EP0000896B1 - Propenyl amines, processes for their production and pharmaceutical compositions containing them - Google Patents

Propenyl amines, processes for their production and pharmaceutical compositions containing them Download PDF

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Publication number
EP0000896B1
EP0000896B1 EP78100611A EP78100611A EP0000896B1 EP 0000896 B1 EP0000896 B1 EP 0000896B1 EP 78100611 A EP78100611 A EP 78100611A EP 78100611 A EP78100611 A EP 78100611A EP 0000896 B1 EP0000896 B1 EP 0000896B1
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formula
radical
alkyl
hydrogen
compound
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French (fr)
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EP0000896A3 (en
EP0000896A2 (en
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Helmut Dr. Hamberger
Adrian Dr. Stephen
Anton Dr. Stütz
Peter Dr. Stütz
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Sandoz AG
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Sandoz AG
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Priority claimed from CH1020377A external-priority patent/CH632251A5/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no 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 the ring nitrogen atom
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

Definitions

  • This invention relates to propenyl-amines, processes for their production and pharmaceutical compositions containing them.
  • the present invention provides a compound of formula I, wherein
  • lower alkyl or “lower alkoxy” radical mean containing 1 to 4 carbon atoms, especially 2 or 1 carbon atoms.
  • Any alkyl (C 1 ⁇ 12 ) moiety is preferably alkyl (C 2 ⁇ 8 ); phenylalkyl or phenylalkoxy has preferably 7 carbon atoms.
  • Any alkenyl or alkynyl radical has preferably 3 to 6 carbon atoms, especially 3 or 4 carbon atoms.
  • the multiple bond is in other than the ⁇ , ⁇ position and is conveniently in the remote terminal position.
  • An example of an alkenyl group is allyl.
  • An example of an alkynyl group is propinyl.
  • Cycloalkylalkyl has preferably an alkyl moiety of 1 to 4 carbon atoms, especially 2 or 1 carbon atoms, and a cycloalkyl moiety preferably of 3 to 6 carbon atoms.
  • R 4 is cycloalkylalkyl this is especially cyclopentyl alkyl or cyclohexylalkyl.
  • R 10 is cycloalkylalkyl this is especially cyclopropylalkyl or cyclobutylalkyl.
  • R 7 and R 8 are identical and are both hydrogen.
  • R 9 is hydrogen or halogen.
  • IIb and IIc the bond to the carbon atom to which R 2 and R 3 are attached is conveniently attached meta to X and para to the ring nitrogen, respectively.
  • X is conveniently sulphur, imino or lower alkylamino.
  • R 1 is preferably a radical of formula IIb, IIc or IId or especially IIa.
  • R 2 is preferably hydrogen.
  • R 3 is preferably hydrogen and R 4 is conveniently alkyl.
  • R 5 is conveniently hydrogen.
  • R 6 when it is a heterocycle, conveniently contains one oxygen or sulphur atom or one or two nitrogen atoms.
  • the bond linking R 6 to the vinylene moiety is attached to a ring carbon atom adjacent to a ring heteroatom.
  • the ring is unsubstituted or substituted by lower alkyl.
  • R 10 is conveniently phenylalkoxy.
  • IIIa is conveniently optionally substituted 2 or 4-pyridyl.
  • IIIc, IIId, IIIe it is to be appreciated that the bond linking R 6 to the vinylene moiety and R 11 to R 13 may be attached to any of the ring carbon atoms present.
  • IIIc is preferably a cycloalk-1-en-1-yl radical.
  • R 11 to R 13 are hydrogen.
  • q is conveniently 0 or 1. Any double bond in IIIf is conveniently trans.
  • R 14 is conveniently alkoxy (C 1 ⁇ 8 ) carbonyl, phenyl or alkyl or phenalkyl.
  • R 17 is conveniently halogen and R 18 is conveniently hydrogen.
  • R 6 is conveniently IIIc.
  • u is conveniently 3, 4 or 5, more conveniently 4.
  • m, n, p, q, s, t and v are conveniently chosen to produce a five or six-membered ring.
  • the double bond between R 6 and the nitrogen atom preferably has the trans configuration.
  • Halogen is conveniently fluorine, or preferably bromine or chlorine.
  • R 1 is IIb or IIe and R 6 is IIIa it is to be appreciated that the two radicals R 9 may be the same or different.
  • the present invention also provides a process for the production of a compound of formula I, selected from
  • Process a) may be effected in conventional manner for the production of tertiary amines by condensation from analogous starting materials.
  • the process may be effected in an inert solvent such as a lower alkanol, e.g. ethanol, optionally in aqueous admixture, an aromatic hydrocarbon solvent, e.g. benzene or toluene, a cyclic ether, e.g. dioxane or a carboxylic acid dialkylamide solvent, e.g. dimethylformamide.
  • the reaction temperature is conveniently from room temperature to the boiling temperature of the reaction mixture, preferably room temperature.
  • the reaction is conveniently effected in the presence of an acid binding agent, such as an alkali metal carbonate, e.g.
  • the leaving group A is conveniently iodine or preferably chlorine or bromine, or an organic sulphonyloxy group having 1 to 10 carbon atoms, e.g. alkylsulphonyloxy, preferably having 1 to 4 carbon atoms such as mesyloxy, or alkylphenylsulphonyloxy preferably having 7 to 10 carbon atoms such as tosyloxy.
  • Process b) may be effected in conventional manner for catalytic hydrogenation in order to produce a compound of formula I wherein the double bond adjacent to R 6 has the cis configuration.
  • the process may be effected in conventional manner for a complex metal hydride reduction in order to produce a compound of formula I wherein the double bond has the trans configuration.
  • the catalytic hydrogenation may be effected in a solvent, e.g. methanol, ethanol, methylene chloride, pyridine or ethyl acetate.
  • the catalyst is preferably palladium on a carrier material such as BaS0 4 or CaC0 3 .
  • the catalyst may be pretreated, e.g. with a lead salt, so as to be partially poisoned (e.g. a Lindlar catalyst).
