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WO1996002511A1 - Nouveaux acides carboxyliques de quinolone a divers n1 substitues par 6-fluoro-8-difluoromethoxy - Google Patents

Nouveaux acides carboxyliques de quinolone a divers n1 substitues par 6-fluoro-8-difluoromethoxy Download PDF

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Publication number
WO1996002511A1
WO1996002511A1 PCT/EP1995/002645 EP9502645W WO9602511A1 WO 1996002511 A1 WO1996002511 A1 WO 1996002511A1 EP 9502645 W EP9502645 W EP 9502645W WO 9602511 A1 WO9602511 A1 WO 9602511A1
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WO
WIPO (PCT)
Prior art keywords
straight
carbon atoms
branched alkyl
chain
formula
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.)
Ceased
Application number
PCT/EP1995/002645
Other languages
German (de)
English (en)
Inventor
Wolfgang Bender
Wolfgang RÖBEN
Arnold Paessens
Stephan Bartel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Priority to AU29280/95A priority Critical patent/AU2928095A/en
Publication of WO1996002511A1 publication Critical patent/WO1996002511A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new N, diverse 6-fluoro-8-difluoromethoxy-substituted quinolonecarboxylic acids, processes for their preparation and their use as medicaments, in particular as antiviral agents.
  • Antiviral quinolonecarboxylic acid derivatives are known from publication EP 422 485.
  • the present invention relates to new N, diverse 6-fluoro-8-difluoromethoxy-substituted quinolonecarboxylic acids of the general formula (I),
  • A represents hydrogen or methyl
  • R 1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, halogen, Cyano, hydroxy or substituted by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each with up to 8 carbon atoms,
  • R 2 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms
  • E represents a radical of the formula -CH 2 -L
  • L means morpholino, or an N-linked 5-membered heteroaromatic with up to 3 further nitrogen atoms, or a group of the formula -NR 3 R 4 ,
  • R 3 and R 4 are the same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or an amino protecting group,
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically acceptable salts can also be alkali, alkaline earth, silver and guanidinium salts of the compounds according to the invention.
  • An N-linked 5-membered heteroaromatic in the context of the invention generally represents an imidazolyl, pyrrolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-1-yl or . l, 2,4-triazol-4-yl or tetrazolyl ring. 1,2,4-Triazol-l-yl is preferred.
  • Amino protecting groups in the context of the invention are the usual amino protecting groups used in peptide chemistry.
  • A represents hydrogen or methyl
  • R 1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxyl or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 6 carbon atoms are substituted,
  • R 2 for hydrogen or for straight-chain or branched alkyl with up to 4
  • E represents a radical of the formula -CH 2 -L
  • L means morpholino, imidazolyl, pyrrolyl, 1,2,3-triazol-l-yl, 1,2,4-triazolyl-1-yl, l, 2,4-triazolyl-4-yl or tetrazolyl, or a group of Formula -NR 3 R 4 means
  • R 3 and R 4 are identical or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyloxycarbonyl or tert.butoxycarbonyl,
  • A represents hydrogen or methyl
  • R 1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched
  • E represents a radical of the formula -CH 2 -L
  • L denotes morpholino or 1,2,4-triazol-l-yl, or denotes a group of the formula -NR 3 R 4 ,
  • R 3 and R 4 are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or benzyloxycarbonyl,
  • R 5 is halogen, preferably fluorine or chlorine
  • a and R 1 have the meaning given above,
  • esters are saponified
  • the acids are reacted with the corresponding alcohols by customary methods.
  • Suitable solvents for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers e.g. Diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric acid triamide, sulfolane, acetic ester, acetic ester, acetic ester Triethylamine, N-methylpyrrolidone, anisole or picoline. It is also possible to use mixtures of the solvents mentioned. Dimethyl sulfoxide and acetonitrile are preferred.
  • bases for individual reaction steps. These include, for example, alkali or alkaline earth metal hydroxides, pyridine, triethylamine, diisopropylethylamine or N-methylpiperidine, or bicyclic amidines such as 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [3,4,0] ⁇ nonenes -5 (DBN) or 1,5-diazabicyclo [3,4,0] undecene-5 (DBU). Diisopropylethylamine is preferred.
  • the bases are generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.
  • the process is generally carried out in a temperature range from 0 ° C. to + 160 ° C., preferably from 0 ° C. to + 140 ° C.
  • the saponification is generally carried out in a mixture of glacial acetic acid / water and in the presence of an inorganic acid, preferably sulfuric acid or hydrochloric acid, in a temperature range from 50 to 100 ° C., preferably at 100 ° C.
