol~eth~lene gl~col~, etc. COm~ositions suitable for oral administration can, if desired, contain flavo~ring and sweetening materials.
~ he dosaging can depend upon variouE factors, such a8 mode of administration, species, age or individual Etate of health. The compoundE according to the invention are usuall~ administered in amounts of 0.1 - 100 mg, preferabl~ 0.2 - 8~ mg per dag and per kg of bod~ weight. It is preferred to divide up the daily dose into 2 - 5 admini~trations, whereb~
in the case of each administration 1 - 2 teblets with an active materisl content of 0.5 - 500 mg are given. The tablets can also be ret~rded, whereb~
the number of administrations per dag i9 reduced to 1 - ~. The active material content of the retsrded tablets can amount to 2 - 1000 mg, The active msterial csn also be given by continuous infusion, whereb~ the amounts of 5 - 1000 mg per da~ normallg suffice~
~or the production of the final forms of administration, the medicements produced according to per se known methods are individuall~ confectioned snd provided with the instruction (as 8 rule in the form of a package leaflet) that the~e medicsments are suitable for the treatment of viral or retro-viral infections.
~ he compounds of the general formuls I sccording to the invention csn be prepared according to instructions of the patent applications and ~itèr-ature references mentioned in the prior art.
In the mesning of the present invention, spartfrom the compounds possible b~ combination of all claims, the following mentioned derivatives especiall~ come into question.
1. 2-eth~1-2H-1,2-4-benzothiadiazine-3(4~)-thione l,l-dioxide, m.p. 143C
~9~.,23:g _9_ 2. 5-chloro-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 125-126C
3. 6-meth~1-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p~ 176-177C
4. 6-chloro-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 176-177C
5. 6-methox~-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 172-173C
6, 5,7-dichlore-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide 7. 5,7-dibromo-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide 8, 7-chloro-2-eth~1-2H-1,2-4-benzothisdiazine-3(4H)-thione l,l-dioxide, m.p. 205-209C
9, 7-bromo-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide 10. 6-chloro-7-sulphonsmido-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide 11 6-trifluorometh~1-7-~ulphonamido-2-eth~1-2H-1,2-4-benzothiadiazine-3(4H)-thione l,l-dioxide 12. 2H-1,2,4-benzothiadiazine-3(4H)-thione 1,1-dioxide, m.p. 220C.
13. 2-meth~l-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 194C
14. 2-prop~1-2e-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide 15. 7-chloro-2-prop~1-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide 16. 2,6-dimethyl-2H-1,2,4-benzothisdiazine-3(4H)-thione l,l-dioxide 17. 5-chloro-2-prop~1-2H-1,2,4-benzothiadiazine-3(4~)-thione l,l-dioxide 18. 7-meth~l-2-eth~l-2~-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 172-177C
19. 5-meth~1-2-eth~1-2H-1,2,4-benzothiadiszine-3(4H)-thione l,l-dioxide, m.p. 167-171C
20~ 5-methox~-2-eth~1-2H-1,2,4-benzothisdiazine-3(4H)-thione l,l-dioxide, m.p. 173-174C
21~ 2-isoprop~1-2H-1,2,4-benzothiadiazine-3(4H)-thione l~l-dioxide, m.p; 161C
22, 2-phen~1-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 210-211C
15 23. 2-isobut~1-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 145-146C
24. 8-methox~-2-eth~1-2H-1,2,4-benzothisdiazine-3(4H)-thione l,l-dioxide, m.p. 198-200C
25. 2-ethyl-4-benzyl-ZH-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 100-103C.
RT test The screening teett system contain~ the purified R~ (rever~ transcriptass) from HIV-l, which W8~
expressed by gene technological methods in E. coli, as well a9 the components of the initiation complex, such a~ the in vitro trsnscripts of the HIV-LTR's with the neighbouring primer binding site a9 templste and an 18mer oligonucleotide ss primer --` 2096~
complementar~ to the primer binding ~ite. The 3H7-th~midine-5'-triphoFphate incorporstion ws~
meaRu~ed b~ counting 1~ e.~-counter.
Results inhibition of the HIV-RT
sub~tance IC50 ~ M~
2-eth~1-2H-1,2,4-benzothiadiazine- 8.3 x 10 6 3(4H)-thione 1,1-dioxide 10 7-chloro-2-eth~1-2H_ 1,2,4-benzothis-1.6 x 10 6 diazine-3(4H)-thione l,l-dioxide _ 2-isoprop~l-2H-1,2,4-15 benzothiadiazine- -5 3(4H)-thione 1,1- 1.6 x 10 dioxide
15 23. 2-isobut~1-2H-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 145-146C
24. 8-methox~-2-eth~1-2H-1,2,4-benzothisdiazine-3(4H)-thione l,l-dioxide, m.p. 198-200C
25. 2-ethyl-4-benzyl-ZH-1,2,4-benzothiadiazine-3(4H)-thione l,l-dioxide, m.p. 100-103C.
RT test The screening teett system contain~ the purified R~ (rever~ transcriptass) from HIV-l, which W8~
expressed by gene technological methods in E. coli, as well a9 the components of the initiation complex, such a~ the in vitro trsnscripts of the HIV-LTR's with the neighbouring primer binding site a9 templste and an 18mer oligonucleotide ss primer --` 2096~
complementar~ to the primer binding ~ite. The 3H7-th~midine-5'-triphoFphate incorporstion ws~
meaRu~ed b~ counting 1~ e.~-counter.