  • the hydrogenation may be effected at room temperature and at normal pressure.
  • the metal hydride reduction may be effected in conventional manner for a lithium aluminium -hydride or a diisobutylaluminium hydride reduction.
  • the reduction is conveniently effected in an inert solvent such as toluene or benzene.
  • the reaction is conveniently effected at room temperature.
  • Process c) may be effected in conventional manner for a photochemical isomerisation of a cis alkene.
  • the reaction may be effected in a solvent such as benzene, petroleum ether, ethanol, or preferably cyclohexane.
  • the solution is conveniently irradiated with light from a mercury high or low pressure lamp.
  • the reaction is conveniently effected at room temperature.
  • an appropriate sensitizer such as eosine or a catalyst such as diphenyldisulphide may be present.
  • Process d) may be effected in manner conventional for the "alkylation" of secondary amines (the term “alkylation” being used here to denote introduction of any of the hydrocarbyl groups R 4 ), for example by direct “alkylation” with an “alkylating” agent, for example a halide or sulphate, or by reductive alkylation, in particular by reaction with an appropriate aldehyde and subsequent or simultaneous reduction.
  • Reductive "alkylation” is suitably effected in an inert organic solvent, such as a lower alkanol, e.g. methanol, and at an elevated temperature, in particular at the boiling temperature of the reaction medium.
  • the subsequent reduction may be effected with, for example, a complex metal hydride reducing agent, e.g. NaBH 4 or LiAIH 4 .
  • a complex metal hydride reducing agent e.g. NaBH 4 or LiAIH 4 .
  • the reduction may also be effected simultaneously to the alkylation, for example by use of formic acid which may serve both as reducing agent and as a reaction medium.
  • side reactions may occur, e.g. reduction of halogen to hydrogen, reduction of a nitro group to an amino group, reduction of an alkenyl moiety to an alkyl moiety and/or reduction of a keto moiety to a carbinol moiety in processes b) or process d) when reductive alkylation is used, or simultaneous cis/trans isomerisation of any double bond present in R 4 or R 6 when process c) is used.
  • the reaction conditions should be chosen to avoid such side reactions, and the desired final product isolated using conventional purification techniques, e.g. thin layer chromatography.
  • Free base forms of the compounds of formula I may be converted into salt forms and vice versa.
  • Suitable acids for acid addition salt formation include hydrochloric acid, fumaric acid and naphthalene-1,5-disulphonic acid.
  • non-cyclic amines of formula IV may be made by condensing a compound of formula VIII, or the corresponding iodide or chloride, with a compound of formula R 4 NH 2 .
  • cyclic amines of formula IV may be made as follows:- wherein
  • Alk lower alkyl
  • the compounds of formula VI are new and may be made by reacting an appropriate amine of formula IV with compounds of formulae R 5 ⁇ CHO and under Mannich reaction conditions.
  • the title compound may also be made in analogous manner to Examples 3, 4 and 5.
  • the title compound may also be made in analogous manner to Examples 1 and 5.
  • the title compound may also be prepared by following Examples 1, 4 and 5.
  • the title compound may also be prepared by following Examples 1, 3 and 5.
  • the title compound may also be prepared in analogous manner to Examples 1, 3 and 4.
  • NMR data on the above-mentioned compounds of formula I, obtained as oils, are given in the following table.
  • the compounds of formula I exhibit chemotherapeutic activity.
  • they exhibit antimycotic activity, as indicated in vitro with tests against various families and types of mycetes, including Trichophton quinkeanum, Aspergillus fumigatus, Microsporum canis Sporotrychium schenkii and Candida albicans, at concentrations of, for example 0.1 to 100 ⁇ g/ml, and in vivo in the experimental skin mycosis model in guinea pigs. In the latter model, guinea pigs are infected by cutaneous application of Trichophyton quinkeanum.
  • test substance is administered daily for 7 days beginning 24 hours after the infection by local application by rubbing the test substance (taken up in polyethylene glycol) on the skin surface, or perorally, the test substance being administered as a suspension.
  • the activity is shown on local application at concentrations of from example 0.1 to 2%, in particular 0.1 to 0.6%.
  • the oral activity is shown at dosages of, for example, 50 to 100 mg/kg.
  • the compounds are therefore indicated for use as anti-mycotic agents.
  • daily dose is from 500 to 2000 mg. If desired, this may be administered in divided doses 2 to 4 times a day in unit dosage form containing from about 125 mg to about 1000 mg or in sustained release form.
  • the compounds may be used in free base form or in the form of chemotherapeutically acceptable acid addition salts. Such salt forms exhibit the same order of activity as the free base forms.
  • the compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and, optionally, other excipients and administered in such forms as tablets or capsules.
  • the compounds may alternatively be administered topically in such conventional forms as ointments or creams.
  • concentration of the active substance in such topical application forms will of course vary depending on the compound employed, the treatment desired and the nature of the form etc. In general, however, satisfactory results are obtained at concentrations of from 0.05 to 3, in particular 0.1 to 1 wt 96.
  • a compound with particularly interesting activity is the compound of Example 4.
  • One group of compounds has a formula Ig, wherein
  • Another group of compounds comprises those of formula Ih, wherein
  • a further group of formula I compounds comprises compounds of formula li, wherein

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  • Pyridine Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

  • This invention relates to propenyl-amines, processes for their production and pharmaceutical compositions containing them.
  • The present invention provides a compound of formula I,
    Figure imgb0001
    wherein
    • a) (i) R1 is a radical of formula IIa,
      Figure imgb0002
      wherein
      • R7 and R8, independently, are hydrogen, halogen of atomic number from 9 to 53, trifluoromethyl, hydroxy, nitro, lower alkyl or lower alkoxy, or a radical of formula IIb, IIc, IId, IIe,
        Figure imgb0003
        wherein
      • R9 is hydrogen, halogen of atomic number from 9 to 53, hydroxy, lower alkyl or lower alkoxy,
      • X is oxygen, sulphur, imino, lower alkylimino or a radical of formula ―(CH2)r― wherein r is 1, 2 or 3,
      • s is 3, 4 or 5, and
      • t is 2, 3 or 4, and
      • R is hydrogen or lower alkyl, or
        • (ii) R1 and R2 together with the carbon atom to which they are bound form a radical of formula IIf or IIg,
          Figure imgb0004
          wherein
      • p is 1, 2 or 3,
      • R3 and R5, independently, are hydrogen or lower alkyl,
      • R4 is alkyl (C1_6), alkenyl (C3―12), alkynyl (C3―12) or cycloalkyl (C3―8)-alkyl (C1―6); and
      • R6 is (i) an aromatic, five-membered heterocycle containing one oxygen, sulphur or nitrogen hetero-ring atom and optionally an additional one or two nitrogen hetero-ring atoms and being optionally substituted on a carbon ring atom by halogen of atomic number from 9 to 53, hydroxy, lower alkyl or lower alkoxy, and any nitrogen ring atom present being optionally substituted when possible, by lower alkyl, (ii) a radical of formula Ilia,
        Figure imgb0005
         wherein
      • R9 is as defined above, (iii) a radical of formula IIIb,
        Figure imgb0006
        wherein
      • R10 is alkyl (C1―12), alkenyl (C3―12), alkynyl (C3―2) cycloalkyl (C3―8) alkyl (C1―6), phenyl-alkyl (C7―12), phenyl, phenylalkoxy (C7―16), or aminoalkyl (C1―12);
        • (iv) a radical of formula IIIc, IIId or IIIe,
          Figure imgb0007
          wherein
      • R11, R12 and R13, independently, are hydrogen or C1―C4 alkyl,
      • m is a whole number from 0 to 4,
      • n is a whole number from 0 to 3, and
      • v is a whole number from 0 to 5,
        • (v) a radical of formula IIIf,
          Figure imgb0008
          wherein
      • R14 is C1―C4 alkyl, alkoxy (C1―12)-carbonyl, alkenyl (C3―12), alkynyl (C3―12), phenylalkyl (C7―12) or phenyl,
      • R15 and R16, independently, are hydrogen or C1―C4 alkyl, and
      • q is a whole number from 0 to 5, or
        • (vi) a radical of formula IIIg
          Figure imgb0009
          wherein
      • R17 and R18, independently, are hydrogen, halogen of atomic number from 9 to 53, trifluoromethyl, hydroxy, nitro, lower alkyl or lower alkoxy, with the proviso that one of R17 and R18is other than hydrogen, and with the general proviso that R1 is not a radical of formula Ila when R6 is a radical of formula IIIg or phenyl, R2 is hydrogen and R3 is hydrogen or lower alkyl,
    • b) R1 is a radical of formula IIa to IIe, as defined above,
      • R2, R5 and R6 are as defined above, and
      • R3 and R4 together are ―(CH2)u―wherein u is a whole number from 1 to 8.
  • As used herein, the terms "lower alkyl" or "lower alkoxy" radical mean containing 1 to 4 carbon atoms, especially 2 or 1 carbon atoms. Any alkyl (C1―12) moiety is preferably alkyl (C2―8); phenylalkyl or phenylalkoxy has preferably 7 carbon atoms. Any alkenyl or alkynyl radical has preferably 3 to 6 carbon atoms, especially 3 or 4 carbon atoms. Preferably the multiple bond is in other than the α, β position and is conveniently in the remote terminal position. An example of an alkenyl group is allyl. An example of an alkynyl group is propinyl. Cycloalkylalkyl has preferably an alkyl moiety of 1 to 4 carbon atoms, especially 2 or 1 carbon atoms, and a cycloalkyl moiety preferably of 3 to 6 carbon atoms. When R4 is cycloalkylalkyl this is especially cyclopentyl alkyl or cyclohexylalkyl. When R10 is cycloalkylalkyl this is especially cyclopropylalkyl or cyclobutylalkyl.
  • Conveniently R7 and R8 are identical and are both hydrogen. Conveniently R9 is hydrogen or halogen. In IIb and IIc the bond to the carbon atom to which R2 and R3 are attached is conveniently attached meta to X and para to the ring nitrogen, respectively. X is conveniently sulphur, imino or lower alkylamino. R1 is preferably a radical of formula IIb, IIc or IId or especially IIa. R2 is preferably hydrogen. R3 is preferably hydrogen and R4 is conveniently alkyl. R5 is conveniently hydrogen. R6, when it is a heterocycle, conveniently contains one oxygen or sulphur atom or one or two nitrogen atoms. Preferably the bond linking R6 to the vinylene moiety is attached to a ring carbon atom adjacent to a ring heteroatom. Conveniently the ring is unsubstituted or substituted by lower alkyl. R10 is conveniently phenylalkoxy. IIIa is conveniently optionally substituted 2 or 4-pyridyl. In IIIc, IIId, IIIe it is to be appreciated that the bond linking R6 to the vinylene moiety and R11 to R13 may be attached to any of the ring carbon atoms present. IIIc is preferably a cycloalk-1-en-1-yl radical. Preferably R11 to R13 are hydrogen. q is conveniently 0 or 1. Any double bond in IIIf is conveniently trans. R14 is conveniently alkoxy (C1―8) carbonyl, phenyl or alkyl or phenalkyl. R17 is conveniently halogen and R18 is conveniently hydrogen. R6 is conveniently IIIc. u is conveniently 3, 4 or 5, more conveniently 4.
  • The values m, n, p, q, s, t and v are conveniently chosen to produce a five or six-membered ring.
  • The double bond between R6 and the nitrogen atom preferably has the trans configuration.
  • Halogen is conveniently fluorine, or preferably bromine or chlorine.
  • When R1 is IIb or IIe and R6 is IIIa it is to be appreciated that the two radicals R9 may be the same or different.
