EP0000928B1 - Neue Nitroimidazole und diese enthaltende pharmazeutische Präparate sowie deren Herstellung - Google Patents

Neue Nitroimidazole und diese enthaltende pharmazeutische Präparate sowie deren Herstellung Download PDF

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Publication number
EP0000928B1
EP0000928B1 EP78100690A EP78100690A EP0000928B1 EP 0000928 B1 EP0000928 B1 EP 0000928B1 EP 78100690 A EP78100690 A EP 78100690A EP 78100690 A EP78100690 A EP 78100690A EP 0000928 B1 EP0000928 B1 EP 0000928B1
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EP
European Patent Office
Prior art keywords
nitro
ethanol
methyl
aryl
imidazole
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.)
Expired
Application number
EP78100690A
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German (de)
English (en)
French (fr)
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EP0000928A1 (de
Inventor
Carey Ernest Smithen
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Filing date
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Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0000928A1 publication Critical patent/EP0000928A1/de
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Expired legal-status Critical Current

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Classifications

    • 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
    • C07D233/66—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 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
    • C07D233/91—Nitro radicals
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new nitroimidazoles, a process for their preparation and pharmaceutical preparations containing these compounds.
  • lower alkyl means a straight or branched chain alkyl group preferably having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl.
  • hydroxy lower alkyl groups are hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and 2-hydroxybutyl.
  • lower cycloalkyl means cycloalkyl groups, preferably having up to 6 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl.
  • aryl means the phenyl group or the mono- or polysubstituted, preferably mono- or polysubstituted phenyl group, where the substituents can be halogens (ie fluorine, chlorine, bromine or iodine) trifluoromethyl, lower alkyl, lower alkoxy, nitro and amino.
  • aryl-lower alkyl denotes a lower alkyl radical substituted by an aryl group.
  • aryl-lower alkyl groups are benzyl, 4-chlorobenzyl, phenethyl and phenylpropyl.
  • saturated heteromonocyclic rings which are formed from the substituents R 1 and R 2 together with the nitrogen atom and which can carry a hydroxyl group on a C atom which is not directly adjacent to the nitrogen atom are pyrrolidino, piperidino, 3-hydroxypyrrolidino, 4-hydroxy-piperidino and 3-hydroxy-hexahydro-1 H-azepino.
  • saturated heteromonocyclic rings which are formed from the substituents R I and R 2 together with the nitrogen atom to which they are attached and which may contain a further oxygen, sulfur or nitrogen atom which may optionally be substituted as indicated above , are piperazino, N-methylpiperazino, N- (2-hydroxyethyl) piperazino, morpholino and thiamorpholino.
  • lower alkoxy means a straight or branched chain alkoxy group with preferably 1-6 carbon atoms, such as methoxy or ethoxy.
  • nitroimidazoles of the present invention are compounds of the formula I in which R I is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl, R 2 is lower alkyl, hydroxy-lower alkyl, aryl or aryl-lower alkyl or R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered saturated heteromonocyclic ring which may contain another oxygen, sulfur or nitrogen atom which may be replaced by a lower alkyl, hydroxy-lower alkyl , Aryl or aryl-lower alkyl group can be substituted, as well as their acid addition salts.
  • a particularly interesting group of nitroimidazole derivatives of the present invention are those compounds of the formula in which R 1 and R 2 together with the nitrogen atom to which they are attached represent a 6-membered heteromonocyclic ring which may contain a further oxygen or nitrogen atom, which is optionally substituted by a lower alkyl group, and their acid addition salts.
  • the reaction of an epoxide of formula II with an amine of formula III according to process variant (a) can be carried out in the presence or absence of an inert organic solvent.
  • Suitable inert organic solvents are lower alkanols (e.g. methanol and ethanol), dimethylformamide or dimethylacetamide.
  • an excess of an amine of formula III can be used as a solvent.
  • Pressure and temperature during the reaction are not critical; the reaction can be carried out at room temperature and under atmospheric pressure or else at elevated temperature and / or elevated pressure. In a preferred embodiment, the reaction is carried out at a temperature of about 50 ° C. to the reflux temperature of the reaction mixture and under normal pressure.
  • the condensation of a compound of formula IV (azomycin) with an epoxide of formula V according to process variant (b) is carried out in the presence of a base.
  • Catalytic amounts of the base are preferably used, although larger amounts can also be used.
  • Preferred bases are alkali metal carbonates (e.g. sodium carbonate or potassium carbonate), although other bases such as alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide) can also be used.
  • the condensation is conveniently carried out in the presence of an inert organic solvent, e.g. B. a lower alkanol (z. B. methanol or ethanol) performed.