Results inhibition of the HIV-RT
sub~tance IC50 ~ M~
2-eth~1-2H-1,2,4-benzothiadiazine- 8.3 x 10 6 3(4H)-thione 1,1-dioxide 10 7-chloro-2-eth~1-2H_ 1,2,4-benzothis-1.6 x 10 6 diazine-3(4H)-thione l,l-dioxide _ 2-isoprop~l-2H-1,2,4-15 benzothiadiazine- -5 3(4H)-thione 1,1- 1.6 x 10 dioxide
Claims (3)
1. Use of 2H-1,2,4-benzothiadiazine-3(4H)-thione 1,1-dioxides of the formula I
(I) , in which R1 signifies a hydrogen atom, a C1-C6-alkyl radical or a phenyl radical possibly substit-uted by C1-C6-alkyl, R2 - R4 are the same or different and, independently of one another, signify a hydrogen atom or halogen atom, a C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or amino-sulphonyl radical end R a hydrogen atom, a C1-C6-alkyl or phenyl-C1-C6-alkyl group, or of their tautomers for the production of medicaments for the treatment of viral or retroviral infections.
(I) , in which R1 signifies a hydrogen atom, a C1-C6-alkyl radical or a phenyl radical possibly substit-uted by C1-C6-alkyl, R2 - R4 are the same or different and, independently of one another, signify a hydrogen atom or halogen atom, a C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or amino-sulphonyl radical end R a hydrogen atom, a C1-C6-alkyl or phenyl-C1-C6-alkyl group, or of their tautomers for the production of medicaments for the treatment of viral or retroviral infections.
2. Use according to claim 1, characterised in that the 2H-1,2,4-benzothiadiazine-3(4H)-thione 1,1-dioxides correspond to the general formula II
(II) in which R1 signifies 8 hydrogen atom, a C1-C3-alkyl radical or a 2-methylphenyl radical, R2 a hydrogen, chlorine or bromine atom, R3 a hydrogen, chlorine or bromine atom or a methoxy, methyl or trifluoromethyl radical and R4 a hydrogen, chlorine or bromine atom or an aminosulphonyl radical.
(II) in which R1 signifies 8 hydrogen atom, a C1-C3-alkyl radical or a 2-methylphenyl radical, R2 a hydrogen, chlorine or bromine atom, R3 a hydrogen, chlorine or bromine atom or a methoxy, methyl or trifluoromethyl radical and R4 a hydrogen, chlorine or bromine atom or an aminosulphonyl radical.
3. Process for the production of medicaments containing at least one compound of the formula I or II according to claim 1 or 2, characterised in that one works up compounds of the formula I or II, respectively, to usual pharmaceutical forms of administration and provides these with the instruction for the treatment of viral or retroviral infections.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4036571A DE4036571A1 (en) | 1990-11-16 | 1990-11-16 | USE OF 2H-1,2,4-BENZOTHIADIAZIN-3 (4H) -THION-1,1-DIOXIDES AS ANTIVIRAL MEDICAMENTS |
| DEP4036571.9 | 1990-11-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2096239A1 true CA2096239A1 (en) | 1992-05-17 |
Family
ID=6418404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002096239A Abandoned CA2096239A1 (en) | 1990-11-16 | 1991-11-14 | Use of 2h-1,2,4-benzothiadiazine-3(4h)-thione 1,1-dioxides as antiviral medicaments |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0557336B1 (en) |
| JP (1) | JPH06502172A (en) |
| AT (1) | ATE121937T1 (en) |
| AU (1) | AU8873591A (en) |
| CA (1) | CA2096239A1 (en) |
| DE (2) | DE4036571A1 (en) |
| WO (1) | WO1992008462A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4135479A1 (en) * | 1991-10-28 | 1993-04-29 | Goedecke Ag | MEDICINES FOR TREATING AIDS |
-
1990
- 1990-11-16 DE DE4036571A patent/DE4036571A1/en not_active Withdrawn
-
1991
- 1991-11-14 DE DE59105404T patent/DE59105404D1/en not_active Expired - Fee Related
- 1991-11-14 AU AU88735/91A patent/AU8873591A/en not_active Abandoned
- 1991-11-14 EP EP91919694A patent/EP0557336B1/en not_active Expired - Lifetime
- 1991-11-14 JP JP3518155A patent/JPH06502172A/en active Pending
- 1991-11-14 CA CA002096239A patent/CA2096239A1/en not_active Abandoned
- 1991-11-14 AT AT91919694T patent/ATE121937T1/en not_active IP Right Cessation
- 1991-11-14 WO PCT/EP1991/002146 patent/WO1992008462A1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06502172A (en) | 1994-03-10 |
| EP0557336A1 (en) | 1993-09-01 |
| ATE121937T1 (en) | 1995-05-15 |
| EP0557336B1 (en) | 1995-05-03 |
| DE4036571A1 (en) | 1992-05-21 |
| AU8873591A (en) | 1992-06-11 |
| DE59105404D1 (en) | 1995-06-08 |
| WO1992008462A1 (en) | 1992-05-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |