WO1994024109A1 - Derives d'indazole et medicaments antiviraux contenant ces derives - Google Patents

Derives d'indazole et medicaments antiviraux contenant ces derives Download PDF

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Publication number
WO1994024109A1
WO1994024109A1 PCT/EP1994/001094 EP9401094W WO9424109A1 WO 1994024109 A1 WO1994024109 A1 WO 1994024109A1 EP 9401094 W EP9401094 W EP 9401094W WO 9424109 A1 WO9424109 A1 WO 9424109A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
halogen
ring
alkylamino
Prior art date
Application number
PCT/EP1994/001094
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German (de)
English (en)
Inventor
Alfred Mertens
Bernhard König
Ulrike Leser
Original Assignee
Boehringer Mannheim Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to AU65663/94A priority Critical patent/AU6566394A/en
Publication of WO1994024109A1 publication Critical patent/WO1994024109A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to new indazole derivatives of the formula I, processes for their preparation and medicaments which contain these compounds.
  • the invention also relates to the use of indazole derivatives for the production of medicaments with antiviral activity.
  • the invention relates to indazole derivatives of the formula I.
  • R denotes a phenyl ring or a mono-, bi- or tricyclic carbocyclic ring with 7-15 C atoms or a heterocyclic mono-, bi- or tricyclic ring system with 5 or 6 ring atoms each and 1-4 or 1 per ring system -5 heteroatoms may be present, the heteroatoms being nitrogen, sulfur or oxygen, and the aforementioned phenyl rings, the mono-, bi- or tricyclic carbocyclic rings or the heterocyclic mono-, bi- or tricyclic ring systems, if appropriate or are substituted several times by C _.- Cg-alkyl, C1-C5-alkoxy, C _.- Cg-alkylmercapto, amino, C -.- Cg-alkylamino, di-C ⁇ -Cg-alkylamino, C _, - Cg- Alkylcarbonylamino, hydroxy, nitro, halogen, trifluoromethyl or azido, R
  • R 2 is Cf-Cg-alkyl, C 2 -Cg-alkenyl, C 4 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl meaning, the above-mentioned alkyl or alkenyl radicals optionally being substituted with fluorine, chlorine, hydroxy and mercapto or can be interrupted by an oxygen or sulfur atom,
  • X represents an oxygen or sulfur atom and i Y represents a nitrogen atom or CR,
  • R is not an unsubstituted phenyl ring or a 3-trifluorophenyl ring if R is a C 1 -C 6 -alkyl group which may be substituted by halogen,
  • the present invention relates to indazole derivatives of the formula I for the production of medicaments for the treatment of viral or retroviral infections or the diseases caused by these infections, where R in addition to the meanings mentioned above also has an unsubstituted phenyl ring or
  • R 2 denotes a 3-trifluoromethylphenyl ring when R represents a C 1 -C 3 -alkyl group which can be substituted by halogen.
  • Indazoles of the formula I in which R is an unsubstituted phenyl ring or a 3-trifluoromethylphenyl ring and R is a C 1 -C 3 -alkyl group which can be substituted by halogen are already known from the prior art.
  • Japanese patent application JP 8245157 describes indazoles with an antithrombotic effect. Anti-allergic activity is attributed to indazoles in German patent application DE 3132916. The synthesis of some indazole derivatives will be in Boll. Chim. Farm. 107, 598, 1968. However, no antiviral activity of indazoles of the formula I has been demonstrated to date.
  • the object of the present invention was to provide new indazole derivatives and to find a further use for the previously known indazole derivatives in the pharmaceutical industry.
  • the indazole derivatives of the formula I have valuable pharmacological properties.
  • they have an antiviral effect and are suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and -2. They are also suitable for the treatment of diseases caused by viruses or retroviruses.
  • DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and
  • the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
  • PDL generalized lymphadenopathy
  • ARC advanced stage of the AIDS-related complex
  • the compounds of general formula I according to the invention have a pronounced antiviral effect and are particularly suitable for the treatment of viral or retroviral infections.
  • Viral infections in mammals, especially humans, are common.
  • chemotherapeutic agents which cause causally or symptomatically interfering with the viral or retroviral-related illness with recognizable substantial success.
  • AIDS Acquired Immune Deficiency Syndrome
  • ARC AIDS-related complex
  • CMV cytomegalovirus
  • AZT 3'-azido-3'-deoxy-thymidine
  • zidovudine or retrovir 3'-azido-3'-deoxy-thymidine
  • AZT is almost exclusively available for the treatment of AIDS.
  • AZT is through one very narrow therapeutic range or characterized by very severe toxicities already occurring in the therapeutic field (Hirsch, MS (1988) J.Infec.Dis. 157, 427-431).
  • the compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.
  • the compounds mentioned can advantageously be used prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.
  • the separation of the racemates into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases using common eluents.
  • Suitable optically active phases are, for example, optically active polyacrylamides or polymethacrylamides, some also on silica gel (e.g. ChiraSpher - 'from Merck, Chiralpak ⁇ R ⁇ OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel ( R OB / OY from Baker / Daicel), phases based on cyclodextrin or crown ether (e.g. Crownpak '' from Daicel) or microcrystalline cellulose triacetate (Merck).
  • silica gel e.g. ChiraSpher - 'from Merck, Chiralpak ⁇ R ⁇ OT / OP from Baker
  • cellulose esters / carbamates e.g. Chiracel ( R OB / OY from Baker / Daicel
  • phases based on cyclodextrin or crown ether e.g. Crownpak '' from Daicel
  • a carbocyclic ring R with 7-15 C atoms can be mono-, bi- or tricyclic and have 5 or 6 C atoms per ring.
  • This ring can be saturated, unsaturated, partially saturated or aromatic.
  • the following ring systems may be mentioned by way of example: the naphthyl, anthracenyl, phenanthrenyl, flourenyl, Indenyl, acenaphthylenyl, norbomyl, adamantyl ring or a C 3 -C cycloalkyl or C ⁇ -Cg cycloalkenyl group.
  • the carbocyclic ring can moreover be mono- or disubstituted, it being possible for the substituents to be, independently of one another, preferably in the o- or m-position.
  • the heterocyclic mono-, bi- or tricyclic ring systems of the radical R contain 5 or 6 carbon atoms per ring, it being possible for 1-4 or 1-5 C atoms to be replaced by the heteroatoms oxygen, sulfur and / or nitrogen.
  • the ring systems can be aromatic, partially or completely hydrogenated.
  • ring systems may be mentioned by way of example: the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazane, Furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzothiazole, indazole, benzimidazole, benzotriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene , Carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system, where the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated.
  • R is preferably unsubstituted phenyl or phenyl mono- or disubstituted by C_ j -CG alkyl, C_-Cg alkoxy, C j -CG-alkylmercapto, Ci-CSS alkyl amino, C j -CG-dialkylamino, C j -Cg-alkylcarbonylamino, amino, hydroxyl, nitro, azido, trifluoromethyl or halogen, the abovementioned aliphatic radicals preferably containing up to 3 carbon atoms.
  • Carbocyclic rings R are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthrenyl, norbomyl, adamantyl, Cs-Cß-cycloalkyl, Cc-Cg-cycloalkenyl, where the carbocyclic rings can be mono- or disubstituted by C_ .-Cg-alkyl, C _.- Cg-A.koxy, C _.- Cg-alkylmercapto, C j- Cg-alkylamino, C- j- Cg-dialkylamino-, C ⁇ Cg-alkylcarbonylamino, amino, hydroxy, nitro, Azido, trifluoromethyl or halogen, the aforementioned aliphatic radicals preferably containing up to 3 carbon atoms.
  • Heterocyclic ring systems R are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaph- then, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine, where the heterocyclic rings can be mono- or disubstituted by C.-Cg-alkyl, C ⁇ -Cg-alkoxy, C.-Cg-alkylmercapto , C j -Cg alkylamino, C j -Cg dialkylamino, C ⁇ -Cg alkylcarbonylamino, amino, hydroxy, nitro, azido, trifluoromethyl or halogen, the aforementioned radicals preferably containing
  • radical R is hydrogen, Cj-Cg-alkyl, C 2 -Cg-alkenyl, C 2 -Cg-alkynyl, C_
  • R Preferred substituents for R are C j -Cg-alkyl, C.-Cg-hydroxyalkyl.
  • X is preferably oxygen.
  • Halogen generally means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Y is preferably a nitrogen atom or the group CH.
  • radicals for R are phenyl, by C _.- C 3 alkyl, C ⁇ -C 3 alkoxy, C.
  • R is particularly preferably hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethylmercapto, methylamino, methoxycarbonyl, Ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, chlorine and bromine being preferred for halogen.
  • R, X and Y have the meaning given above and R is methyl or ethyl.
  • the medicaments contain at least one compound of the formula I for the treatment of viral infections and can be administered in liquid or solid form enterally or parenterally.
  • the usual forms of application are possible, such as tablets, capsules, dragees, syrups, solutions or suspensions.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers.
  • additives are e.g. Tartrate and citrate buffers, ethanol, complexing agents, such as ethylene diamine tetraacetic acid and its non-toxic salts, high molecular weight polymers, such as liquid polyethylene oxide for viscosity regulation.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers, such as polyethylene glycols, etc.
  • Preparations suitable for oral applications can, if desired, contain flavorings or sweeteners.
  • the dosage can depend on various factors, such as the mode of administration, species, age or individual condition.
  • the compounds of the invention are usually administered in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 tablets with an active ingredient content of 0.5-500 mg being administered with each application.
  • the tablets can also be retarded, whereby the number of applications per day is reduced to 1-3.
  • the active substance content of the retarded tablets can be 2 - 1000 mg.
  • the active ingredient can also be given by continuous infusion, with the amounts of 5-1000 mg per day usually being sufficient.
  • the compounds of the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections.
  • these further drugs include agents that can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as S'-azido-S'desoxythymidine, 2 ⁇ 3'-dideoxynucleosides such as, for. B. 2 ⁇ 3'-dideoxycytidine, 2 ', 3'-dideoxyadenosine and 2', 3'-dideoxyinosine, acyclic nucleosides (e.g.
  • interferons such as alpha-interferon
  • renal excretion inhibitors such as probenicide
  • Nucleoside transport inhibitors such as dipyridamole
  • immunomodulators such as immunomodulators
  • B. Interleukin II or stimulation factors such as the granulocyte-macrophage colony factor.
  • the compounds of the present invention and the other medicament can each be administered individually, simultaneously, if appropriate in a single or two separate formulations or at different times.
  • R is a leaving group such as
  • Halogen and R is a hydrogen atom or an alkyl, benzyl or phenyl derivative, with a hydrazine derivative of the general formula V,
  • Hydrazone formation is advantageously carried out in a protic or aprotic solvent at temperatures between -50 ° C and the boiling point of the solvent, possibly with the addition of an acid, such as e.g. p-Toluoisutfonic acid, glacial acetic acid or hydrochloric acid.
  • an acid such as e.g. p-Toluoisutfonic acid, glacial acetic acid or hydrochloric acid.
  • the hydrazones are advantageously cyclized in protic solvents at temperatures between 20 ° C. and 250 ° C., if appropriate under pressure, with the addition of a base such as K ZO- * , pyridine or collidine in the presence of copper powder.
  • a base such as K ZO- * , pyridine or collidine in the presence of copper powder.
  • Compounds of the general formula I can also be subsequently converted into other compounds of the general formula I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés d'indazole de la formule (I), leur procédé de préparation et des médicaments qui contiennent lesdits composés. L'invention concerne tout particulièrement des dérivés d'indazole de la formule (I), dans laquelle R désigne un composé cyclique phényle ou un composé cyclique carbocyclique ayant 7 à 15 atomes de C ou une combinaison cyclique hétérocyclique, et où les composés cycliques précités sont éventuellement substitués par alkyle C1-C6, alcoxy C1-C6, alkylmercapto, amino, alkylamino C1-C6, dialkyle C1-C6-amino, alkylcarbonylamino, hydroxy, nitro, halogène, trifluorométhyle ou azido, R1 désigne un atome d'hydrogène, un reste aliphatique saturé ou insaturé à chaîne droite ou ramifiée, ayant 1-6 atomes de C, R2 désigne alkyle C¿1?-C8, alcényle C2-C8, cycloalkyle C4-C8, cycloalkényle C3-C8, X désigne un atome d'oxygène ou de soufre, Y désigne un atome d'azote ou CR?1¿, ainsi que leurs tautomères, énantiomères, diastéréoisomères et leurs sels physiologiquement tolérables.
PCT/EP1994/001094 1993-04-09 1994-04-08 Derives d'indazole et medicaments antiviraux contenant ces derives WO1994024109A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65663/94A AU6566394A (en) 1993-04-09 1994-04-08 Indazole derivatives and antiviral drugs that contain them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4311782.1 1993-04-09
DE19934311782 DE4311782A1 (de) 1993-04-09 1993-04-09 Indazol-Derivate und diese enthaltende Arzneimittel