  • an inorganic acid preferably sulfuric acid or hydrochloric acid
  • the compounds of the general formula (II) are new and can be prepared by first preparing compounds of the general formula (IV)
  • R 5 has the meaning given above
  • R 7 represents C j -C 4 alkoxy or C 1 -C 4 dialkylamino
  • T represents halogen, preferably chlorine or fluorine, by reaction with amines of the general formula (V)
  • the process is generally carried out in a temperature range from 0 ° C. to + 150 ° C., preferably from 0 ° C. to + 120 ° C.
  • normal pressure In general, normal pressure is used. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).
  • the saponification is generally carried out in a mixture of glacial acetic acid / water and in the presence of an inorganic acid, preferably sulfuric acid or hydrochloric acid, in a temperature range from 50 to 100 ° C., preferably 100 ° C.
  • an inorganic acid preferably sulfuric acid or hydrochloric acid
  • the compounds of the general formula (VI) are new and can be prepared, for example, as described above.
  • the compounds according to the invention showed activity in cell cultures infected with lentivirus. This could be shown using the example of the HTV virus.
  • the HIV test was carried out with minor modifications using the method of Pauwels et al. [see. Journal of Virological Methods 20, (1988), 309-321].
  • PBL normal human blood lymphocytes
  • RPMI 1640 20% fetal calf serum with phythema agglutinin (90 ⁇ g / ml) and interleukin-2 (40U / ml).
  • phythema agglutinin 90 ⁇ g / ml
  • interleukin-2 40U / ml
  • PBLs were pelleted and the cell pellet was then suspended in 1 ml of HTV virus adsorption solution and incubated at 37 ° C. for 1 hour.
  • the virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium so that 1 ⁇ 10 5 cells per ml were set.
  • the cells infected in this way were pipetted into the wells of 96-well microtiter plates at 1 ⁇ 10 4 cells / well.
  • the first vertical row of the microtiter plate contained only growth medium and cells that were not infected but were otherwise treated exactly as described above (cell control).
  • the second vertical row of the microtiter plate received only HTV-infected cells (virus control) in growth medium.
  • the other wells contained the compounds according to the invention in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test substances were diluted 2 to 10 times in steps of two.
  • test batches were incubated at 37 ° C. until the untreated virus control showed the syncytia formation typical of HIV (between days 3 and 6 after infection), which was then evaluated microscopically.
  • the untreated virus control resulted in about 20 syncytia under these test conditions, while the untreated cell control showed no syncytia.
  • the IC 50 values were determined as the concentration of the treated and infected cells at which 50% (approx. 10 syncytia) of the virus-induced syncytia were suppressed by the treatment with the compound according to the invention.
  • the compounds according to the invention are valuable active substances for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine. Areas of indication in human medicine include:
  • HIV II Human Immunodeficiency Virus; formerly called HTLV III / LAV
  • HIV II Human Immunodeficiency Virus
  • AIDS AIDS related complex
  • LAS lymphadenopathy syndrome
  • AIDS carrier state For the treatment or prophylaxis of the AIDS carrier state (AIDS carrier state).
  • Points 2, 3 and 4 from the indication area in human medicine are preferred.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more active compounds of the formula (I), and processes for the preparation of these preparations.
  • the active compounds of the formula (I) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
  • the active ingredient (s) in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg of body weight per 24 hours. if necessary, in the form of several single doses to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight.
  • DC system XVII: R f 0.73
  • Hydrochloric acid stirred at 110 ° C for 2 hours.
  • the mixture is allowed to come to room temperature and the mixture is stirred with 15 ml of diethyl ether. It is suctioned off over a sinter plate and the residue is rinsed with 20 ml of ethanol / diethyl ether 1: 1.
  • the product is stirred on the suction filter in succession with three times 20 ml of diethyl ether and suction filtered, and finally dried in vacuo over calcium chloride.
  • the crystals formed are filtered off with suction and washed successively twice with 1 ml of water, three times with 1 ml of diethyl ether, once with 1.5 ml of ethanol / ether 1:10 and finally with 1.5 ml of diethyl ether.
  • the crude product (267 mg) is dried overnight under high vacuum over potassium hydroxide and recrystallized from 1 ml 1,2-dimethoxyethane, suction filtered, washed with diethyl ether and dried.

