WO1993023405A1 - Utilisation de derives de pyrimidine tricycliques comme medicaments antiviraux - Google Patents

Utilisation de derives de pyrimidine tricycliques comme medicaments antiviraux Download PDF

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Publication number
WO1993023405A1
WO1993023405A1 PCT/EP1993/001124 EP9301124W WO9323405A1 WO 1993023405 A1 WO1993023405 A1 WO 1993023405A1 EP 9301124 W EP9301124 W EP 9301124W WO 9323405 A1 WO9323405 A1 WO 9323405A1
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WIPO (PCT)
Prior art keywords
phenyl
alkyl
alkylamino
ring
atoms
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PCT/EP1993/001124
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German (de)
English (en)
Inventor
Alfred Mertens
Harald Zilch
Bernhard König
Ulrike Leser
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Boehringer Mannheim Gmbh
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Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to EP93909920A priority Critical patent/EP0640087A1/fr
Priority to JP5519843A priority patent/JPH08500089A/ja
Publication of WO1993023405A1 publication Critical patent/WO1993023405A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • the present invention relates to the new use of tricyclic pyrimidine derivatives for the production of medicaments with an antiviral effect.
  • the invention also relates to new pyrimidine derivatives, processes for their preparation and medicaments which contain these compounds.
  • the invention relates to the use of tricyclic pyrimidine derivatives of the general formula I.
  • A is a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with max. 4 represents heteroatoms, where the heteroatoms can be the same or different and oxygen, nitrogen or sulfur mean, and the heterocycles can optionally carry an oxygen atom on one or more nitrogen atoms, and A is optionally substituted by one or more radicals R 1 , which can be identical or different,
  • Y can be an oxygen atom or the NH or Ci-Cs-alkylamino group
  • R is a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-9 C atoms, which can be substituted by phenyl, 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 1-5 heteroatoms per ring system may be contained, 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 system optionally being mono- or polysubstituted by Ci-Cg-alkyl, Ci-Cg-alkoxy, Ci-Cs-alkyl mercapto, Ci-Cg-alkylsulfinyl, Ci-Cg-alkylsulfonyl, C -C 6 alkenyl, C 2 -Cg alkynyl, C 2 -C6 -Alkenyloxy, C 2 -Cg-alkenylmercapto, C 2 -C
  • R, R 3 , R 4 and R 5 can, independently of one another, be the same or different and each represent hydrogen, Ci-C ß- alkyl, Ci-Cg-hydroxyalkyl, cyano, carboxy or Ci-Cg-alkoxycarbonyl, or R 2 and R 4 represent a further bond between the C atoms to which they are attached,
  • R 6 represents hydrogen or Ci-Cg-alkyl
  • n 0 or 1
  • examples 5C - 5F and 101 describe compounds of the formula I, where A is a chlorine atom substituted phenyl ring, R is a cyclopropyl, cyclopentyl or phenyl ring or a propyl group, X and Y are an oxygen atom, R 1 , R 2 , R 3 , R 5 and R 6 are a hydrogen atom and R 4 is a hydrogen atom or an isopropyl group.
  • Analgesic properties are ascribed to the compounds in the application DE 214 1616 and in the application US 3,329,679 compounds were found which act on the central nervous system.
  • the object of the present invention was to find a further medical indication for the compounds known from the prior art.
  • new tricyclic pyrimidine derivatives should be made available, which can be used in particular as active pharmaceutical ingredients for the production of pharmaceuticals.
  • the compounds of formula I have valuable pharmacological properties. They are particularly suitable for therapy and prophylaxis of infections caused by DNA viruses such as, for example, the herpes simplex virus, the cytomegalovirus, papillo a 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, and the lentiviruses Visna and human immunodeficiency virus HIV-1 and -2, are caused.
  • DNA viruses such as, for example, the herpes simplex virus, the cytomegalovirus, papillo a 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, and the lentiviruses Visna and human immunodeficiency virus HIV-1 and -2, are caused.
  • 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 persistent 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 retro-viral infections.
  • Viral infections in mammals, especially humans, are common.
  • Che otherapeutics which cause causally or symptomatically to interfere with the viral or retroviral-related illness with evidently substantial success.
  • AIDS Acguired Immune Deficiency Syndro
  • ARC AIDS-related complex
  • CMV cytomegalovirus
  • AZT 3 '-azido-3 ⁇ deoxy-thymidine
  • Zidovudine or Retrovir R 3 '-azido-3 ⁇ deoxy-thymidine
  • the compounds of general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses. It has now been demonstrated that compounds of general formula I inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription. The substances can influence the multiplication of retroviruses by inhibiting the multiplication of retroviruses by inhibiting the enzyme reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773 1987).