  • The present invention also provides a process for the production of a compound of formula I, selected from
    • a) reacting a compound of formula IV,
      Figure imgb0010
      wherein
      • R1 to R4 are as defined above, with a compound of formula V,
        Figure imgb0011
        wherein
      • A is a leaving group, and
      • R5 and R6 are as defined above, or
    • b) when R4 and R6 are other than alkynyl reducing a compound of formula VI,
      Figure imgb0012
      wherein
      • R1 to R3 and R5 are as defined above, and
        Figure imgb0013
         and
        Figure imgb0014
         are as defined above for R4 and R6, except alkynyl
    • c) when the trans form is required isomerising photochemically a compound of formula lc,
      Figure imgb0015
      wherein
      • R1 to R6 are as defined above, or
    • d) when R3 and R4 together do not form a ―(CH2)u― group introducing the group R4 into a compound ot formula VII,
      Figure imgb0016
      wherein
      • R1, R2, R3, R5 and R6 are as defined above.
  • Process a) may be effected in conventional manner for the production of tertiary amines by condensation from analogous starting materials. The process may be effected in an inert solvent such as a lower alkanol, e.g. ethanol, optionally in aqueous admixture, an aromatic hydrocarbon solvent, e.g. benzene or toluene, a cyclic ether, e.g. dioxane or a carboxylic acid dialkylamide solvent, e.g. dimethylformamide. The reaction temperature is conveniently from room temperature to the boiling temperature of the reaction mixture, preferably room temperature. The reaction is conveniently effected in the presence of an acid binding agent, such as an alkali metal carbonate, e.g. sodium carbonate. The leaving group A is conveniently iodine or preferably chlorine or bromine, or an organic sulphonyloxy group having 1 to 10 carbon atoms, e.g. alkylsulphonyloxy, preferably having 1 to 4 carbon atoms such as mesyloxy, or alkylphenylsulphonyloxy preferably having 7 to 10 carbon atoms such as tosyloxy.
  • Process b) may be effected in conventional manner for catalytic hydrogenation in order to produce a compound of formula I wherein the double bond adjacent to R6 has the cis configuration. Alternatively, the process may be effected in conventional manner for a complex metal hydride reduction in order to produce a compound of formula I wherein the double bond has the trans configuration.
  • The catalytic hydrogenation may be effected in a solvent, e.g. methanol, ethanol, methylene chloride, pyridine or ethyl acetate. The catalyst is preferably palladium on a carrier material such as BaS04 or CaC03. The catalyst may be pretreated, e.g. with a lead salt, so as to be partially poisoned (e.g. a Lindlar catalyst). The hydrogenation may be effected at room temperature and at normal pressure.
  • The metal hydride reduction may be effected in conventional manner for a lithium aluminium -hydride or a diisobutylaluminium hydride reduction. The reduction is conveniently effected in an inert solvent such as toluene or benzene. The reaction is conveniently effected at room temperature.
  • Process c) may be effected in conventional manner for a photochemical isomerisation of a cis alkene. The reaction may be effected in a solvent such as benzene, petroleum ether, ethanol, or preferably cyclohexane. The solution is conveniently irradiated with light from a mercury high or low pressure lamp. The reaction is conveniently effected at room temperature. If desired, an appropriate sensitizer such as eosine or a catalyst such as diphenyldisulphide may be present.
  • Process d) may be effected in manner conventional for the "alkylation" of secondary amines (the term "alkylation" being used here to denote introduction of any of the hydrocarbyl groups R4), for example by direct "alkylation" with an "alkylating" agent, for example a halide or sulphate, or by reductive alkylation, in particular by reaction with an appropriate aldehyde and subsequent or simultaneous reduction. Reductive "alkylation" is suitably effected in an inert organic solvent, such as a lower alkanol, e.g. methanol, and at an elevated temperature, in particular at the boiling temperature of the reaction medium. The subsequent reduction may be effected with, for example, a complex metal hydride reducing agent, e.g. NaBH4 or LiAIH4. The reduction may also be effected simultaneously to the alkylation, for example by use of formic acid which may serve both as reducing agent and as a reaction medium.
  • It is to be appreciated that in any of the above processes, side reactions may occur, e.g. reduction of halogen to hydrogen, reduction of a nitro group to an amino group, reduction of an alkenyl moiety to an alkyl moiety and/or reduction of a keto moiety to a carbinol moiety in processes b) or process d) when reductive alkylation is used, or simultaneous cis/trans isomerisation of any double bond present in R4 or R6 when process c) is used. The reaction conditions should be chosen to avoid such side reactions, and the desired final product isolated using conventional purification techniques, e.g. thin layer chromatography.
  • Free base forms of the compounds of formula I may be converted into salt forms and vice versa. Suitable acids for acid addition salt formation include hydrochloric acid, fumaric acid and naphthalene-1,5-disulphonic acid.
  • The starting materials are either known or may be made in conventional manner. For example non-cyclic amines of formula IV may be made by condensing a compound of formula VIII,
    Figure imgb0017
    or the corresponding iodide or chloride, with a compound of formula R4NH2.
  • The cyclic amines of formula IV may be made as follows:-
    Figure imgb0018
    wherein
  • Alk = lower alkyl.
  • The compounds of formula VI are new and may be made by reacting an appropriate amine of formula IV with compounds of formulae R5―CHO and
    Figure imgb0019
     under Mannich reaction conditions.
  • The compounds of formula VII are also new and may be made as follows:
    Figure imgb0020
  • In the following Examples all temperatures are uncorrected and in degrees Centigrade.
  • In the tables hereinafter, the following indications are used:-
    • 1) All double bonds have the trans configuration; all alkyl groups are unbranched unless stated otherwise.
    • 2) If no melting point is given, the free base form of the compound is obtained and this is an oil. Melting points are for the free base form unless specified otherwise.
    • 3) Monohydrochloride salt form.
    • 4) Dihydrochloride salt form.
    EXAMPLE 1 4-[N-methyl-N-(1-naphthylmethyl)]aminocrotonic acid ethyl ester [process a)]
  • 1.9 g of bromocrotonic acid ethyl ester are added dropwise to a mixture of 1.7 g of N-methyl-N-(1-naphthylmethyl)amine, 1.4 g of K2CO3 and 10 ml dimethylformamide. After the mixture is stirred for 18 hours at room temperature, it is filtered and evaporated under a vacuum. The residue is chromatographed on silica-gel using benzene/ethyl acetate (1:1) as solvent to yield the title compound in free base form, as an oil, after evaporating the appropriate fractions.