  • the condensation can also be carried out at room temperature and under higher pressure, it is preferably carried out at elevated temperature, in particular at the reflux temperature of the reaction mixture, and under atmospheric pressure.
  • a halohydrin of the formula VI When a halohydrin of the formula VI is reacted with an amine of the formula 111 according to process variant (c), at least one mole of amine is advantageously used per mole of halohydrin.
  • the reaction is conveniently carried out in the presence of an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g. pyridine) or, preferably, in the presence of excess amine of the formula III.
  • an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g. pyridine) or, preferably, in the presence of excess amine of the formula III.
  • an acid-binding agent such as an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate) or a tertiary organic amine (e.g
  • the reaction expediently takes place in the presence of an inert organic solvent, for example a lower alkanol (for example methanol or ethanol).
  • an inert organic solvent for example a lower alkanol (for example methanol or ethanol).
  • the temperature and pressure during the reaction are not critical. It can be carried out at room temperature and under normal pressure or at elevated temperature and under pressure. In a preferred embodiment, the reaction is carried out at elevated temperature, in particular at the reflux temperature of the reaction mixture, and under normal pressure. Chlorohydrin is used as the preferred halohydrin of the formula VI.
  • the compounds of formula I can be converted into acid addition salts, e.g. B. by reaction with an inorganic acid such as a hydrohalic acid (e.g. HCl or HBr), sulfuric acid, nitric acid or phosphoric acid or with an organic acid such as acetic acid, citric acid, maleic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid or paratoluenesulfonic acid.
  • Physiologically acceptable acid addition salts especially the hydrochlorides, are preferred.
  • Physiologically unacceptable acid addition salts can be converted into physiologically acceptable acid addition salts by treatment with a base and subsequent reaction with be converted to a physiologically acceptable acid.
  • the starting compounds of the formulas II to VI are known compounds.
  • the compounds of the formula and their physiologically tolerated acid addition salts can be used as so-called "radiosensitizers" for sensitizing hypoxic cells to radiation, in particular in connection with the treatment of hypoxic tumor cells by radiation.
  • radiosensitizers for sensitizing hypoxic cells to radiation, in particular in connection with the treatment of hypoxic tumor cells by radiation.
  • the effectiveness of the compounds of the formula and their physiologically tolerable acid addition salts as radiosensitizers for hypoxic cells can be demonstrated in an in vitro experiment on hypoxic Chinese hamster V 79 cells (cf.
  • the compounds of the formula and their physiologically acceptable acid addition salts can also be used to control infections caused by protozoa, in particular infections caused by Trichomonas vaginalis.
  • the compounds of the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with one for enteral, e.g. B. oral or parenteral application of suitable organic or inorganic inert carrier material, such as.
  • suitable organic or inorganic inert carrier material such as.
  • water gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols or petroleum jelly
  • the preparations can be in solid form, e.g. B. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. B. as ointments; or in liquid form, e.g. B. present as solutions, suspensions or emulsions.
  • the preparations can also contain other therapeutically valuable compounds.
  • the pharmaceutical preparations can be prepared in the manner familiar to any person skilled in the art by mixing one of the compounds according to the invention as an active ingredient with an inert, solid or liquid carrier suitable for therapeutic administration, and if necessary bringing the mixture into a special galenical form.
  • the compounds according to the invention can be administered orally at a dosage of about 20 to 60 mg per kg of body weight and day. In general, however, the total dose administered during a treatment should not exceed about 200 mg per kg body weight and day.
  • the compounds according to the invention can also be administered orally at a daily dosage of about 20 to 60 mg per kg of body weight.
  • the pharmaceutical preparation described above can be produced in a manner known per se, if possible with the exclusion of light, and should be kept in the dark.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP78100690A 1977-08-19 1978-08-17 Neue Nitroimidazole und diese enthaltende pharmazeutische Präparate sowie deren Herstellung Expired EP0000928B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB3490877 1977-08-19
GB3490877 1977-08-19
GB1953478 1978-05-15
GB1953478 1978-05-15

Publications (2)

Publication Number Publication Date
EP0000928A1 EP0000928A1 (de) 1979-03-07
EP0000928B1 true EP0000928B1 (de) 1981-03-18

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Family Applications (1)

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EP78100690A Expired EP0000928B1 (de) 1977-08-19 1978-08-17 Neue Nitroimidazole und diese enthaltende pharmazeutische Präparate sowie deren Herstellung

Country Status (26)