  • 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 compounds of formula I can exist as racemates or as optically active derivatives.
  • 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.
  • Optically active phases are, for example, optically active polyacrylics or polymethacrylamides, e.g. also on silica gel (e.g. ChiraSpher R 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 R from Daicel) or microcrystalline cellulose triacetate (Merck).
  • silica gel e.g. ChiraSpher R 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 R from Daicel
  • microcrystalline cellulose triacetate Merck
  • A denotes a carbocyclic ring, in particular a fused phenyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclopentadienyl ring.
  • the annealed aromatic heteroeyclic ring A has 5-6 carbon atoms, whereby up to 4 of these ring atoms can be replaced by the heteroatoms oxygen, sulfur and / or nitrogen.
  • heterocycles may be mentioned by way of example: the furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, pyrazole, imidazole, oxadiazole, triazole, pyridine, pyridazine, pyrimidine or pyrazine ring .
  • a nitrogen atom is present in the heterocyclic ring A, the corresponding heterocycles can also be present in the form of their N-oxides.
  • the ring A can be substituted by one or more, in particular by one or two, radicals R 1 , it being possible for the substituents to be identical or different.
  • An aliphatic radical R or R 1 denotes a straight-chain or branched alkyl, alkenyl or alkynyl radical with 1-9, preferably 2-7 carbon atoms, such as, for example, the propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or heptyl residue.
  • Possible unsaturated radicals are C 2 -C 7 alkenyl and alkynyl radicals, preferably C2-C5, such as, for example, the allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl radical.
  • An aliphatic radical R which may be substituted by phenyl is in particular a phenyl-Ci-Cg-alkyl group, such as e.g. the benzyl, phenethyl, phenylpropyl or phenylbutyl radical.
  • radicals R or R 1 contain a phenyl ring, this can be mono-, di- or trisubstituted.
  • the substituents can be in o-, - or p-pitch independently of one another.
  • 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, phenanthrhrenyl, flouryl, indenyl, indanyl, acenaphthylenyl, norbornyl, adamantyl ring or a C 3 -C 7 -cycloalkyl or C5-Cg-cycloalkenyl group .
  • the carbocyclic ring can also be mono- or disubstituted, where in the case of the phenyl rings the substituents can independently of one another preferably be 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, where 1-4 or 1-5 C atoms can 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.
  • heterocyclic rings contain a nitrogen atom
  • the corresponding heterocycles can also be in the form of their N-oxides.
  • the heterocyclic ring system can moreover be mono- or disubstituted, and the substituents can independently of one another preferably be in the o- or m-position.
  • R is preferably unsubstituted phenyl or phenyl mono- or disubstituted by C --_- Cg-alkyl, Ci-Cg-alkoxy, C- j _- Cg-alkylmercapto, C ⁇ -Cg-alkylsulfin ⁇ l, Ci-Cg-alkylsulfonyl, C 2 - Cg-alkenyl, C 2 -Cg-alkynyl, C 3 ⁇ C -alkenyloxy, Ci-Cg-alkylamino, Ci-Cg-dialkylamino-, Ci-Cg-alkylcarbonylamino, Ci-Cg-alkylaminocarbonyl, C-] _-Cg-alkoxycarbonyl, amino, hydroxyl, nitro, azido, trifluoromethyl, cyano or halogen, the abovementioned aliphatic radicals preferably containing up to 3 carbon atoms.
  • Carbocyclic rings R are preferably biphenyl, naphthyl, anthracenyl, indenyl, fluorenyl, acenaphthylenyl, phenanthanenyl, norbornyl, adamantyl, Cs-Cg-cycloalkyl, Cs-Cs-cycloalkenyl, where the carbocyclic rings can be mono- or disubstituted by C-j_-Cg-alkyl, Cj-Cg-alkoxy, C ** _- Cg-alkylmercapto, Ci-Cg-alkylsulfinyl, C1-C5-alkylsulfonyl, C 2 - Cg-alkenyl, C 2 -Cg-alkynyl, C 3 -C 4 alkenyloxy, C-j_-Cg-alkylamino, Cj-Cg-dialkylamino, Ci-Cg-alky
  • Heterocyclic ring systems R are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, cu aron, thionaphthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine can be mono- or disubstituted by C ⁇ -Cg-alkyl, C --_- Cg-alkoxy, Ci-Cg-alkylmercapto, Ci-Cg-alkylsulfinyl, Ci-Cg-alkylsulfonyl, C 2 -Cg-alkenyl, C 2 -C 6 -alkynyl, C 2 -Cg-alkenyloxy, Ci-Cg-alkylamino, Cx-C
  • R 1 is hydrogen, Ci-Cg-alkyl., C 2 -C4-alkenyl, c 2 ⁇ c 4 _A alkynyl, C --_- Cg-alkoxy, Ci-Cg-alkyl ercapto, Ci-Cg- Alkyl ⁇ amino, C -Cg-alkoxycarbonyl, amino, halogen, hydroxy, nitro, cyano and azido are preferred, the aliphatic radicals mentioned above preferably containing up to 3 carbon atoms.
  • R 2 , R 3 , R 4 and R 5 are hydrogen, C1-C 3 -alkyl, Ci-Cg-hydroxyalkyl, carboxy, C ⁇ .-Cg-alkoxycarbonyl and cyano or if R 2 and R 4 form an additional bond.
  • X and Y is preferably oxygen.
  • Halogen generally means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Aromatic rings are particularly suitable for A.
  • Preferred fused heterocycles A are aromatic nitrogen-containing rings with 5 or 6 ring atoms or the phenyl ring.