  • The title compound may also be made in analogous manner to Examples 3, 4 and 5.
    • EXAMPLE 2 N-(3-cyclohex-1-en-1-yl-2-cis-propenyl)-N-methyl-N-( 1-naphthylmethyl)amine [process b)]
  • 5 g of N-(3-cyclohex-l-en-1-yl-propynyl)-N-methyl-N-(l-naphthylmethyl)amine are hydrogenated in absolute pyridine using 750 mg Pd/BaS04 as catalyst at room temperature and normal pressure, until the calculated amount of hydrogen is taken up. The reaction mixture is filtered and the pyridine removed in a vacuum. The residue is chromatographed on silica-gel using benzene/ethyl- acetate (9:1) to yield the title compound in free base form as an oil after evaporating the appropriate fractions, m.p. (hydrochloride) 184-188°.
  • The title compound may also be made in analogous manner to Examples 1 and 5.
    • EXAMPLE 3 N-(3-cyclohexyl-2-trans-propenyl)-N-methyl-N-( 1-naphthylmethyl)amine [process b)]
  • 28 ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added to 5 g of N-(3-cyclohexylpropynyl)-N-methyl-N-(1-naphthylmethyl)amine in absolute benzene. After the mixture is stirred for 3 hours at 40°, water is carefully added. The organic phase is separated off, dried and evaporated to yield the title compound in free base form, as an oil.
  • The title compound may also be prepared by following Examples 1, 4 and 5.
    • EXAMPLE 4 N-(3-cyclohex-1-en-1-yl-2-trans-propenyl)-N-methyl-N-( 1-naphthylmethyl)amine [process c)]
  • 1.2 g of N-(3-cyclohex-1-en-1-yl-2-cis-propenyl)-N-methyl-N-(1-naphthylmethyl)amine are irradiated for 3 hours with a Hg high pressure lamp (A >300 nm) in 1 litre cyclohexane in the presence of 50 mg diphenyldisulphide at room temperature under an inert gas atmosphere. After the solvent is evaporated, the title compound is obtained in free base form and converted into the hydrochloride, m.p. 184-188
  • The title compound may also be prepared by following Examples 1, 3 and 5.
    • EXAMPLE 5 N-methyl-N-[3-(5'-methyl-2'-thienyl)-2-trans-propenyl]-N-(1-naphthylmethyl)amine [process d)]
    • a) 15.2 g of 3-(5'-methyl-2'-thienyl)prop-2-enal and 15.7 g of 1-aminomethylnaphthalene in 350 ml benzene are boiled under reflux until the calculated amount of water has boiled off. 3.6 g of the resulting Schiff base in 100 ml methanol are boiled under reflux with 5 g NaBH4 for 30 minutes to yield N-[3-(5'-methyl-2'-thienyl)-2-trans-propenyl]-N-(1-naphthylmethyl)amine, which is used directly in the next stage. [To isolate this intermediate the reaction mixture is evaporated in a vacuum; the residue is partitioned between aqueous sodium carbonate solution and diethyl ether and the organic phase is evaporated].
    • b) The crude reaction mixture obtained in step a) is treated with 20 ml 37% aqueous formaldehyde solution. The mixture is boiled under reflux for 60 minutes, subjected to ice-cooling, treated with 9 g NaBH4 and stirred for another 60 minutes at room temperature. The mixture is evaporated in a vacuum to a residue which is partitioned between aqueous NaHCO3 and diethyl ether. The organic phase is dried and evaporated to yield the title compound in free base form as an oil, m.p. (hydrochloride) 140-156°.
  • The title compound may also be prepared in analogous manner to Examples 1, 3 and 4.
  • In analogous manner to that described in Examples 1, 3, 4 and 5, the following trans compounds of formula le may be produced:
    Figure imgb0021
    wherein
    • R1 and R6 are as follows:
      Figure imgb0022
  • In analogous manner to that described above for Examples 1, 3 and 4 there may be produced the following trans compounds of formula If,
    Figure imgb0023
    wherein
    • R1, R6 and u are as follows:
      Figure imgb0024
    EXAMPLE 42
  • In analogous manner to that described in Examples 1 and 2, the following cis compound of formula I may be produced:
    • aa) N-(3-cyclohex-1-en-1-yl-2-cis-propenyl)-2-(1'-naphthyl)piperidine; free base-oil.
    EXAMPLES 43-47
  • In analogous manner to that described in Examples 1, 3, 4 and 5, the following compounds of formula I may be produced:
    • 43) N-cinnamyl-N-methyl-N-[2-(1'-naphthyl)-2-propyl]amine; free base-oil;
    • 44) N-(1-acenaphthenyl)-N-methyl-N-(3-phenyl-2-transpropenyl)amine, m.p. (hydrochloride) 210-216°;
    • 45) N-(1 -acenaphthenyl)-N-methyl-N-[3-(5'-methyl-2'-thienyl)-2-trans-propenyl]amine, free base-oil;
    • 46) N-(6,7,8,8a-tetrahydro-1-acenaphthenyl)-N-methyl-N-(3-phenyl-2-trans-propenyl)amine, m.p. (hydrochloride) 185-192°;
    • 47) N-methyl-N-(2,3-dihydro-1-phenalenyl)-N-(3-phenyl-2-trans-propenyl), free base-oil.
  • NMR data on the above-mentioned compounds of formula I, obtained as oils, are given in the following table. The data comprises peak position in ppm relative to TMS as standard in CDCI3; type of peak (D = doublet; DD = double doublet; DT = double triplet; M = multiplet; Q = quartet; S = singlet; T = triplet) and in parentheses the corresponding number of hydrogen atoms.