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Publication Number Publication Date
WO1994024109A1 true WO1994024109A1 (fr) 1994-10-27

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DE (1) DE4311782A1 (fr)
WO (1) WO1994024109A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107082763A (zh) * 2016-02-15 2017-08-22 中山大学 一种合成吲唑酮类化合物的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4920128A (en) * 1987-07-08 1990-04-24 Sterling Drug Inc. Pyrazolo[3,4-b]quinolines and their use as antiviral agents
WO1992015310A1 (fr) * 1991-02-28 1992-09-17 Boehringer Mannheim Gmbh Utilisation d'iso-indolinones tricycliques comme medicaments antiviraux, et nouvelles iso-indolinones optiquement actives
WO1992016529A1 (fr) * 1991-03-25 1992-10-01 Boehringer Mannheim Gmbh Nouveaux derives d'isoindole et medicaments les contenant
WO1992016207A1 (fr) * 1991-03-15 1992-10-01 Boehringer Mannheim Gmbh UTILISATION DE DERIVES D'OXAZOLO-[2,3-a]ISOINDOLE ET D'IMIDAZO[2,1-a]-ISOINDOLE COMME MEDICAMENTS ANTIVIRAUX ET NOUVEAUX DERIVES D'OXAZOLO[2,3-a]ISOINDOLE
DE4129779A1 (de) * 1991-09-07 1993-03-11 Boehringer Mannheim Gmbh Neue tricyclische thiazol- und oxazol-derivate und diese enthaltende arzneimittel

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4920128A (en) * 1987-07-08 1990-04-24 Sterling Drug Inc. Pyrazolo[3,4-b]quinolines and their use as antiviral agents
WO1992015310A1 (fr) * 1991-02-28 1992-09-17 Boehringer Mannheim Gmbh Utilisation d'iso-indolinones tricycliques comme medicaments antiviraux, et nouvelles iso-indolinones optiquement actives
WO1992016207A1 (fr) * 1991-03-15 1992-10-01 Boehringer Mannheim Gmbh UTILISATION DE DERIVES D'OXAZOLO-[2,3-a]ISOINDOLE ET D'IMIDAZO[2,1-a]-ISOINDOLE COMME MEDICAMENTS ANTIVIRAUX ET NOUVEAUX DERIVES D'OXAZOLO[2,3-a]ISOINDOLE
WO1992016529A1 (fr) * 1991-03-25 1992-10-01 Boehringer Mannheim Gmbh Nouveaux derives d'isoindole et medicaments les contenant
DE4129779A1 (de) * 1991-09-07 1993-03-11 Boehringer Mannheim Gmbh Neue tricyclische thiazol- und oxazol-derivate und diese enthaltende arzneimittel

Non-Patent Citations (3)

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Title
CHEMICAL ABSTRACTS, vol. 84, no. 21, 24 May 1976, Columbus, Ohio, US; abstract no. 146100p, G.P. NILLES ET AL.: "Photochemistry of bioactive compounds. Multiphase photodegradation and mass spectral analysis of basagran." page 164; column 1; *
J. AGRIC. FOOD CHEM., vol. 23, no. 3, 1975, pages 410 - 415 *
W. SCHÄFER ET AL.: "Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase: Molecular Modeling and X-ray Structure Investigations", JOURNAL OF MEDICINAL CHEMISTRY, vol. 36, no. 6, 19 March 1993 (1993-03-19), WASHINGTON US, pages 726 - 732 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107082763A (zh) * 2016-02-15 2017-08-22 中山大学 一种合成吲唑酮类化合物的方法

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AU6566394A (en) 1994-11-08
DE4311782A1 (de) 1994-10-13

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