  • radicals for R are C 3 -C 5 -alkyl, C 2 -C 5 -alkenyl, C 2 -C 4 -alkynyl, benzyl, phenethyl, phenyl, by C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, c * L-Cg-alkylmercapto, allyl, allyloxy, c --_- Cg-alkylamino, di-C-j_-Cg-alkylamino, amino, hydroxy, azido, trifluoromethyl, cyano or halogen mono- or disubstituted phenyl or by methyl or Halogen trisubstituted phenyl, naphthyl, anthracenyl, indenyl, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, cyclohexen
  • R 1 hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethyl mercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen are particularly preferred, chlorine and bromine being very particular for halogen are preferred.
  • R 2 , R 3 , R 4 and R 5 hydrogen, methyl, ethyl, isopropyl and cyano are particularly preferred, two or three of the radicals R 2 -R 5 in particular representing a hydrogen atom.
  • R 2 and R 4 can preferably also mean a bond together.
  • A is the phenyl, pyrrole, pyrrole, oxazole, thiophene, furan, isoxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine and pyrazine ring.
  • R 1 substituent R 1 , in particular a halogen atom, on the nitrogen atom of the fused pyrimidine ring bonded directly to the six ring A in the para position of the six ring A (9 position of the tricyclic ring system).
  • R, R 1 , X and m have the meaning given above
  • R 2 , R 3 , R 4 and R 5 are hydrogen, methyl or ethyl
  • R 2 to R 5 preferably hydrogen or R 2 and R 4 additionally represent a bond.
  • R 6 hydrogen and C1-C 3 alkyl are particularly preferred. O is particularly preferred for m.
  • Compounds with a pronounced pharmacological activity are in particular those compounds of the formula I in which R represents a phenyl ring which is substituted in the meta position by Ci-Cg-alkyl, in particular by methyl or ethyl, and X represents a sulfur atom and R 1 represents a halogen atom.
  • the medicaments contain at least one compound of the formula I for the treatment of viral infections and can be administered enterally or parenterally in liquid or solid form.
  • pharmaceutical dosage forms 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, for example, tartrate and citrate buffers, ethanol, complexing agents such as ethylene diamine tetraacetic acid and their 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 silicas, 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 application, species, age or individual condition.
  • the compounds according to the invention are usually applied 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 applications with an active ingredient content of 0.5-500 mg being administered for each application.
  • the tablets can also be delayed, which reduces the number of applications per day 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, the amounts of 5-1000 mg per day being normally 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 medicaments include agents which can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3 ' deoxythymidine,' 2 •, 3 '-dides oxynucleosides such as, for. B. 2 *, 3'-dideoxycytidine, 2 ', 3 • -dideoxy-adenosine and 2 ⁇ , 3 ⁇ -dideoxyinosine, acyclic nucleosides (e.g. acyclovir).
  • the compounds of the present invention and the other medicament can each be administered individually, simultaneously, optionally in a single or two separate formulations or at different times, so that a synergistic effect is achieved.
  • R 8 and R 9 can be identical or different and can mean, for example, Ci-Cg-alkyl or substituted or unsubstituted phenyl, phenylalkyl, hetaryl or hetarylalkyl, with substituted or unsubstituted compounds of the general formula III
  • R 2 , R 3 , R 4 , R 5 and m have the meaning given, in a suitable inert solvent at room temperature to reflux temperature, possibly in the presence of catalytic amounts of acid, for example p-toluenesulfonic acid, or base, for example potassium hydroxide, and if appropriate subsequently thereafter Compounds of formula I subsequently converted into other compounds of formula I. and then purified by chromatography or by recrystallization. Racemates can be separated into the anti-pods by chromatography on suitable optically active phases, for example cellulose triacetate.
  • the compounds of general formula II used as starting material are obtained from acobenzophenone derivatives by acylation using processes known from the literature.
  • the substituted or unsubstituted 2-aminobenzophenone derivatives can advantageously be prepared by the processes described by David A. Walsh (Synthesis, 677, 1980).
  • Example 2 Analogously to Example 1, the title compound of mp. Is obtained from l-ethoxycarbonylamino-2- (4-methyl-2-pyridinoyl) benzene and 3-hydroxy-l-propanamine.
  • the screening test system contains the purified RT from HIV-1, which was expressed in E. coli using genetic engineering methods, and the components of the initiation complex, such as the in vitro transcripts of the HIV-LTR with the neighboring primer binding site as a template and one 18mer oligonucleotide complementary to the primer binding site as a primer.
  • the [ 3 H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter.
  • An IC 5Q value for the inhibition of reverse transcriptase (HIV-RT) in the order of magnitude of 0.01-10 / uM could be determined for the compounds of Examples 1-3 examined.