    Figure imgb0025
    Figure imgb0026
  • The compounds of formula I exhibit chemotherapeutic activity. In particular, they exhibit antimycotic activity, as indicated in vitro with tests against various families and types of mycetes, including Trichophton quinkeanum, Aspergillus fumigatus, Microsporum canis Sporotrychium schenkii and Candida albicans, at concentrations of, for example 0.1 to 100 µg/ml, and in vivo in the experimental skin mycosis model in guinea pigs. In the latter model, guinea pigs are infected by cutaneous application of Trichophyton quinkeanum. The test substance is administered daily for 7 days beginning 24 hours after the infection by local application by rubbing the test substance (taken up in polyethylene glycol) on the skin surface, or perorally, the test substance being administered as a suspension. The activity is shown on local application at concentrations of from example 0.1 to 2%, in particular 0.1 to 0.6%. The oral activity is shown at dosages of, for example, 50 to 100 mg/kg.
  • The compounds are therefore indicated for use as anti-mycotic agents. As indicated daily dose is from 500 to 2000 mg. If desired, this may be administered in divided doses 2 to 4 times a day in unit dosage form containing from about 125 mg to about 1000 mg or in sustained release form.
  • The compounds may be used in free base form or in the form of chemotherapeutically acceptable acid addition salts. Such salt forms exhibit the same order of activity as the free base forms.
  • The compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and, optionally, other excipients and administered in such forms as tablets or capsules. The compounds may alternatively be administered topically in such conventional forms as ointments or creams. The concentration of the active substance in such topical application forms will of course vary depending on the compound employed, the treatment desired and the nature of the form etc. In general, however, satisfactory results are obtained at concentrations of from 0.05 to 3, in particular 0.1 to 1 wt 96.
  • A compound with particularly interesting activity is the compound of Example 4.
  • One group of compounds has a formula Ig,
    Figure imgb0027
    wherein
    • Rll is 1-naphthyl, optionally mono-substituted by lower alkyl or alkoxy,
    • u is a whole number from 1 to 8,
    • R"6is of formula
      Figure imgb0028
      wherein
    • R,9 is hydrogen, hydroxy, lower alkoxy or lower alkyl, or of formula
      Figure imgb0029
      wherein
    • R20 is alkyl (C1_12) or phenylalkyl-(C7_12) or of formula
      Figure imgb0030
      wherein
    • m, n and v are as defined above.
  • Another group of compounds comprises those of formula Ih,
    Figure imgb0031
     wherein
    • Figure imgb0032
       is a radical of formula IIa, IIb wherein X is oxygen or sulphur, IIc, IId wherein s is 4, IIe wherein t is 3 or a radical of formula
      Figure imgb0033
      wherein
    • R9 is as defined above,
    • R2 and R5 are independently hydrogen or lower alkyl,
    • u is a whole number from 1 to 8,
    • Figure imgb0034
      is as defined above for R6, with the following provisos,
      • (a) R10 is other than phenyl or phenylalkoxy, and
      • (b) when
        Figure imgb0035
        is 1-naphthyl optionally mono-substituted by lower alkyl or alkoxy and R2 and R5 are each hydrogen,
        Figure imgb0036
         is other than
        • (i) a radical of formula IIIa, IIIb or IIIf,
        • (ii) a radical of formula IIIc, IIId or IIIe, wherein R11, R12 and R13 are each hydrogen, or (iii) a radical of formula IIIg wherein one of R17 and R18 is hydrogen and the other is hydroxy, lower alkyl or lower alkoxy, or
        • (iv) an optionally substituted thiophen or furan radical.
  • A further group of formula I compounds comprises compounds of formula li,
    Figure imgb0037
    wherein
    • Figure imgb0038
       is a radical of formula IIa, IIb wherein X is oxygen or sulphur, IIc,IId wherein s is 4, IIe wherein t is 3, or a radical of formula
      Figure imgb0039
      R2, R3, R4, R5 and R9 are as defined above, with the proviso that R3 and R4 are other than ―(CH2)u―,
    • Figure imgb0040
       is as defined above for R6 with respect to formula I, with the following provisos
      • (i) R10 is other than phenyl or phenylalkoxy and
      • (ii) when R1 is a radical of formula IIa,
        Figure imgb0041
         is other than a radical of formula IIIg, or phenyl.

Claims (9)

1. A compound of formula I,
Figure imgb0042
wherein
a) (i) R, is a radical of formula Ila,
Figure imgb0043
wherein
R7 and R8, independently, are hydrogen, halogen of atomic number from 9 to 53, trifluoromethyl, hydroxy, nitro, C1―C4 alkyl or C1―C4 alkoxy, or a radical of formula IIb, IIc, IId, IIe,
Figure imgb0044
wherein
R9 is hydrogen, halogen of atomic number from 9 to 53, hydroxy, C1―C4 alkyl or C1―C4 alkoxy,
X is oxygen, sulphur, imino, C1―C4 alkylimino or a radical of formula ―(CH2)r― wherein r is 1, 2 or 3,
s is 3, 4 or 5, and
t is 2, 3 or 4, and
R2 is hydrogen or C1―C4 alkyl, or
(ii) R1 and R2 together with the carbon atom to which they are bound form a radical of formula IIf or IIg,
Figure imgb0045
wherein
p is 1, 2 or 3,
R3 and R5, independently, are hydrogen or C1―C4 alkyl,
R4 is alkyl (C1_6), alkenyl (C3_12), alkynyl (C3_12) or cycloalkyl (C3_8)-alkyl (C1―6); and
R6 is (i) an aromatic, five-membered heterocycle containing one oxygen, sulphur or nitrogen hetero-ring atom and optionally an additional one or two nitrogen hetero-ring atoms and being optionally substituted on a carbon ring atom by halogen of atomic number from 9 to 53, hydroxy, C1―C4 alkyl or C1―C4 alkoxy, and any nitrogen ring atom present being optionally substituted when possible, by C1―C4 alkyl, (ii) a radical of formula IIIa,
Figure imgb0046
wherein
R9 is as defined above, (iii) a radical of formula IIIb,
Figure imgb0047
wherein
R10 is alkyl (C1_12), alkenyl (C3_12), alkynyl (C3_12) cycloalkyl (C3_8)-alkyl (C1―6), phenyl-alkyl (C7―12), phenyl, phenylalkoxy (C7―16), or aminoalkyl (C1_12);
(iv) a radical of formula IIIc, IIId or IIIe,
Figure imgb0048
wherein
R11, R12 and R13, independently, are hydrogen or C1―C4 alkyl, m is a whole number from 0 to 4,
n is a whole number from 0 to 3, and
v is a whole number from 0 to 5,
(v) a radical of formula IIIf,
Figure imgb0049
 wherein
R14 is C1―C4 alkyl, alkoxy (C1_12)-carbonyl, alkenyl (C3_12), alkynyl (C3_12), phenylalkyl (C7_12) or phenyl,
R15 and R16, independently, are hydrogen or C1―C4 alkyl, and
q is a whole number from 0 to 5, or
(vi) a radical of formula IIIg
Figure imgb0050
wherein
R17 and R18, independently, are hydrogen, halogen of atomic number from 9 to 53, trifluoromethyl, hydroxy, nitro, C1―C4 alkyl or C1―C4 alkoxy, with the proviso that one of R17 and R18 is other than hydrogen, and with the general proviso that R, is not a radical of formula IIa when R6 is a radical of formula IIIg or phenyl, R2 is hydrogen and R3 is hydrogen or C1―C4 alkyl,
b) R1 is a radical of formula IIa to lie, as defined above,
R2, R5 and R6 are as defined above, and
R3 and R4 together are ―(CH2)u― wherein u is a whole number from 1 to 8, or an acid addition salt thereof.