Country Link
US (1) US4241060A (enrdf_load_stackoverflow)
EP (1) EP0000928B1 (enrdf_load_stackoverflow)
JP (1) JPS5444671A (enrdf_load_stackoverflow)
AR (3) AR218325A1 (enrdf_load_stackoverflow)
AT (1) AT364829B (enrdf_load_stackoverflow)
AU (1) AU516443B2 (enrdf_load_stackoverflow)
CA (1) CA1104133A (enrdf_load_stackoverflow)
DE (2) DE2836073A1 (enrdf_load_stackoverflow)
DK (1) DK155367C (enrdf_load_stackoverflow)
ES (3) ES472661A1 (enrdf_load_stackoverflow)
FI (1) FI70576C (enrdf_load_stackoverflow)
FR (1) FR2400512A1 (enrdf_load_stackoverflow)
GB (1) GB2003154A (enrdf_load_stackoverflow)
GR (1) GR73055B (enrdf_load_stackoverflow)
HU (1) HU179983B (enrdf_load_stackoverflow)
IE (1) IE47132B1 (enrdf_load_stackoverflow)
IL (1) IL55351A (enrdf_load_stackoverflow)
IT (1) IT1098042B (enrdf_load_stackoverflow)
MC (1) MC1210A1 (enrdf_load_stackoverflow)
NL (1) NL7808597A (enrdf_load_stackoverflow)
NO (1) NO151240C (enrdf_load_stackoverflow)
NZ (1) NZ188140A (enrdf_load_stackoverflow)
PH (1) PH16364A (enrdf_load_stackoverflow)
PT (1) PT68441A (enrdf_load_stackoverflow)
SE (1) SE7808773L (enrdf_load_stackoverflow)
YU (1) YU41317B (enrdf_load_stackoverflow)

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MD4150C1 (ro) * 2011-10-11 2012-09-30 Институт Химии Академии Наук Молдовы Procedeu de obţinere a compuşilor coordinativi ai Co(II), Ni(II) şi Zn(II) cu 2-nitro-4,5-difenilimidazol pornind de la 4,5-difenilimidazol şi nitraţii metalelor respective
MD4178C1 (ro) * 2012-02-27 2013-02-28 Институт Химии Академии Наук Молдовы Procedeu de obţinere a 2-nitro-4,5-difenilimidazolului
KR20160030537A (ko) * 2013-07-16 2016-03-18 코닝 인코포레이티드 얇은 유리를 구부리기 위한 방법 및 기기
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US4038410A (en) * 1974-03-14 1977-07-26 Schering Aktiengesellschaft Nitroimidazole derivatives and process for the preparation thereof

Also Published As

Publication number Publication date
AR220216A1 (es) 1980-10-15
EP0000928A1 (de) 1979-03-07
PH16364A (en) 1983-09-08
SE7808773L (sv) 1979-02-20
JPS5444671A (en) 1979-04-09
HU179983B (en) 1983-01-28
JPS6220187B2 (enrdf_load_stackoverflow) 1987-05-06
YU195378A (en) 1983-01-21
AU3891578A (en) 1980-02-21
PT68441A (enrdf_load_stackoverflow) 1978-09-01
FI782530A7 (fi) 1979-02-20
FI70576C (fi) 1986-09-24
GR73055B (enrdf_load_stackoverflow) 1984-01-26
DK366678A (da) 1979-02-20
IE781453L (en) 1979-02-19
ES472661A1 (es) 1979-02-16
ATA601078A (de) 1981-04-15
ES478051A1 (es) 1979-10-16
GB2003154A (en) 1979-03-07
CA1104133A (en) 1981-06-30
AT364829B (de) 1981-11-25
IL55351A (en) 1982-07-30
NZ188140A (en) 1981-01-23
NO151240B (no) 1984-11-26
NO151240C (no) 1985-03-06
AU516443B2 (en) 1981-06-04
FR2400512B1 (enrdf_load_stackoverflow) 1980-07-04
AR218553A1 (es) 1980-06-13
FI70576B (fi) 1986-06-06
DE2836073A1 (de) 1979-03-01
IE47132B1 (en) 1983-12-28
IT1098042B (it) 1985-08-31
ES478052A1 (es) 1979-10-16
NL7808597A (nl) 1979-02-21
DK155367C (da) 1989-08-14
DE2860546D1 (en) 1981-04-16
FR2400512A1 (fr) 1979-03-16
YU41317B (en) 1987-02-28
US4241060A (en) 1980-12-23
AR218325A1 (es) 1980-05-30
MC1210A1 (fr) 1979-05-18
DK155367B (da) 1989-04-03
NO782813L (no) 1979-02-20
IT7826792A0 (it) 1978-08-16
IL55351A0 (en) 1978-10-31

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