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

Abstract

L'invention concerne de nouveaux acides carboxyliques de quinolone à divers N1 substitués par 6-fluoro-8-difluorométhoxy de la formule (I), dans laquelle A désigne hydrogène ou méthyle, R1 désigne phényle, pyridyle, pyrimidyle ou pyrazinyle, éventuellement substitués jusqu'à trois fois de manière identique ou différente par nitro, trifluorométhyle, halogène, cyano, hydroxy ou par alkyle, acyle, alcoxy ou alkylthio linéaire ou ramifié, comportant chacun jusqu'à 8 atomes de carbone, R2 désigne hydrogène ou alkyle linéaire ou ramifié ayant jusqu'à 6 atomes de carbone, D ou E désigne hydrogène et D désigne morpholino ou E désigne un reste de la formule -CH¿2?-L, dans laquelle L désigne morpholino ou un hétéro-aromatique à 5 chaînons lié en N et comportant jusqu'à 3 autres atomes d'azote ou un groupe de la formule -NR?3R4¿, dans laquelle R3 et R4 sont identiques ou différents et désignent hydrogène, alkyle linéaire ou ramifié ayant jusqu'à 6 atomes de carbone ou un groupe protecteur amino. L'invention concerne des procédés permettant de les préparer, ainsi que leur utilisation comme médicaments, notamment comme agents antiviraux.
PCT/EP1995/002645 1994-07-20 1995-07-07 Nouveaux acides carboxyliques de quinolone a divers n1 substitues par 6-fluoro-8-difluoromethoxy Ceased WO1996002511A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29280/95A AU2928095A (en) 1994-07-20 1995-07-07 Novel n1 diverse 6-fluorine-8-difluoromethoxy substituted quinolone carboxylic acids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4425659.0 1994-07-20
DE4425659A DE4425659A1 (de) 1994-07-20 1994-07-20 Neue N1-diverse 6-Fluor-8-difluormethoxy substituierte Chinoloncarbonsäuren

Publications (1)

Publication Number Publication Date
WO1996002511A1 true WO1996002511A1 (fr) 1996-02-01

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PCT/EP1995/002645 Ceased WO1996002511A1 (fr) 1994-07-20 1995-07-07 Nouveaux acides carboxyliques de quinolone a divers n1 substitues par 6-fluoro-8-difluoromethoxy

Country Status (5)

Country Link
AU (1) AU2928095A (fr)
DE (1) DE4425659A1 (fr)
IL (1) IL114621A0 (fr)
WO (1) WO1996002511A1 (fr)
ZA (1) ZA955966B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011068A1 (fr) * 1995-09-22 1997-03-27 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives de l'acide pyridone-carboxylique ou leurs sels et agent antibacterien les contenant comme ingredient actif
CN116444491A (zh) * 2023-03-30 2023-07-18 浙江工业大学 一种喹诺酮类衍生物及其制备方法和应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0927164A1 (fr) 1996-09-10 1999-07-07 PHARMACIA & UPJOHN COMPANY 8-hydroxyquinoleines 7-substituees utilisees comme agents antiviraux

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0422485A2 (fr) * 1989-10-12 1991-04-17 Bayer Ag Dérivés d'acide quinolone carboxylique, procédé pour leur préparation et leur utilisation
EP0523512A1 (fr) * 1991-07-19 1993-01-20 Bayer Ag Acides quinolone-carboxyliques-vinyl-8 et -éthinyl-8
DE4303657A1 (de) * 1993-02-09 1994-08-11 Bayer Ag Neue Chinolon- und Naphthyridoncarbonsäurederivate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0422485A2 (fr) * 1989-10-12 1991-04-17 Bayer Ag Dérivés d'acide quinolone carboxylique, procédé pour leur préparation et leur utilisation
EP0523512A1 (fr) * 1991-07-19 1993-01-20 Bayer Ag Acides quinolone-carboxyliques-vinyl-8 et -éthinyl-8
DE4303657A1 (de) * 1993-02-09 1994-08-11 Bayer Ag Neue Chinolon- und Naphthyridoncarbonsäurederivate

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011068A1 (fr) * 1995-09-22 1997-03-27 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives de l'acide pyridone-carboxylique ou leurs sels et agent antibacterien les contenant comme ingredient actif
US5998436A (en) * 1995-09-22 1999-12-07 Wakunaga Pharmaceuticals Co., Ltd. Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
US6133284A (en) * 1995-09-22 2000-10-17 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
US6156903A (en) * 1995-09-22 2000-12-05 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
CN116444491A (zh) * 2023-03-30 2023-07-18 浙江工业大学 一种喹诺酮类衍生物及其制备方法和应用

Also Published As

Publication number Publication date
ZA955966B (en) 1996-02-21
IL114621A0 (en) 1995-11-27
DE4425659A1 (de) 1996-01-25
AU2928095A (en) 1996-02-16

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