2. A process for the production of a compound as claimed in Claim 1, selected from
a) reacting a compound of formula IV,
Figure imgb0051
wherein
R1 to R4 are as defined above, with a compound of formula V,
Figure imgb0052
wherein
A is a leaving group, and
R5 and R6 are as defined above, or
b) when R4 and R6 are other than alkynyl reducing a compound of formula VI,
Figure imgb0053
wherein
alkynyl R1 to R3, and R5 are as defined above, and
Figure imgb0054
 and
Figure imgb0055
 are as defined above for R4 and R6, except for
c) when the trans-form is required isomerising photochemically a compound of formula Ic,
Figure imgb0056
wherein
R1 to R6 are as defined above, or
d) when R3 and R4 together do not form a ―(CH2)u― group introducing the group R4 into a compound of formula VII,
Figure imgb0057
wherein
R1, R2, R3, R5 and R6 are as defined above.
3. A compound of Claim 1, having the formula Ig,
Figure imgb0058
wherein
Figure imgb0059
 is 1-naphthyl, optionally mono-substituted by C1―C4 alkyl or C1―C4 alkoxy,
u is a whole number from 1 to 8,
Figure imgb0060
 is of formula
Figure imgb0061
wherein
R19 is hydrogen, hydroxy, C1―C4 alkoxy or C1―C4 alkyl, or of formula
Figure imgb0062
wherein
R20 is alkyl (C1―12) or phenylalkyl (C7―12) or of formula
Figure imgb0063
wherein
m, n and v are as defined in Claim 1.
4. A compound of Claim 1, having the formula Ih,
Figure imgb0064
wherein
Figure imgb0065
 is a radical of formula Ila, IIb wherein X is oxygen or sulphur, IIc, lid wherein s is 4, lie wherein t is 3 or a radical of formula
Figure imgb0066
wherein
R9 is as defined in Claim 1,
R2 and R5 are independently hydrogen or C1―C4 alkyl,
u is a whole number from 1 to 8,
Figure imgb0067
 is as defined in Claim 1 for R6, with the following provisos,
(a) R10 is other than phenyl or phenylalkoxy, and
(b) when
Figure imgb0068
 is 1-naphthyl optionally mono-substituted by C1―C4 alkyl or C1―C4 alkoxy and R2 and R5 are each hydrogen,
Figure imgb0069
is other than
(i) a radical of formula Illa, IIIb or IIIf,
(ii) a radical of formula Illc, IIId or Ille, wherein R11, R12 and R13 are each hydrogen, or (iii) a radical of formula IIIg wherein one of R17 and R18 is hydrogen and the other is hydroxy, C1―C4 alkyl or C1―C4 alkoxy, or
(iv) an optionally substituted thiophen or furan radical.
5. A compound of Claim 1 having the formula li,
Figure imgb0070
wherein
Figure imgb0071
 is a radical of formula IIa, IIb wherein X is oxygen or sulphur, IIc, lld wherein s is 4, lie wherein t is 3, or a radical of formula
Figure imgb0072
R2, R3, R4, R5 and R9 are as defined in Claim 1, with the proviso that R3 and R4 are other than ―(CH2)u―.
Figure imgb0073
 is as defined in Claim 1 for R6 with respect to formula I, with the following provisos
(i) R10 is other than phenyl or phenylalkoxy and
(ii) when R1 is a radical of formula Ila,
Figure imgb0074
 is other than a radical of formula IIIg, or phenyl.
6. A compound of Claim 1 which is N-(3-cyclohexyl-2-trans-propenyl)-N-methyl-N-(1-naphthylmethyl)amine or an acid addition salt thereof.
7. A pharmaceutical composition comprising a compound of any one of Claims 1 and 3 to 6 in free base form or in chemotherapeutically acceptable acid addition salt form in association with a chemotherapeutically acceptable diluent or carrier.
8. A compound according to any of Claims 1 and 3 to 6, in free base form or in chemotherapeutically acceptable acid addition salt form, for use in a method of therapeutically treating the human or animal body.
9. A compound according to any one of Claims 1 and 3 to 6, in free base form or in chemotherapeutically acceptable acid addition salt form, for use in the treatment of mycosis in the human or animal body.