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Abstract

L'invention concerne l'utilisation nouvelle de dérivés de pyrimidine tricycliques pour la fabrication de médicaments à action antivirale. L'invention a en outre pour objet de nouveaux dérivés de pyrimidine, leur procédé de fabrication et des médicaments renfermant ces composés. L'invention concerne l'utilisation de dérivés de pyrimidine tricycliques ayant la formule générale (I), pour la fabrication de médicaments à action antivirale, dans laquelle A désigne un noyau carbocyclique ou hétérocyclique, X peut être un atome d'oxygène ou un atome de soufre, ou le groupe =NH, =N-alkyle en C1-C6 ou =S(O)2, Y peut être un atome d'oxygène ou le groupe NH- ou C1-C5-alkylamino, R désigne un reste aliphatique de 1 à 9 atomes de carbone, pouvant être substitué par un phényle, ou bien un noyau phényle ou un noyau carboxyclique de 7 à 15 atomes de carbone, ou un système à noyau hétérocyclique, R1 désigne un atome d'hydrogène, un reste aliphatique de 1 à 6 atomes de carbone ou alkoxy en C1-C6, alkylmercapto en C1-C6, alkylsulfinyle en C1-C6, alkylsulfonyle en C1-C6, amino, alkylamino en C1-C6, di-C1-C6-alkylamino, sulfonamido, alkoxycarbonyle en C1-C6, carboxy, halogène, hydroxy, nitro, cyano, azido, phényle ou benzyloxy, R2, R3, R4 et R5 qui peuvent être identiques ou différents les uns des autres, désignent, respectivement, un hydrogène, un alkyle en C1-C6, hydroxyalkyle en C1-C6, cyano, carboxy ou alkoxycarbonyle en C1-C6, ou bien R2 et R4 représentent une autre liaison entre les atomes de carbone auxquels ils sont liés, R6 est un hydrogène ou un alkyle en C1-C6, m est égal à 0 ou 1, ainsi que l'utilisation des tautomères, énantiomères, diastéréomères ou des sels physiologiquement tolérables de ces composés.
PCT/EP1993/001124 1992-05-10 1993-05-07 Utilisation de derives de pyrimidine tricycliques comme medicaments antiviraux WO1993023405A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93909920A EP0640087A1 (fr) 1992-05-10 1993-05-07 Utilisation de derives de pyrimidine tricycliques comme medicaments antiviraux
JP5519843A JPH08500089A (ja) 1992-05-10 1993-05-07 抗ウイルス治療薬としての三環式ピリミジン誘導体の使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4214829A DE4214829A1 (de) 1992-05-10 1992-05-10 Verwendung von tricyclischen Pyrimidin-Derivaten als antivirale Arzneimittel
DEP4214829.4 1992-05-10

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WO1993023405A1 true WO1993023405A1 (fr) 1993-11-25

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EP (1) EP0640087A1 (fr)
JP (1) JPH08500089A (fr)
AU (1) AU4065493A (fr)
CA (1) CA2134218A1 (fr)
DE (1) DE4214829A1 (fr)
WO (1) WO1993023405A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3891638A (en) * 1970-08-27 1975-06-24 Sumitomo Chemical Co Fused quinazolinones
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
EP0530994A1 (fr) * 1991-08-16 1993-03-10 Merck & Co. Inc. Dérivés de quinazoline utilisés comme inhibiteurs de transcriptase inverse de HIV

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3891638A (en) * 1970-08-27 1975-06-24 Sumitomo Chemical Co Fused quinazolinones
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
EP0530994A1 (fr) * 1991-08-16 1993-03-10 Merck & Co. Inc. Dérivés de quinazoline utilisés comme inhibiteurs de transcriptase inverse de HIV

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CA2134218A1 (fr) 1993-11-11
AU4065493A (en) 1993-12-13
JPH08500089A (ja) 1996-01-09
DE4214829A1 (de) 1993-11-11
EP0640087A1 (fr) 1995-03-01

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