EP78100611A 1977-08-19 1978-08-07 Propenyl amines, processes for their production and pharmaceutical compositions containing them Expired EP0000896B1 (en)

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DE3020113A1 (en) * 1979-06-08 1980-12-18 Sandoz Ag 2- (1-NAPHTHYL) PIPERIDINE DERIVATIVE, THE PRODUCTION THEREOF AND THE USE AS AN ANTIMYCOTIC
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NL8003141A (en) * 1980-05-30 1982-01-04 Akzo Nv BIOLOGICALLY ACTIVE TRICYCLIC AMINES.
IT1150211B (en) * 1981-03-02 1986-12-10 Abbott Lab 1,2,3,4-TETRAIDRONAFTALENI REPLACED WITH AMINO ALKYLS PHARMACEUTICAL ACTION
CH653028A5 (en) * 1982-02-03 1985-12-13 Sandoz Ag BENZTHIOPHENALLYLAMINE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF.
JPS6145A (en) * 1984-06-09 1986-01-06 Kaken Pharmaceut Co Ltd Naphthylmethylamine derivative and antifungal containing the same
US5334628A (en) * 1984-06-09 1994-08-02 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
JPH0676285B2 (en) * 1985-11-01 1994-09-28 三井東圧化学株式会社 Benzylamine derivative, its production method and its use
EP0254677A1 (en) * 1986-07-08 1988-01-27 Sandoz Ag Antimycotic 6-phenyl-2-hexen-4-ynamines
US5084476A (en) * 1986-07-15 1992-01-28 Hoffmann-La Roche Inc. Tetrahydronaphthalene and indane derivatives
US5234946A (en) * 1987-11-27 1993-08-10 Banyu Pharmaceutical Co., Ltd. Substituted alkylamine derivatives
JPH03105465U (en) * 1990-02-16 1991-10-31
GB9513750D0 (en) * 1995-07-06 1995-09-06 Sandoz Ltd Use of allylamines
WO1998005645A1 (en) * 1996-08-01 1998-02-12 Dow Agrosciences Llc 4-substituted quinoline derivatives having fungicidal activity
US6117884A (en) * 1997-07-31 2000-09-12 Daeuble; John 4-substituted quinoline derivatives having fungicidal activity
JP4509327B2 (en) * 2000-08-03 2010-07-21 ダイセル化学工業株式会社 Process for producing N, N-disubstituted-4-aminocrotonic acid ester
WO2007014130A2 (en) * 2005-07-21 2007-02-01 Nomir Medical Technologies, Inc. Near infrared microbial elimination laser system (nimels)
GB0320312D0 (en) * 2003-08-29 2003-10-01 Novartis Ag Purification process
US20050197512A1 (en) * 2003-08-29 2005-09-08 Ulrich Beutler Purification process
JP2008504359A (en) * 2004-07-02 2008-02-14 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー Compositions and methods for treating pathological infections
US20090082469A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched terbinafine
WO2017132912A1 (en) * 2016-02-03 2017-08-10 华东理工大学 Alkylamine with benzoalicyclic substituent and application thereof
CN108084125B (en) 2016-11-23 2020-08-18 华东理工大学 Benzoheterocyclylalkylamines and their use

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE609151C (en) * 1930-02-01 1935-02-08 I G Farbenindustrie Akt Ges Process for the preparation of amino alcohols with a secondary or tertiary amino group
US2601275A (en) * 1949-10-29 1952-06-24 Givaudan Corp Aromatic chlorethylamines and their salts
DK106378C (en) * 1962-10-19 1967-01-30 Koninklijke Pharma Fab Nv Process for the preparation of N-substituted 1-phenyl-2-aminoalkanes or acid addition salts thereof.
GB1041987A (en) * 1964-09-03 1966-09-07 Beecham Group Ltd Acetylenic compounds
GB1134715A (en) * 1966-02-24 1968-11-27 Geistlich Soehne Ag Bisphenylalkenylamine derivatives
US3784642A (en) * 1967-11-03 1974-01-08 E Jenny 1-amine-cyclobutene
BE786748A (en) * 1971-07-26 1973-01-26 Basf Ag 1-AMINOMETHYL-INDANES-N-SUBSTITUTES
BE791133A (en) * 1971-11-10 1973-05-09 Calgon Corp NEW CATIONIC MONOMERS AND THEIR MANUFACTURING PROCESSES
BE791538A (en) * 1971-11-19 1973-05-17 Basf Ag 1-AMINOMETHYL-ACENAPHTENES, THEIR PREPARATION AND THEIR THERAPEUTIC USES
BE794598A (en) * 1972-01-28 1973-05-16 Richardson Merrell Inc NEW OLEFINIC DERIVATIVES OF PIPERIDINES SUBSTITUTED IN 4 AND THEIR PREPARATION PROCESS
JPS4930346A (en) * 1972-07-18 1974-03-18
US4139560A (en) * 1974-02-22 1979-02-13 Ciba Geigy Corporation Nonylamines
HU169507B (en) * 1974-09-25 1976-12-28
DE2716943C2 (en) * 1976-04-28 1986-08-14 Sandoz-Patent-GmbH, 7850 Lörrach N- (3-Phenyl-2-propenyl) -N- (1-naphthylmethyl) amines, their use and preparation

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ES472641A1 (en) 1979-10-16
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DK354678A (en) 1979-02-20
IL55382A0 (en) 1978-10-31
IT7826835A0 (en) 1978-08-18
IT1098253B (en) 1985-09-07
FI65774B (en) 1984-03-30
US4680291A (en) 1987-07-14
FI65774C (en) 1984-07-10
EP0000896A3 (en) 1979-05-30
CA1111852A (en) 1981-11-03
IE781670L (en) 1979-02-19
IE47314B1 (en) 1984-02-22
IL55382A (en) 1981-12-31
JPS6317050B2 (en) 1988-04-12
DK152114B (en) 1988-02-01
PT68448A (en) 1978-09-01
MY8500040A (en) 1985-12-31
DK152114C (en) 1988-06-20
EP0000896A2 (en) 1979-03-07
DE2862103D1 (en) 1982-11-18
FI782446A (en) 1979-02-20

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